Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H(+)-ATPase.

PubMed Central

Laitala, T; Väänänen, H K

1994-01-01

The bone resorbing cells, osteoclasts, express high levels of carbonic anhydrase II (CA II) and vacuolar H(+)-ATPase (V-ATPase) during bone resorption. We have used antisense RNA and DNA molecules targeted against CA II, and against 16- and 60-kD subunits of vacuolar H(+)-ATPase (V-ATPase), to block the expression of these proteins in vitro. Osteoclastic bone resorption was studied in two in vitro culture systems: release of 45Calcium from prelabeled newborn mouse calvaria cultures, and resorption pit assays performed with rat osteoclasts cultured on bovine bone slices. Both antisense RNA and DNA against CA II and the V-ATPase were used to compare their specificities as regards inhibiting bone resorption in vitro. The antisense molecules inhibited the synthesis of these proteins by decreasing the amounts of mRNA in the cells in a highly specific manner. In osteoclast cultures treated with the 16-kD V-ATPase antisense RNA, acidification of an unknown population of intracellular vesicles was highly stimulated. The acidification of these vesicles was not sensitive to amiloride or bafilomycin A1. This suggests the existence of a back-up system for acidification of intracellular vesicles, when the expression of the V-ATPase is blocked. Our results further indicate that blocking the expression of CA II and V-ATPase with antisense RNA or DNA leads to decreased bone resorption. Images PMID:8200964

Emerging treatments for postmenopausal osteoporosis – focus on denosumab

PubMed Central

Geusens, Piet

2009-01-01

The pathway of the receptor activator of the nuclear factor κB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget’s disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed. PMID:19554095

Bone Markers, Calcium Metabolism, and Calcium Kinetics During Extended-Duration Space Flight on the Mir Space Station

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Wastney, Meryl E.; O'Brien, Kimberly O.; Morukov, Boris V.; Larina, Irina M.; Abrams, Steven A.; Davis-Street, Janis E.; Oganov, Victor; Shackelford, Linda C.

2005-01-01

Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.

Simulation of bone resorption-repair coupling in vitro.

PubMed

Jones, S J; Gray, C; Boyde, A

1994-10-01

In the normal adult human skeleton, new bone formation by osteoblasts restores the contours of bone surfaces following osteoclastic bone resorption, but the evidence for resorption-repair coupling remains circumstantial. To investigate whether sites of prior resorption, more than the surrounding unresorbed surface, attract osteoblasts or stimulate them to proliferate or make new matrix, we developed a simple in vitro system in which resorption-repair coupling occurs. Resorption pits were produced in mammalian dentine or bone slabs by culturing chick bone-derived cells on them for 2-3 days. The chick cells were swept off and the substrata reseeded with rat calvarial osteoblastic cells, which make bone nodules in vitro, for periods of up to 8 weeks. Cell positions and new bone formation were investigated by ordinary light microscopy, fluorescence and reflection confocal laser microscopy, and SEM, in stained and unstained samples. There was no evidence that the osteoblasts were especially attracted to, or influenced by, the sites of resorption in dentine or bone before cell confluence was reached. Bone formation was identified by light microscopy by the accumulation of matrix, staining with alizarin and calcein and by von Kossa's method, and confirmed by scanning electron microscopy (SEM) by using backscattered electron (BSE) and transmitted electron imaging of unembedded samples and BSE imaging of micro-milled embedded material. These new bone patches were located initially in the resorption pits. The model in vitro system may throw new light on the factors that control resorption-repair coupling in the mineralised tissues in vivo.

Effect of odanacatib on root resorption and alveolar bone metabolism during orthodontic tooth movement.

PubMed

Wei, X X; Chu, J P; Zou, Y Z; Ru, N; Cui, S X; Bai, Y X

2015-12-22

The aim of this study was to investigate the effect of local administration of odanacatib (ODN) on orthodontic root resorption and the status of alveolar bone metabolism in rat molars. All specimens were scanned using microcomputed tomography and then the raw images were reconstructed. The total volume of the root resorption craters of the 60 g-NS (normal saline) group was higher than in the 60 g-ODN group and the control group. In the 60 g-NS group, the bone volume fraction values of alveolar bone were significantly decreased compared with the other 2 groups. There were no significant differences in the bone volume fraction values of the tibiae among the 3 groups. The results of tartrate-resistant acid phosphatase-positive (TRAP+) numbers showed that there was no difference between the 60 g-NS group and the 60 g-ODN group. The expression of cathepsin K was decreased significantly in the 60 g-ODN group. These results indicate that ODN reduces orthodontics-induced external root resorption and increases alveolar bone metabolism. This may be because ODN inhibits the activity of odontoclasts, but maintains the quantity of odontoclasts and enhances bone formation. ODN promotes local alveolar bone metabolism, but does not affect systemic bone metabolism.

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis).

PubMed

McGee, Meghan E; Maki, Aaron J; Johnson, Steven E; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

2008-02-01

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate that bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis.

Calcium intake in winter pregnancy attenuates impact of vitamin D inadequacy on urine NTX, a marker of bone resorption.

PubMed

O'Brien, Eileen C; Kilbane, Mark T; McKenna, Malachi J; Segurado, Ricardo; Geraghty, Aisling A; McAuliffe, Fionnuala M

2018-04-01

Pregnancy is characterised by increased bone turnover, but high bone turnover with resorption exceeding formation may lead to negative maternal bone remodelling. Recent studies are conflicting regarding the effect of calcium on skeletal health in pregnancy. The aim of this study was to examine the seasonal effect of serum 25-hydroxyvitamin D (25OHD) and dietary calcium on a marker of bone resorption. This was prospective study of 205 pregnant women [two cohorts; early pregnancy at 13 weeks (n = 96), and late pregnancy at 28 weeks (n = 109)]. Serum 25OHD and urine cross-linked N-telopeptides of type I collagen (uNTX) were measured at both time points. Intakes of vitamin D and calcium were recorded using 3-day food diaries at each trimester. Compared to summer pregnancies, winter pregnancies had significantly lower 25OHD and significantly higher uNTX. Higher calcium intakes were negatively correlated with uNTX in winter, but not summer. In late pregnancy, compared to those reporting calcium intakes ≥1000 mg/day, intakes of <1000 mg/day were associated with a greater increase in uNTX in winter pregnancies than in summer (41.8 vs. 0.9%). Increasing calcium intake in winter by 200 mg/day predicted a 13.3% reduction in late pregnancy uNTX. In late pregnancy, during winter months when 25OHD is inadequate, intakes of dietary calcium <1000 mg/day were associated with significantly increased bone resorption (uNTX). Additional dietary calcium is associated with reduced bone resorption in late pregnancy, with greater effect observed in winter. Further research regarding optimal dietary calcium and 25OHD in pregnancy is required, particularly for women gestating through winter.

A Retrospective Radiographic Survey of Pathology Associated with Impacted Third Molars among Patients Seen in Oral & Maxillofacial Surgery Clinic of College of Dentistry, Riyadh.

PubMed

Khawaja, Naveed Ahmad; Khalil, Hesham; Parveen, Kauser; Al-Mutiri, Abdulmajeed; Al-Mutiri, Saif; Al-Saawi, Abdullah

2015-04-01

The purpose of this study is to determine the type and frequency of pathological conditions around third molar teeth among randomly selected patient's records in Oral and Maxillofacial Surgery, College of Dentistry, King Saud University, Riyadh. Totally, 281 patient panoramic radiographs were selected with detectable pathology among 570 files of patients seen in oral and maxillofacial surgery clinics 2 years retrospectively. Almost 17-55 years age (mean age 25.43) was selected. The following radiographs were analyzed for all pathology associated impacted teeth; dental caries, bone resorption, periodontitis, and apical pathology. The study found caries, external bone resorption and periodontitis are highly frequent to mesioangular and horizontal in mandibular impacted third molar compared to maxillary impacted third molar. Overall result evaluated that tooth #28 related periodontitis is significant (P = 0.021), and tooth #38 related bone resorption, tooth #48 related root caries, bone resorption and apical pathology are highly significant (P = 0.000) comparing to others. This study also concluded the high frequency of root caries, bone resorption and apical pathology reported in relation to mandibular impacted third teeth. Significant results were also achieved with periodontitis in relation to mesiangular and vertical angulation of left impacted maxillary third molars. Prophylactic removal of impacted third molars is recommended in many studies to avoid future risk of associated pathology. Retained asymptomatic impacted third molars imply pathology that could be difficult in later ages as less morbidity in younger ages.

Reduction of bone resorption by the application of fibrin glue in the reconstruction of the alveolar cleft.

PubMed

Segura-Castillo, José L; Aguirre-Camacho, Humberto; González-Ojeda, Alejandro; Michel-Perez, Jorge

2005-01-01

A major complication in 30% to 75% of cases of surgical treatment of alveolar cleft is resorption of the bone graft. A treatment alternative is the application of fibrin glue, which has the capacity to favor the integration of the graft. The main objective of the study was to evaluate if the use of the fibrin glue reduces bone resorption when it is applied locally. The authors designed a randomized clinical trial. Patients were divided into two groups: group 1, fibrin glue; and group 2, control. Pre- and postoperative graft volume, bone density, bone quality (Lekholm and Zarb, and Norton and Gamble classifications), and postoperative complications were evaluated. The follow-up for all patients was 3 months after discharge. Twenty-seven patients were surgically treated, 13 in group 1 and 14 in group 2. Group 1 had increased graft volume compared with group 2 (64.32 cm v 21.70 cm; P < 0.0001). Bone density was higher in group 1 than in group 2 (396.57 v 245.68; P > 0.076). Bone quality was type 1, 2 and 3 and 4 in group 1. Resorption in group 2 was 62.26%; in group 1, it was 29.72% (P > 0.081). The observed complications were infection and dehiscence of sutures (P > 0.537). The authors conclude that the fibrin glue significantly diminishes bone resorption, allowing improved graft integration and quality.

Strontium ranelate: a novel mode of action leading to renewed bone quality.

PubMed

Ammann, Patrick

2005-01-01

Various bone resorption inhibitors and bone stimulators have been shown to decrease the risk of osteoporotic fractures. However, there is still a need for agents promoting bone formation by inducing positive uncoupling between bone formation and bone resorption. In vitro studies have suggested that strontium ranelate enhances osteoblast cell replication and activity. Simultaneously, strontium ranelate dose-dependently inhibits osteoclast activity. In vivo studies indicate that strontium ranelate stimulates bone formation and inhibits bone resorption and prevents bone loss and/or promotes bone gain. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture, without affecting the intrinsic bone tissue quality. Thus, all the determinants of bone strength are positively influenced. In conclusion, strontium ranelate, a new treatment of postmenopausal osteoporosis, acts through an innovative mode of action, both stimulating bone formation and inhibiting bone resorption, resulting in the rebalancing of bone turnover in favor of bone formation. Strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in improvement in bone strength and bone quality.

μCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy.

PubMed

de Bakker, Chantal M J; Altman, Allison R; Tseng, Wei-Ju; Tribble, Mary Beth; Li, Connie; Chandra, Abhishek; Qin, Ling; Liu, X Sherry

2015-04-01

Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a μCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our μCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72-0.83) confirm the accuracy of this method. Bone remodeling parameters measured through μCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. Copyright © 2014 Elsevier Inc. All rights reserved.

Hydroxychloroquine affects bone resorption both in vitro and in vivo.

PubMed

Both, Tim; Zillikens, M Carola; Schreuders-Koedam, Marijke; Vis, Marijn; Lam, Wai-Kwan; Weel, Angelique E A M; van Leeuwen, Johannes P T M; van Hagen, P Martin; van der Eerden, Bram C J; van Daele, Paul L A

2018-02-01

We recently showed that patients with primary Sjögren syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favorable effects on BMD. The aim of the study was to evaluate whether HCQ modulates osteoclast function. Osteoclasts were cultured from PBMC-sorted monocytes for 14 days and treated with different HCQ doses (controls 1 and 5 μg/ml). TRAP staining and resorption assays were performed to evaluate osteoclast differentiation and activity, respectively. Staining with an acidification marker (acridine orange) was performed to evaluate intracellular pH at multiple timepoints. Additionally, a fluorescent cholesterol uptake assay was performed to evaluate cholesterol trafficking. Serum bone resorption marker β-CTx was evaluated in rheumatoid arthritis patients. HCQ inhibits the formation of multinuclear osteoclasts and leads to decreased bone resorption. Continuous HCQ treatment significantly decreases intracellular pH and significantly enhanced cholesterol uptake in mature osteoclasts along with increased expression of the lowdensity lipoprotein receptor. Serum β-CTx was significantly decreased after 6 months of HCQ treatment. In agreement with our clinical data, we demonstrate that HCQ suppresses bone resorption in vitro and decreases the resorption marker β-CTx in vivo. We also showed that HCQ decreases the intracellular pH in mature osteoclasts and stimulates cholesterol uptake, suggesting that HCQ induces osteoclastic lysosomal membrane permeabilization (LMP) leading to decreased resorption without changes in apoptosis. We hypothesize that skeletal health of patients with increased risk of osteoporosis and fractures may benefit from HCQ by preventing BMD loss. © 2017 Wiley Periodicals, Inc.

Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation

PubMed Central

McGee-Lawrence, Meghan; Buckendahl, Patricia; Carpenter, Caren; Henriksen, Kim; Vaughan, Michael; Donahue, Seth

2015-01-01

ABSTRACT Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. PMID:26157160

Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis.

PubMed

Tominari, Tsukasa; Hirata, Michiko; Matsumoto, Chiho; Inada, Masaki; Miyaura, Chisato

2012-01-01

Nobiletin, a polymethoxy flavonoid (PMF), inhibits systemic bone resorption and maintains bone mass in estrogen-deficient ovariectomized mice. This study examined the anti-inflammatory effects of PMFs, nobiletin, and tangeretin on lipopolysaccharide (LPS)-induced bone resorption. Nobiletin and tangeretin suppressed LPS-induced osteoclast formation and bone resorption and suppressed the receptor activator of NFκB ligand-induced osteoclastogenesis in RAW264.7 macrophages. Nobiletin clearly restored the alveolar bone mass in a mouse experimental model for periodontitis by inhibiting LPS-induced bone resorption. PMFs may therefore provide a new therapeutic approach for periodontal bone loss.

Leptin regulation of bone resorption by the sympathetic nervous system and CART.

PubMed

Elefteriou, Florent; Ahn, Jong Deok; Takeda, Shu; Starbuck, Michael; Yang, Xiangli; Liu, Xiuyun; Kondo, Hisataka; Richards, William G; Bannon, Tony W; Noda, Masaki; Clement, Karine; Vaisse, Christian; Karsenty, Gerard

2005-03-24

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

Efficacy of bone substitute material in preserving volume when placing a maxillary immediate complete denture: study protocol for the PANORAMIX randomized controlled trial.

PubMed

Rignon-Bret, Christophe; Hadida, Alain; Aidan, Alexis; Nguyen, Thien-Huong; Pasquet, Gerard; Fron-Chabouis, Helene; Wulfman, Claudine

2016-05-20

Bone preservation is an essential issue in the context of last teeth extraction and complete edentulism. The intended treatment, whether a complete denture or an implant placement, is facilitated with a voluminous residual ridge. Bone resorption after multiple extractions has not been as well studied as the bone resorption that occurs after the extraction of a single tooth. Recent advances in bone substitute materials have revived this issue. The purpose of this study is to evaluate the interest in using bone substitute material to fill the socket after last teeth extraction in a maxillary immediate complete denture procedure compared with the conventional protocol without socket filling. A randomized, controlled, clinical trial was designed. The 34 participants eligible for maxillary immediate complete denture were divided into two groups. Complete dentures were prepared despite persistence of the last anterior teeth. The control group received a conventional treatment including denture placement immediately after extractions. In the experimental group, in addition to the immediate denture placement, a xenograft bone-substitute material (Bio-Oss Collagen®) was placed in the fresh sockets. The primary outcome of the study is to compare mean bone ridge height loss 1 year after maxillary immediate complete denture placement, with or without bone-substitute material, in incisor and canine sockets. The secondary outcomes are to compare the average bone ridge height and width loss for each extraction site. An original quantitative evaluation method using cone beam computed tomography was designed for reproducible measurements, with a radio-opaque denture duplicate. Two independent operators perform the radiologic measurements. The immediate complete denture technique limits bone resorption in multiple extraction situations and thus allows better denture retention and better options for implant placement. To compare the benefit of using any bone socket-filling material, we proposed a quantitative evaluation protocol of resorption in the specific case of the last anterior maxillary teeth extraction with immediate denture placement. ClinicalTrials.gov, NCT02120053 . Registered on 18 April 2014.

Serum markers of bone metabolism show bone loss in hibernating bears

USGS Publications Warehouse

Donahue, S.W.; Vaughan, M.R.; Demers, L.M.; Donahue, H.J.

2003-01-01

Disuse osteopenia was studied in hibernating black bears (Ursus americanus) using serum markers of bone metabolism. Blood samples were collected from male and female, wild black bears during winter denning and active summer periods. Radioimmunoassays were done to determine serum concentrations of cortisol, the carboxy-terminal cross-linked telopeptide, and the carboxy-terminal propeptide of Type I procollagen, which are markers of hone resorption and formation, respectively. The bone resorption marker was significantly higher during winter hibernation than it was in the active summer months, but the bone formation marker was unchanged, suggesting an imbalance in bone remodeling and a net bone loss during disuse. Serum cortisol was significantly correlated with the bone resorption marker, but not with the bone formation marker. The bone formation marker was four- to fivefold higher in an adolescent and a 17-year-old bear early in the remobilization period compared with the later summer months. These findings raise the possibility that hibernating black bears may minimize bone loss during disuse by maintaining osteoblastic function and have a more efficient compensatory mechanism for recovering immobilization-induced bone loss than that of humans or other animals.

Determination of orthodontic tooth movement and tissue reaction following demineralized freeze-dried bone allograft grafting intervention

PubMed Central

Seifi, Massoud; Ghoraishian, Seyed Ahmad

2012-01-01

Background: Socket preservation after tooth extraction is one of the indications of bone grafting to enhance preorthodontic condition. The aim of this study is to determine the effects of socket preservation on the immediate tooth movement, alveolar ridge height preservation and orthodontic root resorption. Materials and Methods: In a split-mouth technique, twelve sites in three dogs were investigated as an experimental study. Crushed demineralized freeze-dried bone allograft (DFDBA) (CenoBone®) was used as the graft material. The defects were made by the extraction of 3rd premolar. On one side of each jaw, the defects were preserved by DFDBA and defects of the other side left opened as the control group. Simultaneously the teeth adjacent to the defects were pulled together by a NiTi coil spring. After eight weeks, the amount of (OTM), alveolar height, and root resorption were measured. Analysis of variance was used for purpose of comparison. Results: There was a slight increase in OTM at grafted sites as they were compared to the control sites (P<0.05). Also a significant bone resorption in control site and successful socket preservation in experimental site were observed. Reduction of root resorption at the augmented site was significant compared to the normal healing site (P<0.05). Conclusion: Using socket preservation, tooth movement can be immediately started without waiting for the healing of the recipient site. This can provide some advantages like enhanced rate of OTM, its approved effects on ridge preservation that reduces the chance of dehiscence and the reduction of root resorption. PMID:22623939

Divergent Resorbability and Effects on Osteoclast Formation of Commonly Used Bone Substitutes in a Human In Vitro-Assay

PubMed Central

Busse, Björn; Schilling, Arndt F.; Schinke, Thorsten; Amling, Michael; Lange, Tobias

2012-01-01

Bioactive bone substitute materials are a valuable alternative to autologous bone transplantations in the repair of skeletal defects. However, clinical studies have reported varying success rates for many commonly used biomaterials. While osteoblasts have traditionally been regarded as key players mediating osseointegration, increasing evidence suggests that bone-resorbing osteoclasts are of crucial importance for the longevity of applied biomaterials. As no standardized data on the resorbability of biomaterials exists, we applied an in vitro-assay to compare ten commonly used bone substitutes. Human peripheral blood mononuclear cells (PBMCs) were differentiated into osteoclasts in the co-presence of dentin chips and biomaterials or dentin alone (control) for a period of 28 days. Osteoclast maturation was monitored on day 0 and 14 by light microscopy, and material-dependent changes in extracellular pH were assessed twice weekly. Mature osteoclasts were quantified using TRAP stainings on day 28 and their resorptive activity was determined on dentin (toluidin blue staining) and biomaterials (scanning electron microscopy, SEM). The analyzed biomaterials caused specific changes in the pH, which were correlated with osteoclast multinuclearity (r = 0.942; p = 0.034) and activity on biomaterials (r = 0.594; p = 0.041). Perossal led to a significant reduction of pH, nuclei per osteoclast and dentin resorption, whereas Tutogen bovine and Tutobone human strikingly increased all three parameters. Furthermore, natural biomaterials were resorbed more rapidly than synthetic biomaterials leading to differential relative resorption coefficients, which indicate whether bone substitutes lead to a balanced resorption or preferential resorption of either the biomaterial or the surrounding bone. Taken together, this study for the first time compares the effects of widely used biomaterials on osteoclast formation and resorbability in an unbiased approach that may now aid in improving the preclinical evaluation of bone substitute materials. PMID:23071629

Modulation of bone resorption by phosphorylation state of bone sialoprotein.

PubMed

Curtin, Paul; McHugh, Kevin P; Zhou, Hai-Yan; Flückiger, Rudolf; Goldhaber, Paul; Oppenheim, Frank G; Salih, Erdjan

2009-07-28

We have determined transmembrane protein tyrosine phosphorylation (outside-in signaling) in cultured osteoclasts and macrophages in response to added native purified bone sialoprotein (nBSP) and its dephosphorylated form (dBSP). There were selective/differential and potent inhibitory effects by dBSP and minimal effect by nBSP on intracellular tyrosine phosphorylation in macrophages and osteoclasts. Further studies on the downstream gene expression effects led to identification of a large number of differentially expressed genes in response to nBSP relative to dBSP in both macrophages and osteoclasts. These studies were extended to a bone resorption model using live mouse neonatal calvarial bone organ cultures stimulated by parathyroid hormone (PTH) to undergo bone resorption. Inclusion of nBSP in such cultures showed no effect on type I collagen telopeptide fragment release, hence overall bone resorption, whereas addition of dBSP abolished the PTH-induced bone resorption. The inhibition of bone resorption by dBSP was shown to be unique since in complementary experiments use of integrin receptor binding ligand, GRGDS peptide, offered only partial reduction on overall bone resorption. Quantitative RANKL analysis indicated that mechanistically the PTH-induced bone resorption was inhibited by dBSP via down-regulation of the osteoblastic RANKL production. This conclusion was supported by the RANKL analysis in cultured MC3T3-E1 osteoblast cells. Overall, these studies provided direct evidence for the involvement of covalently bound phosphates on BSP in receptor mediated "outside-in" signaling via transmembrane tyrosine phosphorylation with concurrent effects on downstream gene expressions. The use of a live bone organ culture system augmented these results with further evidence that links the observed in vivo variable state of phosphorylation with bone remodeling.

Resorption of Autogenous Bone Graft in Cranioplasty: Resorption and Reintegration Failure

PubMed Central

Lee, Si Hoon; Lee, Uhn; Park, Cheol Wan; Lee, Sang Gu; Kim, Woo Kyung

2014-01-01

Objective Re-implantation of autologous skull bone has been known to be difficult because of its propensity for resorption. Moreover, the structural characteristics of the area of the defect cannot tolerate physiologic loading, which is an important factor for graft healing. This paper describes our experiences and results with cranioplasty following decompressive craniectomy using autologous bone flaps. Methods In an institutional review, the authors identified 18 patients (11 male and 7 female) in whom autologous cranioplasty was performed after decompressive craniectomy from January 2008 to December 2011. We examined the age, reasons for craniectomy, size of the skull defect, presence of bony resorption, and postoperative complications. Results Postoperative bone resorption occurred in eight cases (44.4%). Among them, two experienced symptomatic breakdown of the autologous bone graft that required a second operation to reconstruct the skull contour using porous polyethylene implant (Medpor®). The incidence of bone resorption was more common in the pediatric group and in those with large cranial defects (>120 cm2). No significant correlation was found with sex, reasons for craniectomy, and cryopreservation period. Conclusion The use of autologous bone flap for reconstruction of a skull defect after decompressive craniectomy is a quick and cost-effective method. But, the resorption rate was greater in children and in patients with large skull defects. As a result, we suggest compressive force of the tightened scalp, young age, large skull defect, the gap between bone flap and bone edge and heat sterilization of autologous bone as risk factors for bone resorption. PMID:27169026

Bone mineral density and metabolic indices in hyperthyroidism.

PubMed

Al-Nuaim, A; El-Desouki, M; Sulimani, R; Mohammadiah, M

1991-09-01

Hyperthyroidism can alter bone metabolism by increasing both bone resorption and formation. The increase in bone resorption predominates, leading to a decrease in bone mass. To assess the effect of hyperthyroidism on bone and mineral metabolism, we measured bone density using single photon absorptiometry in 30 untreated hyperthyroid patients. Patients were categorized into three groups based on sex and alkaline phosphatase levels: 44 sex- and age-matched subjects were used as controls. Bone densities were significanlty lower in all patient groups compared with controls. Alkaline phosphatase was found to be a useful marker for assessing severity of bone disease in hyperthyroid patients as there is significant bone density among patients with higher alkaline phosphatase value. Hyperthyroidism should be considered in the differential diagnosis of unexplained alkaline phophatase activity.

[Clinical usefulness of bone turnover markers in the management of osteoporosis].

PubMed

Yano, Shozo

2013-09-01

Osteoporosis is a state of elevated risk for bone fracture due to depressed bone strength, which is considered to be the sum of bone mineral density and bone quality. Since a measure of bone quality has not been established, bone mineral density and bone turnover markers are the only way to evaluate bone strength. Bone turnover markers are classified into bone formation marker and resorption marker, which are correlated with the bone formation rate and resorption rate, respectively, and bone matrix-related marker. Bone is always metabolized; old tissue is resorbed by acids and proteases derived from osteoclasts, whereas new bone is produced by osteoblasts. Bone formation and resorption rates should be balanced (also called coupled). When the bone resorption rate exceeds the formation rate(uncoupled state), bone volume will be reduced. Thus, we can comprehend bone metabolism by measuring both formation and resorption markers at the same time. Increased fracture risk is recognized by elevated bone resorption markers and undercarboxylated osteocalcin, which reflects vitamin K insufficiency and bone turnover. These values and the time course give us helpful information to choose medicine suitable for the patients and to judge the responsiveness. If the value is extraordinarily high without renal failure, metabolic bone disorder or bone metastatic tumor should be considered. Bone quality may be assessed by measuring bone matrix-related markers such as homocystein and pentosidine. Since recent studies indicate that the bone is a hormone-producing organ, it is possible that glucose metabolism or an unknown mechanism could be assessed in the future.

Exploring the Bone Proteome to Help Explain Altered Bone Remodeling and Preservation of Bone Architecture and Strength in Hibernating Marmots.

PubMed

Doherty, Alison H; Roteliuk, Danielle M; Gookin, Sara E; McGrew, Ashley K; Broccardo, Carolyn J; Condon, Keith W; Prenni, Jessica E; Wojda, Samantha J; Florant, Gregory L; Donahue, Seth W

2016-01-01

Periods of physical inactivity increase bone resorption and cause bone loss and increased fracture risk. However, hibernating bears, marmots, and woodchucks maintain bone structure and strength, despite being physically inactive for prolonged periods annually. We tested the hypothesis that bone turnover rates would decrease and bone structural and mechanical properties would be preserved in hibernating marmots (Marmota flaviventris). Femurs and tibias were collected from marmots during hibernation and in the summer following hibernation. Bone remodeling was significantly altered in cortical and trabecular bone during hibernation with suppressed formation and no change in resorption, unlike the increased bone resorption that occurs during disuse in humans and other animals. Trabecular bone architecture and cortical bone geometrical and mechanical properties were not different between hibernating and active marmots, but bone marrow adiposity was significantly greater in hibernators. Of the 506 proteins identified in marmot bone, 40 were significantly different in abundance between active and hibernating marmots. Monoaglycerol lipase, which plays an important role in fatty acid metabolism and the endocannabinoid system, was 98-fold higher in hibernating marmots compared with summer marmots and may play a role in regulating the changes in bone and fat metabolism that occur during hibernation.

Role of carbonic anhydrase in bone resorption induced by prostaglandin E2 in vitro

NASA Technical Reports Server (NTRS)

Hall, G. E.; Kenny, A. D.

1985-01-01

The possible role of carbonic anhydrase in bone resorption induced by prostaglandin E2 (PGE2) was studied using an in vitro neonatal mouse calvarial culture system. PGE2 (10 to the -6th M) was effective in stimulating resorption, as assessed by calcium release into culture media. This enhanced resorption was accompanied by significant increases in calvarial carbonic anhydrase activity over control values at 48 and 96 h. At 48 h, bones treated with PGE2 had 20 percent more carbonic anhydrase activity than controls. By 96 h, treated bones contained 79 percent more carbonic anhydrase activity than controls. PGE2-induced bone resorption was inhibited by the carbonic anhydrase inhibitor acetazolamide in a dose-dependent fashion from 10 to the -5th to 10 to the -4th M with 77 percent inhibition observed at 10 to the -4th M. The acetazolamide analogue CL 13,850 (N-t-butylacetazolamide), which does not inhibit carbonic anhydrase, failed to inhibit PGE2-induced resorption. These results are consistent with the hypothesis that carbonic anhydrase is a necessary component of the osteoclastic bone resorptive mechanism.

Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice.

PubMed

Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2015-01-01

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

Self-assembling bisphosphonates into nanofibers to enhance their inhibitory capacity on bone resorption

NASA Astrophysics Data System (ADS)

Tang, Anming; Qian, Yu; Liu, Shuang; Wang, Weijuan; Xu, Bing; Qin, An; Liang, Gaolin

2016-05-01

Osteoporosis (OP) is an important aging-related disease and the effective prevention/treatment of this disease remains challenging. Considering the acidic microenvironment of bone resorption lacunae, herein, we rationally designed two pamidronate (Pami)-derivative and alendronate (Alen)-derivative hydrogelators Pami-D and Alen-D which self-assemble into nanofibers to form supramolecular hydrogels under acidic conditions. Cell viability assay, osteoclastogenesis, osteoclastic gene expression, and in vitro bone resorption results indicated that both Pami-D and Alen-D have better inhibitory effects on osteoclastic formation and bone resorption than Pami and Alen, respectively. We anticipate that our new drugs Pami-D and Alen-D could ``smartly'' self-assemble and locally concentrate the drugs at bone resorption lacunae in vivo and subsequently prevent/treat osteoporosis more efficiently.Osteoporosis (OP) is an important aging-related disease and the effective prevention/treatment of this disease remains challenging. Considering the acidic microenvironment of bone resorption lacunae, herein, we rationally designed two pamidronate (Pami)-derivative and alendronate (Alen)-derivative hydrogelators Pami-D and Alen-D which self-assemble into nanofibers to form supramolecular hydrogels under acidic conditions. Cell viability assay, osteoclastogenesis, osteoclastic gene expression, and in vitro bone resorption results indicated that both Pami-D and Alen-D have better inhibitory effects on osteoclastic formation and bone resorption than Pami and Alen, respectively. We anticipate that our new drugs Pami-D and Alen-D could ``smartly'' self-assemble and locally concentrate the drugs at bone resorption lacunae in vivo and subsequently prevent/treat osteoporosis more efficiently. Electronic supplementary information (ESI) available: Experiment methods and details; syntheses and characterization of Pami-D and Alen-D; HPLC conditions; Fig. S1-S15, Schemes S1 and S2, Tables S1 and S2. See DOI: 10.1039/c6nr00843g

Increasing the amount of corticotomy does not affect orthodontic tooth movement or root resorption, but accelerates alveolar bone resorption in rats.

PubMed

Kurohama, Takeshi; Hotokezaka, Hitoshi; Hashimoto, Megumi; Tajima, Takako; Arita, Kotaro; Kondo, Takanobu; Ino, Airi; Yoshida, Noriaki

2017-06-01

The purpose of this study was to evaluate the relationships among the volume of bone cut during corticotomy, amount of tooth movement, volume of root resorption, and volume of the resultant alveolar bone resorption after tooth movement. Ten-week-old female Wistar rats were distributed into the corticotomy groups and a control group that underwent sham corticotomy. Two experiments employing two different orthodontic forces (10 or 25g) and experimental periods (14 or 21 days) were performed. The volumes of the bone cut by corticotomy were 0.1, 1.0, and 1.7mm3 in the 25g groups, and 1.0 and 1.7mm3 in the 10g groups. Nickel-titanium closed-coil springs were set on the maxillary left first molars to induce mesial movement. After orthodontic tooth movement, the amount of tooth movement, volume of root resorption, and volume of alveolar bone resorption were measured. Despite differences in the volume of bone cut among the different corticotomy groups, there were not significant differences in the amount of tooth movement and volume of root resorption between the control group and any of the corticotomy groups. However, higher volume of bone cut during corticotomy was significantly related to the decreased alveolar bone volume-in particular, to the reduced height of the alveolar bone crest after tooth movement. The volume of the alveolar bone cut during corticotomy does not affect tooth movement or root resorption in 10-week-old female Wistar rats; however, it may increase alveolar bone loss after tooth movement. © The Author 2016. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com

3H-tetracycline as a proxy for 41Ca for measuring dietary perturbations of bone resorption

NASA Astrophysics Data System (ADS)

Weaver, Connie; Cheong, Jennifer; Jackson, George; Elmore, David; McCabe, George; Martin, Berdine

2007-06-01

Our group is interested in evaluating early effects of dietary interventions on bone loss. Postmenopausal women lose bone following reduction in estrogen which leads to increased risk of fracture. Traditional means of monitoring bone loss and effectiveness of treatments include changes in bone density, which takes 6 months to years to observe effects, and changes in biochemical markers of bone turnover, which are highly variable and lack specificity. Prelabeling bone with 41Ca and measuring urinary 41Ca excretion with accelerator mass spectrometry provides a sensitive, specific, and rapid approach to evaluating effectiveness of treatment. To better understand 41Ca technology as a tool for measuring effective treatments on reducing bone resorption, we perturbed bone resorption by manipulating dietary calcium in rats. We used 3H-tetracycline (3H-TC) as a proxy for 41Ca and found that a single dose is feasible to study bone resorption. Suppression of bone resorption, as measured by urinary 3H-TC, by dietary calcium was observed in rats stabilized after ovariectomy, but not in recently ovariectomized rats.

Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Morey-Holton, E. R.; Doty, S. B.; Currier, P. A.; Tanner, S. J.; Halloran, B. P.

1994-01-01

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

Preliminary evidence of early bone resorption in a sheep model of acute burn injury: an observational study.

PubMed

Klein, Gordon L; Xie, Yixia; Qin, Yi-Xian; Lin, Liangjun; Hu, Minyi; Enkhbaatar, Perenlei; Bonewald, Lynda F

2014-03-01

Treatment with bisphosphonates within the first 10 days of severe burn injury completely prevents bone loss. We therefore postulated that bone resorption occurs early post burn and is the primary explanation for acute bone loss in these patients. Our objective was to assess bone for histological and biomechanical evidence of early resorption post burn. We designed a randomized controlled study utilizing a sheep model of burn injury. Three sheep received a 40 % total body surface area burn under isoflurane anesthesia, and three other sheep received cotton-smoke inhalation and served as control. Burned sheep were killed 5 days post procedure and controls were killed 2 days post procedure. Backscatter scanning electron microscopy was performed on iliac crests obtained immediately postmortem along with quantitative histomorphometry and compression testing to determine bone strength (Young's modulus). Blood ionized Ca was also determined in the first 24 h post procedure as was urinary CTx. Three of three sheep killed at 5 days had evidence of scalloping of the bone surface, an effect of bone resorption, whereas none of the three sheep killed at 2 days post procedure had scalloping. One of the three burned sheep killed at 5 days showed quantitative doubling of the eroded surface and halving of the bone volume compared to sham controls. Mean values of Young's modulus were approximately one third lower in the burned sheep killed at 5 days compared to controls, p = 0.08 by unpaired t test, suggesting weaker bone. These data suggest early post-burn bone resorption. Urine CTx normalized to creatinine did not differ between groups at 24 h post procedure because the large amounts of fluids received by the burned sheep may have diluted urine creatinine and CTx and because the urine volume produced by the burned sheep was threefold that of the controls. We calculated 24 h urinary CTx excretion, and with this calculation CTx excretion/24 h in the burned sheep was nearly twice that of the controls. Moreover, whole blood ionized Ca measured at 3- to 6-h intervals over the first 24 h in both burn and control sheep showed a 6 % reduction versus baseline in the burned sheep with <1 % reduction in the control animals. This sheep model was previously used to demonstrate upregulation of the parathyroid calcium-sensing receptor within the timeframe of the present study. Because both early bone resorption, supported by this study, and calcium-sensing receptor upregulation, consistent with the observed reduction in blood ionized Ca, are mediated by proinflammatory cytokines that are present as part of the post-burn systemic inflammatory response, we may postulate that post-burn upregulation of the parathyroid calcium-sensing receptor may be an adaptive response to clear the blood of excess calcium liberated by cytokine-mediated bone resorption.

Bone formation: roles of genistein and daidzein

USDA-ARS?s Scientific Manuscript database

Bone remodeling consists of a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoporosis is the result of increased bone resorption and decreased bone formation causing a decreased bone mass density, loss of bone microarchitecture, and an increased risk of fractu...

Th1/Th17/Th22 immune response and their association with joint pain, imagenological bone loss, RANKL expression and osteoclast activity in temporomandibular joint osteoarthritis: A preliminary report.

PubMed

Monasterio, G; Castillo, F; Rojas, L; Cafferata, E A; Alvarez, C; Carvajal, P; Núñez, C; Flores, G; Díaz, W; Vernal, R

2018-05-15

It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno-inflammatory response in the joint environment, such as IL-1β, IL-17 and IL-22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ-OA), IL-1β and IL-17 have been implicated in the inflammation and resorption of sub-chondral bone; however, the role of Th22 response in the TMJ-OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22-type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ-OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast-induced bone resorption. Higher levels of IL-1β, IL-17 and IL-22 were expressed in TMJ-OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL-1β, IL-17 and IL-22-producing cells, were over-expressed in TMJ-OA compared with DDWR subjects. Osteoclastogenesis and osteoclast-induced bone resorption were significantly greater in presence of synovial fluid from TMJ-OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno-inflammatory response are involved in TMJ-OA pathogenesis. These findings suggest that IL-22 is involved in the RANKL expression in TMJ-OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub-chondral bone. © 2018 John Wiley & Sons Ltd.

Spaceflight-induced vertebral bone loss in ovariectomized rats is associated with increased bone marrow adiposity and no change in bone formation

PubMed Central

Keune, Jessica A; Philbrick, Kenneth A; Branscum, Adam J; Iwaniec, Urszula T; Turner, Russell T

2016-01-01

There is often a reciprocal relationship between bone marrow adipocytes and osteoblasts, suggesting that marrow adipose tissue (MAT) antagonizes osteoblast differentiation. MAT is increased in rodents during spaceflight but a causal relationship between MAT and bone loss remains unclear. In the present study, we evaluated the effects of a 14-day spaceflight on bone mass, bone resorption, bone formation, and MAT in lumbar vertebrae of ovariectomized (OVX) rats. Twelve-week-old OVX Fischer 344 rats were randomly assigned to a ground control or flight group. Following flight, histological sections of the second lumbar vertebrae (n=11/group) were stained using a technique that allowed simultaneous quantification of cells and preflight fluorochrome label. Compared with ground controls, rats flown in space had 32% lower cancellous bone area and 306% higher MAT. The increased adiposity was due to an increase in adipocyte number (224%) and size (26%). Mineral apposition rate and osteoblast turnover were unchanged during spaceflight. In contrast, resorption of a preflight fluorochrome and osteoclast-lined bone perimeter were increased (16% and 229%, respectively). The present findings indicate that cancellous bone loss in rat lumbar vertebrae during spaceflight is accompanied by increased bone resorption and MAT but no change in bone formation. These findings do not support the hypothesis that increased MAT during spaceflight reduces osteoblast activity or lifespan. However, in the context of ovarian hormone deficiency, bone formation during spaceflight was insufficient to balance increased resorption, indicating defective coupling. The results are therefore consistent with the hypothesis that during spaceflight mesenchymal stem cells are diverted to adipocytes at the expense of forming osteoblasts. PMID:28725730

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption.

PubMed

Wu, Wei-Jie; Kim, Min Seuk; Ahn, Byung-Yong

2015-10-01

To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p < 0.01) in a dose dependent manner. These results suggest that vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

Yeast-incorporated gallium attenuates glucocorticoid-induced bone loss in rats by inhibition of bone resorption.

PubMed

Ren, Zhaozhou; Yang, Liqing; Xue, Feng; Meng, Qingjie; Wang, Kejia; Wu, Xian; Ji, Chao; Jiang, Teng; Liu, Da; Zhou, Long; Zhang, Jing; Fu, Qin

2013-06-01

Glucocorticoids (GC) are potent anti-inflammatory agents and widely used for the treatment of many immune-mediated and inflammatory diseases, whereas GC-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and significantly increases the patients' morbidity and mortality. GIOP is characterized as diminished osteogenesis and accelerated bone resorption. Yeast-incorporated gallium (YG) as an organic compound not only reduces elements-associated toxicity, but also maintains its therapeutic effect on improving bone loss or promoting fracture healing in ovariectomized female rats. The aim of this study was to examine whether YG could prevent GC-induced bone loss. Five-month-old male Sprague-Dawley rats were randomly divided into three groups (n = 6): two groups were administered dexamethasone (0.1 mg/kg/day) or vehicle (PBS) subcutaneously for 5 weeks; one other group was received dexamethasone subcutaneously and YG (120 μg/kg/day) orally. Trabecular bone microarchitectural parameters, bone mineral density (BMD), bone strength, body weight, and serum biochemical markers of bone resorption and formation were examined. Compared to the GC alone group, treatment with YG not only prevented microarchitectural deterioration of trabecular bone volume relative to tissue volume, trabecular number, and trabecular separation, but also significantly improved BMD, mechanical strength, and body weight in GC-treated rats. Moreover, YG decreased tartrate-resistant acid phosphatase 5b level but failed to change alkaline phosphatase level in GC-treated rats. This is the first study to show that YG prominently attenuates bone loss and microarchitectural deterioration and inhibits the increased bone resorption in GIOP. It implies that YG might be an alternative therapy for prevention of GC-induced bone loss in humans.

Cortical bone resorption rate in elderly persons: Estimates from long-term in vivo measurements of 90Sr in the skeleton

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shagina, N. B.; Tolstykh, E. I.; Degteva, M. O.

2012-06-01

The rate of cortical bone resorption was assessed from long-term in vivo measurements of 90Sr content in the skeleton for men aged 50-80 years and for women 0-30 years after menopause. Measurements of 90Sr were conducted with a whole body counter for residents of the Techa Riverside communities (Southern Urals, Russia), who ingested large amounts of 90Sr as a result of releases of liquid radioactive wastes into the river from the Mayak plutonium facility in early 1950s. The results of this study showed an increase in the rate of cortical bone resorption in both men and women, as based onmore » the use of accidentally ingested 90Sr as a tracer for bone metabolism. In men there was a continuous gradual increase in the rate of cortical bone resorption after 55 years from 2.8 to 4.5%/year by the age of 75 years. In women, there was a doubled increase in the rate of cortical bone resorption after menopause of up to 6%/year; then the rate remained unchanged for 10-12 years with a subsequent gradual decline down to 5-5.5%/year. Comparison of the rate of cortical bone resorption in men and women older than 55 years showed that women expressed significantly higher levels of cortical bone resorption.« less

An automatic early stage alveolar-bone-resorption evaluation method on digital dental panoramic radiographs

NASA Astrophysics Data System (ADS)

Zhang, Min; Katsumata, Akitoshi; Muramatsu, Chisako; Hara, Takeshi; Suzuki, Hiroki; Fujita, Hiroshi

2014-03-01

Periodontal disease is a kind of typical dental diseases, which affects many adults. The presence of alveolar bone resorption, which can be observed from dental panoramic radiographs, is one of the most important signs of the progression of periodontal disease. Automatically evaluating alveolar-bone resorption is of important clinic meaning in dental radiology. The purpose of this study was to propose a novel system for automated alveolar-bone-resorption evaluation from digital dental panoramic radiographs for the first time. The proposed system enables visualization and quantitative evaluation of alveolar bone resorption degree surrounding the teeth. It has the following procedures: (1) pre-processing for a test image; (2) detection of tooth root apices with Gabor filter and curve fitting for the root apex line; (3) detection of features related with alveolar bone by using image phase congruency map and template matching and curving fitting for the alveolar line; (4) detection of occlusion line with selected Gabor filter; (5) finally, evaluation of the quantitative alveolar-bone-resorption degree in the area surrounding teeth by simply computing the average ratio of the height of the alveolar bone and the height of the teeth. The proposed scheme was applied to 30 patient cases of digital panoramic radiographs, with alveolar bone resorption of different stages. Our initial trial on these test cases indicates that the quantitative evaluation results are correlated with the alveolar-boneresorption degree, although the performance still needs further improvement. Therefore it has potential clinical practicability.

A novel use of 3D printing model demonstrates the effects of deteriorated trabecular bone structure on bone stiffness and strength.

PubMed

Barak, Meir Max; Black, Margaret Arielle

2018-02-01

Trabecular bone structure is crucial to normal mechanical behavior of bones. Studies have shown that osteoporosis negatively affects trabecular bone structure, mainly by reducing bone volume fraction (BV/TV) and thus increasing fracture risk. One major limitation in assessing and quantifying the effect of this structural deterioration is that no two trabecular structures are identical. Thus, when we compare a group of healthy bones against a different group of bones that experienced resorption (i.e. decreased BV/TV) we only discover an "average" mechanical effect. It is impossible to quantify the mechanical effect of individual structural deterioration for each sample, simply because we never have the same sample in both states (intact and deteriorated structure). 3D printing is a new technology that can assist in overcoming this issue. Here we report a preliminary study that compares a healthy 3D printed trabecular bone model with the same model after bone resorption was simulated. Since the deteriorated structural bone model is derived from the healthy one, it is possible to directly estimate (percentage wise) the decrease of tissue stiffness and strength as a result of bone resorption for this specific structure. Our results demonstrate that a relatively small decrease in BV/TV (about 8%) leads to a dramatic decrease in structural strength (24%) and structural stiffness (17%), (P < 0.01). Structural strength decreased from an average of 9.14 ± 2.85MPa to 6.97 ± 2.44MPa, while structural stiffness decreased from an average of 282.5 ± 63.4N/mm to 233.8 ± 51.2N/mm. This study demonstrates that 3D printing is a novel and valuable tool for quantifying the effect of structural deterioration on the mechanical properties of trabecular bone. In the future, this approach may help us attain better personal fracture risk assessments by CT scanning, 3D printing and mechanically testing individual bone replicas from patients suffering excessive bone resorption. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Low Impact Aerobic Dance and Fitball Training on Bone Resorption and Health-Related Physical Fitness in Thai Working Women.

PubMed

Na Ayudthaya, Wanitcha Chatkun; Kritpet, Thanomwong

2015-09-01

To investigate the effects of low impact aerobic dance and fitball training on bone resorption in Thai working women. The samples of this study consisted of 47 females at the age from 35-45. The subjects were divided into two groups: A) 23 females in a low impact aerobic dance (20 min) and fitball (15 min) training group, and B) 24 females in a low impact aerobic dance training group (35 min). Both groups wore a heart rate monitor during the exercise training. The sessions in the training program over 12 weeks were performed a 3-day a week, 35-minute for work out per session at an intensity of 60-80% of maximum heart rate. Before and after the 12-week training program, bone resorption (Telopeptidecrosslinked: β-CrossLaps) and bone formation (N-terminal propeptine of procollagen type 1: P1NP) including physiological and fitness data were assessed. The data of pre and post trainings within and between the groups as well as the data of changes in dependent variables were compared and analyzed by using paired t-test and independent-test. The statistically significant difference was set at the 0.05 level. Both the low impact aerobic dance and fitball training group and the low impact aerobic dance training group revealed their lower level of bone resorption (β-CrossLaps) while the first group showed statistically significant change (p < 0.05). In addition, there were no significant changes of bone resorption (β-CrossLaps) and bone formation (P1NP) between these two groups. However; both groups had not only a significant decrease in resting heart rate, systolic and diastolic pressure, but also an increase in muscular strength and endurance and maximum oxygen uptake when the training was completed. Flexibility ofthe group withfitball was increased significantly (p < 0.05). Low impact aerobic dance and fitball training has the positive effect of slowing down bone resorption and is beneficial to healthy bones. They concurrently increase lower back flexibility.

Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

PubMed

Aoki, Motokuni; Kawahata, Hirohisa; Sotobayashi, Daisuke; Yu, Hisahiro; Moriguchi, Atsushi; Nakagami, Hironori; Ogihara, Toshio; Morishita, Ryuichi

2015-08-01

Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome. Elderly bedridden women (aged >75 years) receiving antihypertensive therapy treated with CCB were recruited in the present study. The participants were divided into two groups--CCB group and ARB group--and followed up to 12 months. Markers of bone resorption were markedly increased, suggesting accelerated bone resorption in the participants of the present study. In the follow-up period, the patients treated with a CCB showed a significant decrease in bone mineral density in a time-dependent manner, accompanied by a significant increase in bone resorption markers, whereas treatment with olmesartan inhibited bone loss, associated with attenuation of increased bone resorption markers. Bone mineral density of femoral neck in the CCB group was significantly lower than that in the ARB group at 6 months. The present study showed inhibitory effects of an ARB on bone resorption in hypertensive patients with accelerated bone resorption, such as elderly bedridden women, and indicated an important role of the renin-angiotensin system in bone metabolism. In elderly hypertensive patients, ARB might be expected to have additional beneficial potential to maintain bone health in bedridden patients. © 2014 Japan Geriatrics Society.

Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study

PubMed Central

Lin, Lawrence; Olson, Jeffrey; Kwon, Taewoo; Bezouglaia, Olga; Tran, Jaime; Hoang, Michael; Bui, Kimberly; Kim, Reuben H.; Tetradis, Sotirios

2018-01-01

A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients. PMID:29304080

Effect of local injection of Zolena, zoledronic acid made in Iran, on orthodontic tooth movement and root and bone resorption in rats.

PubMed

Seifi, Massoud; Asefi, Sohrab; Hatamifard, Ghazal; Lotfi, Ali

2017-01-01

Background. Anchorage control is an essential part of orthodontic treatment planning, especially in adult patients who demand a more convenient treatment. Zoledronic acid (ZA) is an effective choice to address this problem. It is the most potent member of the bisphosphonates family that has an inhibitory effect on bone resorption by suppressing osteoclast function. Therefore, ZA might be a good option for orthodontic anchorage control. The current study evaluated the effect of local administration of Zolena (ZA made in Iran) on orthodontic tooth movement (OTM) and root and bone resorption. Methods. The experimental group consisted of 30 rats in 3 subgroups (n=10). Anesthesia was induced, and one closed NiTi coil spring was installed between the first molar and central incisor unilaterally, except for the negative control group. The positive control group received vestibular injection of 0.01 mL of saline next to the maxillary first molar, and 0.01 mL of the solution was injected at the same site in the ZA group. After 21 days, the rats were sacrificed and the distance between the first and second molars was measured with a leaf gauge. Histological analysis was conducted by a blind pathologist for the number of Howship's lacunae, blood vessels, osteoclast-like cells and root resorption lacunae. Data were analyzed with ANOVA, Tukey test and t-test. Results. There were no significant differences in OTM between the force-applied groups. ZA significantly inhibited bone/root resorption and angiogenesis compared to the positive control group. Conclusion. Zolena did not decrease OTM but significantly inhibited bone and root resorption. Zolena might be less potent than its foreign counterparts.

Intermittent minodronic acid treatment with sufficient bone resorption inhibition prevents reduction in bone mass and strength in ovariectomized rats with established osteopenia comparable with daily treatment.

PubMed

Kimoto, Aishi; Tanaka, Makoto; Nozaki, Kazutoshi; Mori, Masamichi; Fukushima, Shinji; Mori, Hiroshi; Shiroya, Tsutomu; Nakamura, Toshitaka

2013-07-01

This study examined and compared the effects of four-week intermittent and daily administrations of minodronic acid, a highly potent nitrogen-containing bisphosphonate, on bone mineral density (BMD), bone strength, bone turnover, and histomorphometry on established osteopenia in ovariectomized (OVX) rats. Fourteen-week-old female F344 rats were OVX or sham-operated. At 12 weeks post surgery, minodronic acid was orally administered once every 4 weeks at 0.2, 1, and 5 mg/kg and once daily at 0.006, 0.03, and 0.15 mg/kg for 12 months. The total dosing amount was comparable between the two dosing regimens. The levels of urinary deoxypyridinoline and serum osteocalcin were measured to assess bone turnover. BMD as assessed via dual-energy X-ray absorptiometry, bone structure and dynamical changes in vertebral trabecula and biomechanical properties were measured ex vivo at 12 months to assess bone content and material properties. Minodronic acid dose-dependently ameliorated the decrease in BMD of lumbar vertebrae and the femur in both treatment regimens similarly. Minodronic acid suppressed elevated urinary levels of deoxypyridinoline, a bone resorption marker, and reduced the serum levels of osteocalcin, a bone formation marker. In the mechanical test at 12 months of treatment, minodronic acid dose-dependently ameliorated the reduction in bone strength in femur and vertebral body. There is no significant difference in parameters between the two regimens except maximal load of lower doses in lumbar vertebral body and absorption energy of middle doses in femur. With these parameters with significant differences, values of the intermittent regimen were significantly lower than that of daily repeated regimen. Bone histomorphometric analysis of the lumbar vertebral body showed that minodronic acid significantly ameliorated the decrease in bone mass, trabecular thickness and number, and the increase in trabecular separation, bone resorption indices (Oc.S/BS and N.Oc/BS), and bone formation indices (BFR/BS, MAR and OV/BV) in both regimens. Minodronic acid suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, thereby improving the deterioration of bone quality under osteoporotic disease conditions regardless of the regimen. In conclusion, a four-week intermittent treatment of minodronic acid suppressed increased bone resorption as daily treatment when considering the total administered dose in OVX rats with established osteopenia. The improvement of microarchitectural destruction in low dose of intermittent treatment was weaker than that observed in a daily repeated regimen; however the effects of high and middle doses of intermittent treatment were equivalent to that observed in daily repeated regimen accompanied by sufficient bone resorption inhibition in rats. These findings suggest that minodronic acid at an appropriate dose in an intermittent regimen may be as clinically useful in osteoporosis therapy as in daily treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

Adenosine A2A Receptor Activation Prevents Wear Particle-Induced Osteolysis

PubMed Central

Mediero, Aránzazu; Frenkel, Sally R.; Wilder, Tuere; He, Wenjie; Mazumder, Amitabha; Cronstein, Bruce N.

2012-01-01

Prosthesis loosening, associated with wear-particle–induced inflammation and osteoclast-mediated bone destruction, is a common cause for joint implant failure, leading to revision surgery. Adenosine A2A receptors (A2AR) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A2AR agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear-particle–induced bone resorption. C57Bl/6 and A2A knockout (A2ARKO) mice received ultrahigh-molecular weight polyethylene particles (UHMWPE) and were treated daily with either saline or the A2AR agonist CGS21680. After 2 weeks, micro-computed tomography of calvaria demonstrated that CGS21680 reduced particle-induced bone pitting and porosity in a dose-dependent manner, increasing cortical bone and bone volume compared to control mice. Histological examination demonstrated diminished inflammation after treatment with CGS21680. In A2AKO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone-resorption markers receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL), cathepsin K, CD163, and osteopontin were reduced following CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin 1β (IL-1β) and TNFα was significantly decreased, whereas IL-10 was markedly increased in bone by CGS21680. These results in mice suggest that site-specific delivery of an adenosine A2AR agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery. PMID:22623741

Proteinase-activated receptor (PAR)-2 activation impacts bone resorptive properties of human osteoarthritic subchondral bone osteoblasts.

PubMed

Amiable, Nathalie; Tat, Steeve Kwan; Lajeunesse, Daniel; Duval, Nicolas; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Boileau, Christelle

2009-06-01

In osteoarthritis (OA), the subchondral bone undergoes a remodelling process involving several factors synthesized by osteoblasts. In this study, we investigated the expression, production, modulation, and role of PAR-2 in human OA subchondral bone osteoblasts. PAR-2 expression and production were determined by real-time PCR and flow cytometry, respectively. PAR-2 modulation was investigated in OA subchondral bone osteoblasts treated with IL-1 beta (100 pg/ml), TNF-alpha (5 ng/ml), TGF-beta1 (10 ng/ml), PGE(2) (500 nM), IL-6 (10 ng/ml) and IL-17 (10 ng/ml). Membranous RANKL protein was assessed by flow cytometry, and OPG, MMP-1, MMP-9, MMP-13, IL-6 and intracellular signalling pathways by specific ELISAs. Bone resorptive activity was measured by using a co-culture model of human PBMC and OA subchondral bone osteoblasts. PAR-2 expression and production (p<0.05) were markedly increased when human OA subchondral bone osteoblasts were compared to normal. On OA osteoblasts, PAR-2 production was significantly increased by IL-1 beta, TNF-alpha and PGE(2). Activation of PAR-2 with a specific agonist, SLIGKV-NH(2), induced a significant up-regulation of MMP-1, MMP-9, IL-6, and membranous RANKL, but had no effect on MMP-13 or OPG production. Interestingly, bone resorptive activity was also significantly enhanced following PAR-2 activation. The PAR-2 effect was mediated by activation of the MAP kinases Erk1/2 and JNK. This study is the first to demonstrate that PAR-2 activation plays a role in OA subchondral bone resorption via an up-regulation of major bone remodelling factors. These results shed new light on the potential of PAR-2 as a therapeutic target in OA.

Hypercalcaemia and hypocalcaemia: finding the balance.

PubMed

Body, Jean-Jacques; Niepel, Daniela; Tonini, Giuseppe

2017-05-01

The balance between bone formation and resorption may be disrupted in patients with cancer, leading either to increased bone resorption, calcium release, and possibly hypercalcaemia, or to increased bone formation, sequestration of calcium, and possibly hypocalcaemia. In adults, hypercalcaemia of malignancy is most common in patients with tumours that produce factors that induce osteoclast activation and enhance bone resorption. Impaired renal function and increased renal tubular calcium resorption may further affect calcium levels. Inhibitors of bone resorption, first the bisphosphonates and, later, denosumab, have been shown to be effective in hypercalcaemia treatment. Bisphosphonates (which are administered intravenously) are approved for hypercalcaemia of malignancy and are the current mainstay of treatment, whereas denosumab (which is administered subcutaneously) may offer an option for patients who do not respond to bisphosphonates or suffer from renal insufficiency. TREATMENT AND PREVENTION: Hypocalcaemia is most common in patients with prostate cancer and osteoblastic bone metastases, but can occur in patients with a variety of tumour types who are receiving inhibitors of bone resorption. While patients often respond to calcium and vitamin D supplementation, prevention should be the aim; at-risk patients should be identified before starting treatment with inhibitors of bone resorption, be closely monitored during at least the first few months of treatment, and receive concomitant calcium and vitamin D supplementation unless hypercalcaemia is present. Both hypercalcaemia and hypocalcaemia can be serious if left untreated. It is therefore important that patients with cancer are closely monitored and receive adequate prevention and treatment measures to maintain normal blood calcium levels.

Inhibitory effect of auranofin (I) and chloroquine (II) on bone degradation induced by the interleukin 1-like (IL-1-like) factor released from rheumatoid synovial tissue (RAST) in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hodges, Y.; Maser, M.R.; Britton, M.C.

1986-03-01

RAST, maintained in organ culture, releases two distinct types of bone resorptive factors and one co-resorptive factor. The first is prostaglandin E/sub 2/ (PGE/sub 2/), while the second is a protein with properties of IL-1. The co-resorptive factor collagenase, cannot induce bone resorption by itself, but augments the bone resorptive activity initiated by either PGE/sub 2/ or the IL-l-like factor. Bone resorptive activity was assessed by measuring the release of /sup 45/Ca from prelabelled rat fetal bones. We investigated the effects of five non-steroidal anti-inflammatory drugs (NSAIDs) and two disease-modifying anti-rheumatic drugs (DMARDs), (I) and (II), on bone degradation mediatedmore » by the IL-l-like factor. None of the NSAIDs tested inhibited bone degradation at 5 x 10/sup -5/ M. On the other hand, both (I) and (II) inhibited bone degradation 60 to 100% at 1 x 10/sup -6/ M and 8 x 10/sup -6/ M respectively. They can inhibit the action of IL-l-like factor on bone at therapeutically attainable concentrations. Additionally, both (I) and (II) block the release of collagenase from the organ culture of RAST with IC/sub 50/s of 5 x 10/sup -6/ M. This unique ability to inhibit collagenase release may contribute to their effectiveness is preventing bone loss in this test model.« less

Low-level laser therapy stimulates bone metabolism and inhibits root resorption during tooth movement in a rodent model.

PubMed

Suzuki, Selly Sayuri; Garcez, Aguinaldo Silva; Suzuki, Hideo; Ervolino, Edilson; Moon, Won; Ribeiro, Martha Simões

2016-12-01

This study evaluated the biological effects of low-level laser therapy (LLLT) on bone remodeling, tooth displacement and root resorption, occurred during the orthodontic tooth movement. Upper first molars of a total of sixty-eight male rats were subjected to orthodontic tooth movement and euthanized on days 3, 6, 9, 14 and 21 days and divided as negative control, control and LLLT group. Tooth displacement and histomorphometric analysis were performed in all animals; scanning electron microscopy analysis was done on days 3, 6 and 9, as well as the immunohistochemistry analysis of RANKL/OPG and TRAP markers. Volumetric changes in alveolar bone were analyzed using MicroCT images on days 14 and 21. LLLT influenced bone resorption by increasing the number of TRAP-positive osteoclasts and the RANKL expression at the compression side. This resulted in less alveolar bone and hyalinization areas on days 6, 9 and 14. LLLT also induced less bone volume and density, facilitating significant acceleration of tooth movement and potential reduction in root resorption besides stimulating bone formation at the tension side by enhancing OPG expression, increasing trabecular thickness and bone volume on day 21. Taken together, our results indicate that LLLT can stimulate bone remodeling reducing root resorption in a rat model. LLLT improves tooth movement via bone formation and bone resorption in a rat model. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

PubMed Central

Florencio-Silva, Rinaldo; Sasso-Cerri, Estela; Simões, Manuel Jesus; Cerri, Paulo Sérgio

2015-01-01

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling. PMID:26247020

Health of periodontal tissues and resorption status after orthodontic treatment of impacted maxillary canines.

PubMed

Oz, A Z; Ciger, S

2018-03-01

The aim of the present study was to evaluate the changes of incisor root resorption associated with impacted maxillary canines and health of periodontal tissues around maxillary canines erupted with orthodontic treatment. Twenty patients with a unilateral palatally impacted maxillary canine were included in the study. Cone-beam computed tomography images taken before and after orthodontic treatment were compared with the contralateral canines serving as control teeth. Root resorption was present in 10% of central and 40% of lateral incisors before treatment. After treatment, the incidence of resorption decreased. The thickness of the buccal bone surrounding the impacted canines was similar to that surrounding the contralateral canines, except in the apical area. Periodontal pocket depth and alveolar bone loss were greater for the impacted canine teeth than for the contralateral canines. Incisor root resorption associated with impacted canine teeth showed signs of repair after orthodontic treatment. Slight differences related to periodontal health were found between the previously impacted teeth and contralateral canine teeth.

Inhibitory effects of melatonin on titanium particle-induced inflammatory bone resorption and osteoclastogenesis via suppression of NF-κB signaling.

PubMed

Ping, Zichuan; Wang, Zhirong; Shi, Jiawei; Wang, Liangliang; Guo, Xiaobin; Zhou, Wei; Hu, Xuanyang; Wu, Xiexing; Liu, Yu; Zhang, Wen; Yang, Huilin; Xu, Yaozeng; Gu, Ye; Geng, Dechun

2017-10-15

Wear debris-induced peri-implant osteolysis challenges the longevity of implants. The host response to wear debris causes chronic inflammation, promotes bone resorption, and impairs bone formation. We previously demonstrated that melatonin enhances bone formation and attenuates wear debris-induced bone loss in vivo. However, whether melatonin inhibits chronic inflammation and bone resorption at sites of wear debris-induced osteolysis remains unclear. In this study, we examined the potential inhibitory effects of melatonin on titanium particle-induced inflammatory osteolysis in a murine calvarial model and on RANKL-induced osteoclastic formation in bone marrow-derived macrophages. We found that the exogenous administration of melatonin significantly inhibited wear debris-induced bone resorption and the expression of inflammatory cytokines in vivo. Additionally, melatonin inhibited RANKL-induced osteoclast differentiation, F-actin ring formation, and osteoclastic resorption in a concentration-dependent manner in vitro. We also showed that melatonin blocked the phosphorylation of IκB-α and p65, but not IKKα, and significantly inhibited the expression of NFATc1 and c-Fos. However, melatonin had no effect on MAPK or PI3K/AKT signaling pathways. These results provide novel mechanistic insight into the anti-inflammatory and anti-bone resorptive effects of melatonin on wear debris-induced bone loss and provide an evidence-based rationale for the protective effects of melatonin as a treatment for peri-implant osteolysis. Wear debris-induced chronic inflammation, osteoclastic activation and osteoblastic inhibition have been identified as critical factors of peri-implant bone loss. We previously demonstrated that melatonin, a bioactive indolamine secreted mainly by the pineal gland, activates Wnt/β-catenin signaling pathway and enhances bone regeneration at osteolytic site in vivo. In the current study, we further demonstrated that melatonin significantly suppresses wear debris-induced bone resorption and inflammatory cytokine expression in vivo. In addition, melatonin inhibits receptor activator of nuclear factor kappa-B ligand induced osteoclast formation and osteoclastic bone resorption in vitro. Meanwhile, we found that melatonin mediates its anti-inflammation and anti-bone resorption effects by abrogating nuclear factor kappa-B activation. These results further support the protective effects of melatonin on wear debris-induced peri-implant bone loss, and strongly suggest that melatonin could be considered as a potential candidate for the prevention and treatment of wear debris-induced osteolysis and subsequent aseptic loosening. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The biodegradation of hydroxyapatite bone graft substitutes in vivo.

PubMed

Rumpel, E; Wolf, E; Kauschke, E; Bienengräber, V; Bayerlein, T; Gedrange, T; Proff, P

2006-02-01

Hydroxyapatite (HA) ceramics are widely used for bone reconstruction. They are osteoconductive and serve as structural scaffolds for the deposition of new bone. Generally, scaffold materials should be degradable as they affect the mechanical properties of the reconstructed bone negatively. Degradation by osteoclasts during the bone remodelling process is desirable but often does not take place. In the current study we analysed by light microscopy the degradation of two granular HA implants in critically sized defects in the mandibula of Goettingen mini-pigs five weeks after implantation. Bio-Oss consists of sintered bovine bone and NanoBone is a synthetic HA produced in a sol-gel process in the presence of SiO2. We found that both biomaterials were degraded by osteoclasts with ruffled borders and acid phosphatase activity. The osteoclasts created resorption lacunae and resorptive trails and contained mineral particles. Frequently, resorption surfaces were in direct contact with bone formative surfaces on one granule. Granules, especially of NanoBone, were also covered by osteoclasts if located in vascularised connective tissue distant from bone tissue. However, this usually occurred without the creation of resorption lacunae. The former defect margins consisted of newly formed bone often without remnants of bone substitutes. Our results show that the degradation of both biomaterials corresponds to the natural bone degradation processes and suggest the possibility of complete resorption during bone remodelling.

Radiographic Appearance of Transforaminal Lumbar Interbody Fusion Performed With and Without Recombinant Human Morphogenetic Protein-2.

PubMed

Stensby, J Derek; Kaliney, Ryan W; Alford, Bennett; Shen, Francis H; Patrie, James T; Fox, Michael G

2016-03-01

The purpose of this study is to determine whether recombinant human morphogenetic protein-2 (rhBMP-2) alters the findings on routine radiographs performed after transforaminal lumbar interbody fusion (TLIF). A retrospective review of 256 TLIF procedures in 200 patients was performed over a 4-year period. The rhBMP-2 group included 204 TLIFs in 160 patients, and the control group included 52 TLIFs in 40 patients. Two musculoskeletal radiologists reviewed the postoperative radiographs for endplate resorption, resorption resolution, new bone formation, bridging bone, and allograft migration. Statistical analysis was performed using logistic regression. The median age was 53 years in the rhBMP-2 group and 54 years in the control group (p = 0.182). The groups were similar with regard to sex (p = 0.517), single or multilevel TLIF (p = 0.921), specific TLIF levels (p = 0.53), and median radiographic follow-up (373 vs 366 days; p = 0.34). Findings that were more common in the rhBMP-2 group than in the control group included endplate resorption (38% [78/204] vs 12% [6/52]; odds ratio [OR], 4.67; 95% CI, 1.99-12.54; p < 0.001), resorption resolution (59% [46/78] vs 0% [0/6]; OR, 8.09; 95% CI, 1.41 to ∞; p = 0.022), new bone formation (84% [171/204] vs 67% [35/52]; OR, 2.51; 95% CI, 1.24-4.99; p = 0.011), bridging bone (55% [112/204] vs 31% [16/52]; OR, 2.73; 95% CI, 1.43-5.34; p = 0.002), and allograft migration (17% [35/204] vs 2% [1/52]; OR, 6.30; 95% CI, 0.91-151.41; p = 0.065). A statistically significant higher frequency of endplate resorption, new bone formation, and bone bridging is present in TLIF augmented by rhBMP-2 compared with TLIF performed without rhBMP-2. Endplate resorption resolves without treatment in most cases after rhBMP-2 use.

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone*

PubMed Central

Ghayor, Chafik; Correro, Rita M.; Lange, Katrin; Karfeld-Sulzer, Lindsay S.; Grätz, Klaus W.; Weber, Franz E.

2011-01-01

Regulation of RANKL (receptor activator of nuclear factor κB ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption. PMID:21613210

Osteopenia in anorexia nervosa: specific mechanisms of bone loss.

PubMed

Lennkh, C; de Zwaan, M; Bailer, U; Strnad, A; Nagy, C; el-Giamal, N; Wiesnagrotzki, S; Vytiska, E; Huber, J; Kasper, S

1999-01-01

Osteopenia is a well recognized medical complication of anorexia nervosa (AN). The mechanism of bone loss is not fully understood and there is uncertainty about its management. New markers of bone turnover have been developed. C-terminal type 1 propeptide (PICP) is a measure of bone formation and urinary pyridinolines such as deoxypyridinoline (DPYRX) and serum carboxyterminal crosslinked telopeptide (ICTP) are markers of bone resorption. The aim of this study was to examine these bone markers in patients with AN. Twenty female patients with AN and 12 healthy controls were included in the study. Bone mineral density (BMD) of AN patients was measured by dual energy X-ray absorptiometry (DEXA). Lumbar bone density was significantly reduced in the AN group compared to standardised values of thirty year old adults (t-score 83.2%, S.D. 12.1). Femoral neck bone density showed an even greater reduction (t-score 79.4%, S.D. 13.5). We found a significant negative correlation between femoral BMD and the duration of the illness. Femoral BMD correlated significantly with minimal body weight (r(16) = 0.504, p = 0.033). The markers of bone resorption were significantly higher in the patients with AN compared to the values of the control group (ICTP t(30) = -2.15, p = 0.04, DPYRX t(25) = -2.26, p = 0.033), whereas the markers of bone formation did not differ significantly between the groups. AN appears to be a low turn over state associated with increased bone resorption without concomitant bone formation. This pattern differs from osteopenia in menopausal women and should, therefore, lead to the development of specific therapeutic strategies in AN associated osteopenia. Hormone replacement therapy as well as calcium and vitamine D-supplementation are so far discussed controversially. Long-term treatment studies are warranted.

Feeding Blueberry Diets to Young Rats Dose-Dependently Inhibits Bone Resorption through Suppression of RANKL in Stromal Cells

PubMed Central

Zhang, Jian; Lazarenko, Oxana P.; Kang, Jie; Blackburn, Michael L.; Ronis, Martin J. J.; Badger, Thomas M.; Chen, Jin-Ran

2013-01-01

Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for two weeks beginning on postnatal day 21 (PND21) significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce these effects is, as yet, unknown. The current study examined the effects of three different levels of BB diet supplementation (1, 3, and 5%) for 35 days beginning on PND25 on bone quality, and osteoclastic bone resorption in female rats. Peripheral quantitative CT scan (pQCT) of tibia, demonstrated that bone mineral density (BMD) and content (BMC) were dose-dependently increased in BB-fed rats compared to controls (P<0.05). Significantly increased bone mass after feeding 5% BB extracts was also observed in a TEN (total enteral nutrition) rat model in which daily caloric and food intake was precisely controlled. Expression of RANKL (receptor activator of nuclear factor-κB ligand) a protein essential for osteoclast formation was dose-dependently decreased in the femur of BB animals. In addition, expression of PPARγ (peroxisome proliferator-activated receptor γ) which regulates bone marrow adipogenesis was suppressed in BB diet rats compared to non-BB diet controls. Finally, a set of in vitro cell cultures revealed that the inhibitory effect of BB diet rat serum on RANKL expression was more profound in mesenchymal stromal cells compared to its effect on mature osteoblasts, pre-adipocytes and osteocytes. These results suggest that inhibition of bone resorption may contribute to increased bone mass during early development after BB consumption. PMID:23936431

Volume changes of autogenous bone after sinus lifting and grafting procedures: a 6-year computerized tomographic follow-up.

PubMed

Sbordone, Carolina; Toti, Paolo; Guidetti, Franco; Califano, Luigi; Bufo, Pantaleo; Sbordone, Ludovico

2013-04-01

To evaluate long-term bone remodelling of autografts over time (annually, for 6 years), comparing the block and particulate bone procedures for sinus floor elevation, as well as to evaluate the survival of positioned dental implants. Twenty-three sinus lift procedures with autogenous bone were performed: seven sinus lift procedures using particulate graft and 10 with block autogenous bone were performed in 17 patients. Employing a software program, pre- and post-surgical computerized tomography (CT) scans were used to compare the volume (V) and density (D) of inlay grafts over time (up to 6 years), and to determine the percentage of remaining bone (%R). All variable (V, D and %R) measurements were then compared statistically. At the 6-year survey for block form, a resorption of 21.5% was seen, whereas for particulate grafts there was a resorption of 39.2%. Both groups exhibited bone remodelling between the first and second follow-up which was significant regarding volume for the block form and regarding density for the particulate group. During the initial period of healing, the cortico-cancellous block bone grafted into the maxillary sinus underwent a negative remodelling of the volume, which is most probably due to graft cortex resorption, coupled with, primarily, an increase in density in the spongious area; for the particulate grafts, significant augmentations in density were obtained. The lack of significant differences among volumes was due to the wide degree of dispersion of the data. The rough data presented in this paper seem to support the use of a bone-block grafting procedure in maxillary sinus augmentation. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

[Osteoporosis treatment in patients with hyperthyroidism].

PubMed

Saito, Jun; Nishikawa, Tetsuo

2009-05-01

Childhood thyroid hormone (T3) is essential for the normal development of endochondral and intramembranous bone and plays an important role in the linear growth and maintenance of bone mass. In adult, T3 stimulates osteoclastic bone resorption mediated primarily by TR alpha and local conversion by deiodinase D2 may play a role in local activation. TSH seems to be an inhibitor of bone resorption and formation. In thyrotoxicosis patients with Graves' disease, there is increased bone remodelling, characterized by an imbalance between bone resorption and formation, which results in a decrease of bone mineral density (BMD) and an increased risk for osteoporotic fracture. Antithyroid treatment is able to reduce dramatically the bone resorption and to normalize BMD reduction. But previous hyperthyroidism is independently associated with an increased risk for fracture. Although further studies relating to the mechanism for possible impaired bone strength in these patients will be needed, bisphosphonates may be beneficial treatment for prevention of bone fractures in patients with severe risk for fractures, such as post-menopausal women.

Decreased nitric oxide levels stimulate osteoclastogenesis and bone resorption both in vitro and in vivo on the chick chorioallantoic membrane in association with neoangiogenesis.

PubMed

Collin-Osdoby, P; Rothe, L; Bekker, S; Anderson, F; Osdoby, P

2000-03-01

High nitric oxide (NO) levels inhibit osteoclast (OC)-mediated bone resorption in vivo and in vitro, and nitrate donors protect against estrogen-deficient bone loss in postmenopausal women. Conversely, decreased NO production potentiates OC bone resorption in vitro and is associated with in vivo bone loss in rats and humans. Previously, we reported that bone sections from rats administered aminoguanidine (AG), a selective inhibitor of NO production via inducible NO synthase, exhibited both increased OC resorptive activity as well as greater numbers of OC. Here, we investigated further whether AG promoted osteoclastogenesis, in addition to stimulating mature OC function, using a modified in vivo chick chorioallantoic membrane (CAM) system and an in vitro chick bone marrow OC-like cell developmental model. AG, focally administered in small agarose plugs placed directly adjacent to a bone chip implanted on the CAM, dose-dependently elicited neoangiogenesis while stimulating the number, size, and bone pit resorptive activity of individual OC ectopically formed in vivo. In addition to enhancing OC precursor recruitment via neoangiogenesis, AG also exerted other vascular-independent effects on osteoclastogenesis. Thus, AG promoted the in vitro fusion and formation from bone marrow precursor cells of larger OC-like cells that contained more nuclei per cell and exhibited multiple OC differentiation markers. AG stimulated development was inversely correlated with declining medium nitrite levels. In contrast, three different NO donors each dose-dependently inhibited in vitro OC-like cell development while raising medium nitrite levels. Therefore, NO sensitively regulates OC-mediated bone resorption through affecting OC recruitment (angiogenesis), formation (fusion and differentiation), and bone resorptive activity in vitro and in vivo. Possibly, the stimulation of neoangiogenesis and OC-mediated bone remodeling via AG or other pro-angiogenic agents may find clinical applications in reconstructive surgery, fracture repair, or the treatment of avascular necrosis.

Novel use of a Dektak 150 surface profiler unmasks differences in resorption pit profiles between control and Charcot patient osteoclasts.

PubMed

Petrova, Nina L; Petrov, Peter K; Edmonds, Michael E; Shanahan, Catherine M

2014-04-01

We hypothesized that newly formed osteoclasts from patients with acute Charcot osteoarthropathy can resorb surfaces of bone more extensively compared with controls. Peripheral blood monocytes, isolated from eight Charcot patients and nine controls, were cultured in vitro on 24-well plates and bovine bone discs in duplicate with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κβ ligand (RANKL). Osteoclast formation was assessed by tartrate-resistant acid phosphatase staining (TRAcP) at day 17. Resorption was measured at day 21 after toluidine blue staining by two methods: (1) area of resorption at the surface by image analysis (%) and (2) area of resorption under the surface (μm(2)) measured by a Dektak 150 Surface Profiler. Ten 1,000 μm-long scans were performed per disc. Pits were classified as unidented, bidented, and multidented according to their shape. Although the number of newly formed TRAcP positive multinucleated cells (>3 nuclei) was similar in M-CSF + RANKL-treated cultures between controls and Charcot patients, the latter exhibited increased resorbing activity. The area of resorption on the surface by image analysis was significantly greater in Charcot patients compared with controls (21.1 % [14.5-26.2] vs. 40.8 % [35.4-46.0], median [25-75th percentile], p < 0.01), as was the area of resorption under the surface (2.7 x 10(3) μm(2) [1.6 x 10(3)- 3.9 x 10(3)] vs. 8.3 x 10(3) μm (2) [5.6 x 10(3)- 10.6 x 10(3), [corrected] p < 0.01) after profilometry. In Charcot patients pits were deeper and wider and more frequently presented as multidented pits. This application of the Dektak 150 Surface Profiler revealed novel differences in resorption pit profile from osteoclasts derived from Charcot patients compared with controls. Resorption in Charcot patients was mediated by highly aggressive newly formed osteoclasts from monocytes eroding large and deep areas of bone.

Monocyte recruitment and expression of monocyte chemoattractant protein-1 are developmentally regulated in remodeling bone in the mouse.

PubMed Central

Volejnikova, S.; Laskari, M.; Marks, S. C.; Graves, D. T.

1997-01-01

Tooth eruption is defined as the movement of a tooth from its site of development within the alveolar bone to its position of function in the oral cavity. It represents an excellent model to examine osseous metabolism as bone resorption and bone formation occur simultaneously and are spatially separated. Bone resorption occurs in the coronal (occlusal) area, whereas bone formation occurs in the basal area. Monocytes are thought to have a significant role in the regulation of osseous metabolism. The goal of this study was to examine the recruitment of monocytes to bone in C57BL/6J mice that are undergoing developmentally regulated bone remodeling. Monocytes were detected by immunohistochemistry and osteoclasts were counted as bone-associated multi-nucleated, tartrate-resistant acid phosphatase (TRAP)-positive cells. Cell numbers were obtained from histological sections of animals sacrificed daily for 14 days after birth; an image analysis system was used for quantification. The results demonstrated that, immediately after birth, there were relatively few monocytic cells. In the area of bone resorption, the number of monocytes increased with time, reaching peaks at 5 and 9 days, and decreased thereafter. A similar pattern was observed for osteoclasts. In the area of bone formation, there was a time-dependent increase in the number of monocytes. In contrast, the number of osteoclasts in this area was highest at the earliest time points and decreased after day 3. To investigate potential mechanisms for the recruitment of monocytes, expression of monocyte chemoattractant protein (MCP)-1 was assessed. The number of MCP-1-positive cells increased with time and was generally proportional to the recruitment of mononuclear phagocytes. Osteoblasts were the principal bone cell type expressing MCP-1. The results demonstrate that the recruitment of mononuclear cells in the occlusal area is associated with bone resorption. In contrast, recruitment of monocytes in the basal area is associated with bone formation and a decrease in the number of osteoclasts. These results suggest that monocytes have different functional roles in areas of bone formation compared with bone resorption. Furthermore, the expression of MCP-1 is developmentally regulated and may provide a mechanistic basis to explain the recruitment of monocytic cells. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9137095

Effect of nanocrystalline hydroxyapatite socket preservation on orthodontically induced inflammatory root resorption.

PubMed

Seifi, Massoud; Arayesh, Ali; Shamloo, Nafise; Hamedi, Roya

2015-01-01

Orthodontically induced inflammatory root resorption (OIIRR) is considered to be an important sequel associated with orthodontic tooth movement (OTM). OTM after Socket preservation enhances the periodontal condition before orthodontic space closure. The purpose of this study is to investigate the histologic effects of NanoBone®, a new highly nonsintered porous nano-crystalline hydroxyapatite bone on root resorption following OTM. This experimental study was conducted on four male dogs. In each dog, four defects were created at the mesial aspects of the maxillary and mandibular first premolars. The defects were filled with NanoBone®. We used the NiTi closed coil for mesial movement of the first premolar tooth. When the experimental teeth moved approximately halfway into the defects, after two months, the animals were sacrificed and we harvested the area of interest. The first premolar root and adjacent tissues were histologically evaluated. The three-way ANOVA statistical test was used for comparison. The mean root resorption in the synthetic bone substitute group was 22.87 ± 11.25×10(-4)mm(2) in the maxilla and 21.41 ± 11.25×10(-4)mm(2) in the mandible. Statistically, there was no significant difference compared to the control group (p>0.05). The use of a substitution graft in the nano particle has some positive effects in accessing healthy periodontal tissue following orthodontic procedures without significant influence on root resorption (RR). Histological evaluation in the present study showed osteoblastic activity and remodeling environment of nanoparticles in NanoBone®.

Effect of Nanocrystalline Hydroxyapatite Socket Preservation on Orthodontically Induced Inflammatory Root Resorption

PubMed Central

Seifi, Massoud; Arayesh, Ali; Shamloo, Nafise; Hamedi, Roya

2015-01-01

Objective Orthodontically induced inflammatory root resorption (OIIRR) is considered to be an important sequel associated with orthodontic tooth movement (OTM). OTM after Socket preservation enhances the periodontal condition before orthodontic space closure. The purpose of this study is to investigate the histologic effects of NanoBone®, a new highly nonsintered porous nano-crystalline hydroxyapatite bone on root resorption following OTM. Materials and Methods This experimental study was conducted on four male dogs. In each dog, four defects were created at the mesial aspects of the maxillary and mandibular first premolars. The defects were filled with NanoBone®. We used the NiTi closed coil for mesial movement of the first premolar tooth. When the experimental teeth moved approximately halfway into the defects, after two months, the animals were sacrificed and we harvested the area of interest. The first premolar root and adjacent tissues were histologically evaluated. The three-way ANOVA statistical test was used for comparison. Results The mean root resorption in the synthetic bone substitute group was 22.87 ± 11.25×10-4mm2 in the maxilla and 21.41 ± 11.25×10-4mm2 in the mandible. Statistically, there was no significant difference compared to the control group (p>0.05). Conclusion The use of a substitution graft in the nano particle has some positive effects in accessing healthy periodontal tissue following orthodontic procedures without significant influence on root resorption (RR). Histological evaluation in the present study showed osteoblastic activity and remodeling environment of nanoparticles in NanoBone®. PMID:25685742

Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans

PubMed Central

Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna

2011-01-01

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research PMID:21509823

A Comparison between the Effects of Aerobic Dance Training on Mini-Trampoline and Hard Wooden Surface on Bone Resorption, Health-Related Physical Fitness, Balance, and Foot Plantar Pressure in Thai Working Women.

PubMed

Sukkeaw, Wittawat; Kritpet, Thanomwong; Bunyaratavej, Narong

2015-09-01

To compare the effects of aerobic dance training on mini-trampoline and hard wooden surface on bone resorption, health-related physical fitness, balance, and foot plantar pressure in Thai working women. Sixty-three volunteered females aged 35-45 years old participated in the study and were divided into 3 groups: A) aerobic dance on mini-trampoline (21 females), B) aerobic dance on hard wooden surface (21 females), and C) control group (21 females). All subjects in the aerobic dance groups wore heart rate monitors during exercise. Aerobic dance worked out 3 times a week, 40 minutes a day for 12 weeks. The intensity was set at 60-80% of the maximum heart rate. The control group engaged in routine physical activity. The collected data were bone formation (N-terminal propeptine of procollagen type I: P1NP) bone resorption (Telopeptide cross linked: β-CrossLaps) health-related physical fitness, balance, and foot plantar pressure. The obtained data from pre- and post trainings were compared and analyzed by paired samples t-test and one way analysis of covariance. The significant difference was at 0.05 level. After the 12-week training, the biochemical bone markers of both mini-trampoline and hard wooden surface aerobic dance training subjects decreased in bone resorption (β-CrossLaps) but increased in boneformation (P1NP). Health-related physical fitness, balance, and foot plantar pressure were not only better when comparing to the pre-test result but also significantly different when comparing to the control group (p < 0.05). The aerobic dance on mini-trampoline showed that leg muscular strength, balance and foot plantar pressure were significantly better than the aerobic dance on hard wooden surface (p < 0.05). The aerobic dance on mini-trampoline and hard wooden surface had positive effects on biochemical bone markers. However, the aerobic dance on mini-trampoline had more leg muscular strength and balance including less foot plantar pressure. It is considered to be an appropriate exercise programs in working women.

Toll-Like Receptor 2 Stimulation of Osteoblasts Mediates Staphylococcus Aureus Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL

PubMed Central

Kassem, Ali; Lindholm, Catharina; Lerner, Ulf H

2016-01-01

Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S. aureus regulates osteoclastogenesis to obtain better understanding of the complex mechanisms of S. aureus induced bone destruction in vivo. PMID:27311019

Bone cell communication factors and Semaphorins

PubMed Central

Negishi-Koga, Takako; Takayanagi, Hiroshi

2012-01-01

Bone tissue is continuously renewed throughout adult life by a process called 'remodeling', which involves a dynamic interplay among bone cells including osteoclasts, osteoblasts and osteocytes. For example, a tight coupling between bone resorption and formation is essential for the homeostasis of the skeletal system. Studies on the coupling mechanism in physiological and pathological settings have revealed that osteoclasts or osteoclastic bone resorption promote bone formation through the production of diverse coupling factors. The classical coupling factors are the molecules that promote bone formation after resorption, but there may be distinct mechanisms at work in various phases of bone remodeling. A recent study revealed that the Semaphorin 4D expressed by osteoclasts inhibits bone formation, which represents a mechanism by which coupling is dissociated. Furthermore, it has been demonstrated that osteoblastic expression of Semaphorin 3A exerts an osteoprotective effect by both suppressing bone resorption and increasing bone formation. Thus, recent advances have made it increasingly clear that bone remodeling is regulated by not only classical coupling factors, but also molecules that mediate cell–cell communication among bone cells. We propose that such factors be called bone cell communication factors, which control the delicate balance of the interaction of bone cells so as to maintain bone homeostasis. PMID:24171101

Probiotics Protect Mice from Ovariectomy-Induced Cortical Bone Loss

PubMed Central

Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H.; Farman, Helen H.; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

2014-01-01

The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice. PMID:24637895

Probiotics protect mice from ovariectomy-induced cortical bone loss.

PubMed

Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H; Farman, Helen H; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

2014-01-01

The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice.

Impairment of osteoclastic bone resorption in rapidly growing female p47phox knockout mice

USDA-ARS?s Scientific Manuscript database

Bone formation is dependent on the activity and differentiation of osteoblasts; whereas resorption of preexisting mineralized bone matrix by osteoclasts is necessary not only for bone development but also for regeneration and remodeling. Bone remodeling is a process in which osteoblasts and osteocla...

Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis

PubMed Central

Takeda, Tsuyoshi; Sato, Yoshihiro

2006-01-01

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest. PMID:16642543

Effects of O-methylated (-)-epigallocatechin gallate (EGCG) on LPS-induced osteoclastogenesis, bone resorption, and alveolar bone loss in mice.

PubMed

Tominari, Tsukasa; Ichimaru, Ryota; Yoshinouchi, Shosei; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Inada, Masaki; Miyaura, Chisato

2017-12-01

(-)-Epigallocatechin-3- O -gallate (EGCG), present in green tea, exhibits antioxidant and antiallergy effects. EGCG3″Me, a 3- O -methylated derivative of EGCG, has been reported to show similar biological functions; the inhibitory activity of EGCG3″Me in a mouse allergy model was more potent than that of EGCG, probably due to the efficiency of absorption from the intestine. However, the functional potency of these EGCGs is controversial in each disease model. We previously observed that EGCG suppressed inflammatory bone resorption and prevented alveolar bone loss in a mouse model of periodontosis. In this study, we examined the role of EGCG3″Me in bone resorption using a mouse model of periodontitis. Lipopolysaccharide (LPS)-induced osteoclast formation was suppressed by adding EGCG3″Me to cocultures of osteoblasts and bone marrow cells, and LPS-induced bone resorption was also inhibited by EGCG3″Me in calvarial organ cultures. EGCG3″Me acted on osteoblasts and suppressed prostaglandin E (PGE) production, which is critical for inflammatory bone resorption, by inhibiting the expression of COX-2 and mPGES-1, key enzymes for PGE synthesis. In osteoclast precursor macrophages, EGCG3″Me suppressed RANKL-dependent differentiation into mature osteoclasts. In a mouse model of periodontitis, LPS-induced bone resorption was suppressed by EGCG3″Me in organ culture of mouse alveolar bone, and the alveolar bone loss was further attenuated by the treatment of EGCG3″Me in the lower gingiva in vivo . EGCG3″Me may be a potential natural compound for the protection of inflammatory bone loss in periodontitis.

Effects of corticopuncture (CP) and low-level laser therapy (LLLT) on the rate of tooth movement and root resorption in rats using micro-CT evaluation.

PubMed

Suzuki, Selly Sayuri; Garcez, Aguinaldo Silva; Reese, Patricia Oblitas; Suzuki, Hideo; Ribeiro, Martha Simões; Moon, Won

2018-05-01

The aim of this study was to compare the rate of tooth displacement, quantity of root resorption, and alveolar bone changes in five groups: corticopuncture (CP), low-level laser therapy (LLLT), CP combined with LLLT (CP + LLLT), control (C), and negative control (NC). A total of 60 half-maxilla from 30 male Wistar rats (10 weeks old) were divided randomly into five groups: three (CP, LLLT, and CP + LLLT) test groups with different stimulation for accelerated-tooth-movement (ATM), one control (C) group, and one negative control (NC) group with no tooth movement. Nickel-titanium coil springs with 50 g of force were tied from the upper left and right first molars to micro-implants placed behind the maxillary incisors. For the CP and CP + LLLT groups, two perforations in the palate and one mesially to the molars were performed. For the LLLT and CP + LLLT groups, GaAlAs diode laser was applied every other day for 14 days (810 nm, 100 mW, 15 s). The tooth displacements were measured directly from the rat's mouth and indirectly from microcomputer (micro-CT) tomographic images. Bone responses at the tension and compression sites and root resorption were analyzed from micro-CT images. The resulting alveolar bone responses were evaluated by measuring bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular thickness (TbTh). Root resorption crater volumes were measured on both compression and tension sides of mesial and distal buccal roots. The tooth displacement in the CP + LLLT group was the greatest when measured clinically, followed by the CP, LLLT, and control groups (C and NC), respectively (p <0.05). The tooth movements measured from micro-CT images showed statistically higher displacement in the CP and CP + LLLT groups compared to the LLLT and control groups. The BMD, BV/TV, and TbTh values were lower at the compression side and higher at the tension side for all three test groups compared to the control group. The root resorption crater volume of the distal buccal root was higher in the control group, followed by CP, LLLT, and CP + LLLT, mostly at the compression site. Combining corticopuncture and low-level laser therapy (CP + LLLT) produced more tooth displacement and less root resorption at the compression side. The combined technique also promoted higher alveolar bone formation at the tension side.

Effect of the up-front heat treatment of gelatin particles dispersed in calcium phosphate cements on the in vivo material resorption and concomitant bone formation.

PubMed

Yamamoto, Shoko; Matsushima, Yuta; Kanayama, Yoshitaka; Seki, Azusa; Honda, Haruya; Unuma, Hidero; Sakai, Yasuo

2017-03-01

Calcium phosphate cements (CPCs), consisting of a mixture of calcium phosphate powders and setting liquid, have been widely used in orthopedic applications. One of the drawbacks of CPCs is their poor resorbability in the living body, which hinders substitution with natural bones. One of the strategies to facilitate the resorption of CPCs is the incorporation of bioresorbable or water-soluble pore-generating particles (porogens), such as gelatin, in the CPC matrices. In spite of numerous reports, however, little is known about the effect of the dissolution/resorption rate of the porogens on concomitant bone regeneration. In the present study, we prepared preset CPCs dispersed with 10 mass% of low-endotoxin gelatin particles 200-500 μm in diameter having different heat-treatment histories, therefore exhibiting different dissolution rate, and then the obtained CPC/gelatin composites were evaluated for in vivo resorption and concomitant in vivo bone formation behaviors. As the results, the dispersion of gelatin particles markedly promoted in vivo resorption of CPC, and enhanced concomitant bone formation, connective tissue formation, osteoblast proliferation, and vascularization. The dissolution/resorption rate was able to be controlled by changing the up-front heat-treatment temperature. In particular, when CPC/gelatin composites were implanted in distal metaphysis of rabbits, the optimum dissolution/resorption was attained by heat-treating gelatin particles at 383 K for 24 h before dispersing in CPC. Quick resorption of calcium phosphate cement and concomitant bone formation by dispersing properly heat-treated with gelatin particles.

Bone remodeling and calcium homeostasis in patients with spinal cord injury: a review.

PubMed

Maïmoun, Laurent; Fattal, Charles; Sultan, Charles

2011-12-01

Patients with spinal cord injury exhibit early and acute bone loss with the major functional consequence being a high incidence of pathological fractures. The bone status of these patients is generally investigated by dual-energy x-ray absorptiometry, but this technique does not reveal the pathophysiological mechanism underlying the bone loss. Bone cell activity can be indirectly evaluated by noninvasive techniques, including measurement of specific biochemical markers of bone formation (such as osteocalcin or bone-alkaline phosphatase) and resorption (such as procollagen type I N- or C-terminal propeptide). The bone loss in spinal cord injury is clearly due to an uncoupling of bone remodeling in favor of bone resorption, which starts just after the injury and peaks at about 1 to 4 months. Beyond 6 months, bone resorption activity decreases progressively but remains elevated for many years after injury. Conversely, bone formation is less affected. Antiresorptive treatment induces an early and acute reduction in bone resorption markers. Level of injury and health-related complications do not seem to be implicated in the intensity of bone resorption. During the acute phase, the hypercalcemic status is associated with the suppression of parathyroid hormone and vitamin D metabolites. The high sensitivity of these markers after treatment suggests that they can be used for monitoring treatment efficacy and patient compliance. The concomitant use of bone markers and dual-energy x-ray absorptiometry may improve the physician's ability to detect patients at risk of severe bone loss and subsequent fractures. Copyright © 2011 Elsevier Inc. All rights reserved.

Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We?

PubMed Central

Szulc, Pawel

2011-01-01

In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men. PMID:22220284

Quantitative and qualitative analysis of bone flap resorption in patients undergoing cranioplasty after decompressive craniectomy.

PubMed

Korhonen, Tommi K; Salokorpi, Niina; Niinimäki, Jaakko; Serlo, Willy; Lehenkari, Petri; Tetri, Sami

2018-02-23

OBJECTIVE Autologous bone cranioplasty after decompressive craniectomy entails a notable burden of difficult postoperative complications, such as infection and bone flap resorption (BFR), leading to mechanical failure. The prevalence and significance of asymptomatic BFR is currently unclear. The aim of this study was to radiologically monitor the long-term bone flap survival and bone quality change in patients undergoing autologous cranioplasty. METHODS The authors identified all 45 patients who underwent autologous cranioplasty at Oulu University Hospital, Finland, between January 2004 and December 2014. Using perioperative and follow-up CT scans, the volumes and radiodensities of the intact bone flap prior to surgery and at follow-up were calculated. Relative changes in bone flap volume and radiodensity were then determined to assess cranioplasty survival. Sufficient CT scans were obtainable from 41 (91.1%) of the 45 patients. RESULTS The 41 patients were followed up for a median duration of 3.79 years (25th and 75th percentiles = 1.55 and 6.66). Thirty-seven (90.2%) of the 41 patients had some degree of BFR and 13 (31.7%) had a remaining bone flap volume of less than 80%. Patients younger than 30 years of age had a mean decrease of 15.8% in bone flap volume compared with the rest of the cohort. Bone flap volume was not found to decrease linearly with the passing of time, however. The effects of lifestyle factors and comorbidities on BFR were nonsignificant. CONCLUSIONS In this study BFR was a very common phenomenon, occurring at least to some degree in 90% of the patients. Decreases in bone volume were especially prominent in patients younger than 30 years of age. Because the progression of resorption during follow-up was nonlinear, routine follow-up CT scans appear unnecessary in monitoring the progression of BFR; instead, clinical follow-up with mechanical stability assessment is advised. Partial resorption is most likely a normal physiological phenomenon during the bone revitalization process.

Neogambogic Acid Suppresses Receptor Activator of Nuclear Factor κB Ligand (RANKL)-Induced Osteoclastogenesis by Inhibiting the JNK and NF-κB Pathways in Mouse Bone Marrow-Derived Monocyte/Macrophages.

PubMed

Jin, Gu; Wang, Fang-Fang; Li, Tao; Jia, Dong-Dong; Shen, Yong; Xu, Hai-Chao

2018-04-26

BACKGROUND Neogambogic acid (NGA) is used in traditional Chinese medicine. The aim of this study was to investigate the effects of NGA on gene signaling pathways involved in osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages (BMMs) and on bone resorption in vitro. MATERIAL AND METHODS Primary mouse BMMs were cultured with increasing concentrations of NGA. Real-time polymerase chain reaction was used to study the expression of mRNAs corresponding to gene products specific to receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, including tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), cathepsin K (CTSK), and nuclear factor of activated T cells c1 (NFATc1). A cell counting kit-8 assay was used to evaluate cell proliferation. Western blotting and confocal immunofluorescence microscopy were used to investigate the signaling pathways. A bone resorption model was used to quantify bone resorption. RESULTS An NGA dose of ≤0.4 μg/ml had no significant effect on the proliferation of mouse BMMs in vitro (P>0.05); concentrations of between 0.1-0.4 μg/ml significantly inhibited RANKL-induced osteoclastogenesis (P<0.01) in a dose-dependent manner. Compared with the control group, NGA significantly reduced RANKL-induced bone resorption in vitro (P <0.01), and downregulated the expression of osteoclast-related mRNAs of TRAP, CTR, CTSK, and NFATc1. NGA suppressed the activation of JNK but not the p38 signaling pathway and significantly reduced NF-κB p65 phosphorylation and the nuclear transport of NF-κB molecules, which inhibited NFATc1 expression. CONCLUSIONS NGA suppressed RANKL-induced osteoclastogenesis by inhibiting the JNK and NF-κB pathways in mouse BMMs in vitro and reduced osteoclastic bone resorption.

Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

PubMed

Hussein, H; Dulin, J; Smanik, L; Drost, W T; Russell, D; Wellman, M; Bertone, A

2017-08-01

Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases. © 2016 John Wiley & Sons Ltd.

Experiment K-317: Bone resorption in rats during spaceflight

NASA Technical Reports Server (NTRS)

Cann, C. E.; Adachi, R. R.

1981-01-01

Direct measurement of bone resorption in flight and synchronous control rats is described. Continuous tracer administration techniques were used, with replacement of dietary calcium with isotopically enriched Ca40 and measurement by neutron activation analysis of the Ca48 released by the skeleton. There is no large change in bone resorption in rats. Based on the time course of changes, the measured 20-25% decrease in resorption is probably secondary to a decrease in total body calcium turnover. The excretion of sodium, potassium and zinc all increase during flight, sodium and potassium to a level 4-5 times control values.

Consumption of yogurts fortified in vitamin D and calcium reduces serum parathyroid hormone and markers of bone resorption: a double-blind randomized controlled trial in institutionalized elderly women.

PubMed

Bonjour, Jean-Philippe; Benoit, Valérie; Payen, Flore; Kraenzlin, Marius

2013-07-01

Nutritional prevention of bone deterioration with fortified foods seems particularly suitable in institutionalized elderly women at risk of vitamin D deficiency, secondary hyperparathyroidism, increased bone resorption, and osteoporotic fracture. The objective was to evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum PTH and bone resorption markers as compared with isocaloric and isoprotein dairy products in elderly women. A randomized double-blind controlled-trial, 56-day intervention was conducted in institutionalized women (mean age 85.5 years) consuming 2 125-g servings of either vitamin D- and calcium-fortified yogurt (FY) at supplemental levels of 10 μg/d vitamin D₃ and 800 mg/d calcium or nonfortified control yogurt (CY) providing 280 mg/d calcium. The endpoints were serum changes from baseline (day 0) to day 28 and day 56 in 25-hydroxyvitamin-D (25OHD), PTH, and bone resorption markers tartrate-resistant acid phosphatase isoform-5b (TRAP5b), the primary outcome, and carboxyl-terminal cross-linked telopeptide of type I collagen (CTX). At day 56, serum 25OHD increased (mean ± SEM) by 25.3 ± 1.8 vs 5.2 ± 2.5 nmol/L in FY (n = 29) and CY (n = 27), respectively (P < .0001). The corresponding changes in PTH were -28.6% ± 7.2% vs -8.0% ± 4.3% (P = .0003); in TRAP5b, -21.9% ± 4.3% vs 3.0% ± 3.2% (P < .0001); and in CTX, -11.0% ± 9.7% vs -3.0% ± 4.1% (P = .0146), in FY and CY, respectively. At day 28, these differences were less pronounced but already significant for 25OHD, PTH, and TRAP5b. This study in institutionalized elderly at high risk for osteoporotic fracture suggests that fortification of dairy products with vitamin D₃ and calcium provides a greater prevention of accelerated bone resorption as compared with nonfortified equivalent foods.

Bone and Calcium Metabolism During Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.

2004-01-01

Understanding bone loss during space flight is one of the most critical challenges for maintaining astronaut health on space exploration missions. Flight and ground-based studies have been conducted to better understand the nature and mechanisms of weightlessness-induced bone loss, and to identify a means to counteract the loss. Maintenance of bone health requires a balance between bone formation and bone resorption. Early space research identified bone loss as a critical health issue, but could not provide a distinction between the bone formation and breakdown processes. The recent identification of collagen crosslinks as markers of bone resorption has made possible a clear understanding that a decrease in bone resorption is an important effect of space flight, with bone formation being unchanged or only slightly decreased. Calcium regulatory factors have also been studied, in an attempt to understand their role in bone loss. The lack of ultraviolet light exposure and insufficient dietary sources of vitamin D often lead to reduced vitamin D stores on long-duration flights. Serum parathyroid hormone (PTH) concentrations are decreased during flight compared to before flight, although small subject numbers often make this hard to document statistically. As expected, reduced PTH concentrations are accompanied by reduced 1,25-dihydroxyvitamin D concentrations. Calcium kinetic studies during space flight confirm and extend the information gained from biochemical markers of bone metabolism. Calcium kinetic studies demonstrate that bone resorption is increased, bone formation is unchanged or decreased, and dietary calcium absorption is reduced during space flight. Evaluations have also been conducted of countermeasures, including dietary, exercise, and pharmacological treatments. In recent studies, many potential countermeasures show promise at mitigating bone loss in ground-based analogs of weightlessness (e.g., bed rest), but require further ground and flight testing to ensure that the beneficial effects are seen in space flight. As we begin to plan for missions to go back to the Moon, and even off to Mars, many questions are yet to be answered. Maintaining bone is one of the greatest challenges, but with a better understanding of the mechanical processes of bone loss, countermeasures can be designed more efficiently, and the solution (or solutions) may be just over the horizon.

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

PubMed Central

Mohanty, Sindhu T.; Seckinger, Anja; Terry, Rachael L.; Pettitt, Jessica A.; Simic, Marija K.; Le, Lawrence M. T.; Kramer, Ina; Falank, Carolyne; Fairfield, Heather; Ghobrial, Irene M.; Baldock, Paul A.; Little, David G.; Kneissel, Michaela; Vanderkerken, Karin; Bassett, J. H. Duncan; Williams, Graham R.; Oyajobi, Babatunde O.; Hose, Dirk

2017-01-01

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM. PMID:28515094

Radiographic signs of pathology determining removal of an impacted mandibular third molar assessed in a panoramic image or CBCT

PubMed Central

Schropp, Lars; Spin-Neto, Rubens; Wenzel, Ann

2017-01-01

Objectives: To (1) compare pathological findings related to the mandibular third molar in panoramic images (PAN) and CBCT; (2) estimate the frequency of removals if pathological findings were indicative; and (3) assess factors in PAN associated with resorption and marginal bone loss at the second molar as observed in CBCT. Methods: 379 mandibular third molars were examined with PAN and CBCT. Four observers registered resorption and marginal bone loss at the second molar and increased periodontal space at the third molar in both imaging modalities. Agreement between PAN and CBCT, frequency of removals based on pathological findings in either of the two modalities and interobserver reproducibility was calculated. Logistic regression analyses assessed factors in PAN, which could predict marginal bone loss and resorption observed in CBCT. Results: Agreement between PAN and CBCT: resorption 54–74%; marginal bone loss 66–85%; and increased periodontal space 92–97%. Removals based on CBCT and PAN: 58–71% and 36–65%. Interobserver percentage accordance and kappa values ranged from 57 to 98% and 0.10–0.91 for PAN and 61–97% and 0.22–0.78 for CBCT, respectively. Mesioangulated/horizontally positioned third molars were associated with marginal bone loss [odds ratio (OR) = 7.0–31.3; p < 0.001] and resorption (OR = 2.9–35.6; p < 0.001) in CBCT. Overprojection between the third and the second molars in PAN predicted resorption observed in CBCT (OR = 5.6–21.2; p < 0.001). Conclusions: Pathology associated with the third molar is more often observed in CBCT than in PAN. More third molars would be removed if pathological findings are based on CBCT. Mesioangulated/horizontally positioned third molars overprojecting the cervical/root part of the second molar in PAN are strongly associated with pathology observed in CBCT. PMID:27681861

Radiographic signs of pathology determining removal of an impacted mandibular third molar assessed in a panoramic image or CBCT.

PubMed

Matzen, Louise H; Schropp, Lars; Spin-Neto, Rubens; Wenzel, Ann

2017-01-01

To (1) compare pathological findings related to the mandibular third molar in panoramic images (PAN) and CBCT; (2) estimate the frequency of removals if pathological findings were indicative; and (3) assess factors in PAN associated with resorption and marginal bone loss at the second molar as observed in CBCT. 379 mandibular third molars were examined with PAN and CBCT. Four observers registered resorption and marginal bone loss at the second molar and increased periodontal space at the third molar in both imaging modalities. Agreement between PAN and CBCT, frequency of removals based on pathological findings in either of the two modalities and interobserver reproducibility was calculated. Logistic regression analyses assessed factors in PAN, which could predict marginal bone loss and resorption observed in CBCT. Agreement between PAN and CBCT: resorption 54-74%; marginal bone loss 66-85%; and increased periodontal space 92-97%. Removals based on CBCT and PAN: 58-71% and 36-65%. Interobserver percentage accordance and kappa values ranged from 57 to 98% and 0.10-0.91 for PAN and 61-97% and 0.22-0.78 for CBCT, respectively. Mesioangulated/horizontally positioned third molars were associated with marginal bone loss [odds ratio (OR) = 7.0-31.3; p < 0.001] and resorption (OR = 2.9-35.6; p < 0.001) in CBCT. Overprojection between the third and the second molars in PAN predicted resorption observed in CBCT (OR = 5.6-21.2; p < 0.001). Pathology associated with the third molar is more often observed in CBCT than in PAN. More third molars would be removed if pathological findings are based on CBCT. Mesioangulated/horizontally positioned third molars overprojecting the cervical/root part of the second molar in PAN are strongly associated with pathology observed in CBCT.

Buckling and bone modeling as factors in the development of idiopathic scoliosis.

PubMed

Goto, Manabu; Kawakami, Noriaki; Azegami, Hideyuki; Matsuyama, Yukihiro; Takeuchi, Kenzen; Sasaoka, Ryu

2003-02-15

Computational analysis using the finite-element method was used to examine a possible etiology of idiopathic scoliosis. To compare changes in the coronal and the transverse planes of idiopathic thoracic scoliosis with changes produced in a finite-element buckling model, and to investigate the influence of bone modeling on the buckling spine. Although it is now widely accepted that growth is related strongly to the onset and progression of scoliosis, the pathomechanism or etiology of idiopathic scoliosis still is not clear. A previous study showed that a buckling phenomenon caused by anterior spinal overgrowth can produce scoliosis, and that the fourth buckling mode matched the clinical characteristics associated with the thoracic type of idiopathic scoliosis. The fourth buckling mode occurs when the first, second, and third buckling modes are prevented. The spinal finite-element model used in this study consisted of 68,582 elements and 84,603 nodes. The transverse changes seen in the computed tomography images of 41 patients with idiopathic thoracic scoliosis (apex, T8; average Cobb angle, 52.5 degrees) were compared with those produced in the fourth buckling mode. Bone modeling (bone formation and resorption) was simulated as heat deformation caused by changes in temperature. The bone formation and resorption were simulated, respectively, by positive and negative volume changes in proportion to the stress that occurred in the buckling spine. Computed tomography images of scoliosis show that as the scoliosis becomes more severe, the thoracic cage decreases on the convex side of the curve and increases on the concave side. The opposite thoracic cage deformation was obtained in the fourth buckling mode. In patients with scoliosis, the sternum essentially remains in its original position with respect to the vertebrae, but in the linear buckling model, it shifted in the direction of vertebral body rotation. In contrast to clinical data, the incremental deformation resulting from bone formation corrected the original curve, and the thoracic cage distorted. On the other hand, incremental deformation resulting from bone resorption worsened the original curve, and the thoracic cage distorted in a manner similar to that described by the clinical data. This computational investigation suggests that scoliotic changes in the spinal column triggered by the buckling phenomenon are counteracted by bone formation, but worsened by bone resorption. The authors hypothesized that scoliosis progressed with resorption of loaded bone. However, it is unclear whether this hypothesis applies to a living body in practice because of the effects from additional factors.

Pharmacological inhibition of cathepsin K: A promising novel approach for postmenopausal osteoporosis therapy.

PubMed

Mukherjee, Kakoli; Chattopadhyay, Naibedya

2016-10-01

Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix. Available anti-resorptive drugs affect osteoclast survival and influence both resorption and formation of bone. CatK inhibitors are distinct from the existing anti-resorptives as they only target the resorption process itself without impairing osteoclast differentiation and do not interfere with bone formation. An inhibitor of CatK, odanacatib, robustly increased both trabecular and cortical BMD in postmenopausal osteoporosis patients. The phase III fracture prevention trial with odanacatib ended early due to good efficacy and a favorable benefit/risk profile, thus, enhancing the opportunity for CatK as a pharmacological target for osteoporosis. So far, all the inhibitors that reached to the stage of clinical trial targeted active site of CatK to abrogate the entire proteolytic activity of the enzyme in addition to the desired blockage of excessive elastin and collagen degradation, and could thus pose safety concerns with long term use. Identification of selective exosite inhibitors that inhibit CatK's elastase and/or collagenase activity but do not affect the hydrolysis of other physiologically relevant substrates of CatK would be an improved strategy to inhibit this enzyme. Copyright © 2016 Elsevier Inc. All rights reserved.

Th1 biased response to a novel Porphyromonas gingivalis protein aggravates bone resorption caused by this oral pathogen

PubMed Central

Leshem, Onir; Kashino, Suely S.; Gonçalves, Reginaldo B.; Suzuki, Noriyuki; Onodera, Masao; Fujimura, Akira; Sasaki, Hajime; Stashenko, Philip; Campos-Neto, Antonio

2013-01-01

In previous studies we showed that biasing the immune response to Porphyromonas gingivalis antigens to the Th1 phenotype increases inflammatory bone resorption caused by this organism. Using a T cell screening strategy we identified eight P. gingivalis genes coding for proteins that appear to be involved in T-helper cell responses. In the present study we characterized the protein, encoded by PG_1841 gene and evaluated its relevance in the in bone resorption caused by P. gingivalis because subcutaneous infection of mice with this organism resulted in the induction of Th1 biased response to the recombinant PG1841 antigen molecule. Using an immunization regime that strongly biases toward the Th1 phenotype followed by challenge with P. gingivalis in dental pulp tissue, we demonstrate that mice pre-immunized with rPG1841 developed severe bone loss compared with control immunized mice. Pre-immunization of mice with the antigen using a Th2 biasing regime resulted in no exacerbation of the disease. These results support the notion that selected antigens of P. gingivalis are involved in a biased Th1 host response that leads to the severe bone loss caused by this oral pathogen. PMID:18457976

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.

PubMed

Saito, Mitsuru; Grynpas, Marc D; Burr, David B; Allen, Matthew R; Smith, Susan Y; Doyle, Nancy; Amizuka, Norio; Hasegawa, Tomoka; Kida, Yoshikuni; Marumo, Keishi; Saito, Hitoshi

2015-04-01

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0 mg/mL) and low-density (<2.0 mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality. Copyright © 2014. Published by Elsevier Inc.

Mineral metabolism in isolated mouse long bones: Opposite effects of microgravity on mineralization and resorption

NASA Technical Reports Server (NTRS)

Veldhuijzen, Jean Paul; Vanloon, Jack J. W. A.

1994-01-01

An experiment using isolated skeletal tissues under microgravity, is reported. Fetal mouse long bones (metatarsals) were cultured for 4 days in the Biorack facility of Spacelab during the IML-1 (International Microgravity Laboratory) mission of the Space Shuttle. Overall growth was not affected, however glucose consumption was significantly reduced under microgravity. Mineralization of the diaphysis was also strongly reduced under microgravity as compared to the on-board 1 g group. In contrast, mineral resorption by osteoclasts was signficantly increased. These results indicate that these fetal mouse long bones are a sensitive and useful model to further study the cellular mechanisms involved in the changed mineral metabolism of skeletal tissues under microgravity.

Leukemia inhibitory factor: a novel bone-active cytokine.

PubMed

Reid, L R; Lowe, C; Cornish, J; Skinner, S J; Hilton, D J; Willson, T A; Gearing, D P; Martin, T J

1990-03-01

A number of cytokines have been found to be potent regulators of bone resorption and to share the properties originally attributed to osteoclast-activating factor. One such activity, differentiation-inducing factor (DIF, D-factor) from mouse spleen cells, shares a number of biological and biochemical properties with the recently characterized and cloned leukemia inhibitory factor (LIF). We have assessed the effects of recombinant LIF on bone resorption and other parameters in neonatal mouse calvaria. Both recombinant murine and human (h) LIFs stimulated 45Ca release from prelabeled calvaria in a dose-dependent manner. The increase in bone resorption was associated with an increase in the number of osteoclasts per mm2 bone. The osteolytic effect of hLIF were blocked by 10(-7) M indomethacin. hLIF also stimulated incorporation of [3H] thymidine into calvaria, but the dose-response relationship was distinct from that for bone resorption, and this effect was not blocked by indomethacin. Similarly, hLIF increased [3H]phenylalanine incorporation into calvaria, and this was also not inhibited by indomethacin. It is concluded that LIF stimulates bone resorption by a mechanism involving prostaglandin production, but that a distinct mechanism is responsible for its stimulation of DNA and protein synthesis. The primary structure of LIF differs from that of other fully characterized, bone-active cytokines, and it, thus, represents a novel factor which may be involved in the normal regulation of bone cell function.

Novel Radiomitigator for Radiation-Induced Bone Loss

NASA Technical Reports Server (NTRS)

Schreurs, A-S; Shirazi-fard, Y.; Terada, M.; Alwood, J. S.; Steczina, S.; Medina, C.; Tahimic, C. G. T.; Globus, R. K.

2016-01-01

Radiation-induced bone loss can occur with radiotherapy patients, accidental radiation exposure and during long-term spaceflight. Bone loss due to radiation is due to an early increase in oxidative stress, inflammation and bone resorption, resulting in an imbalance in bone remodeling. Furthermore, exposure to high-Linear Energy Transfer (LET) radiation will impair the bone forming progenitors and reduce bone formation. Radiation can be classified as high-LET or low-LET based on the amount of energy released. Dried Plum (DP) diet prevents bone loss in mice exposed to total body irradiation with both low-LET and high-LET radiation. DP prevents the early radiation-induced bone resorption, but furthermore, we show that DP protects the bone forming osteoblast progenitors from high-LET radiation. These results provide insight that DP re-balances the bone remodeling by preventing resorption and protecting the bone formation capacity. This data is important considering that most of the current osteoporosis treatments only block the bone resorption but do not protect bone formation. In addition, DP seems to act on both the oxidative stress and inflammation pathways. Finally, we have preliminary data showing the potential of DP to be radio-protective at a systemic effect and could possible protect other tissues at risk of total body-irradiation such as skin, brain and heart.

Pressure Bearing Device Affects Extraction Socket Remodeling of Maxillary Anterior Tooth. A Prospective Clinical Trial.

PubMed

Jiang, Xi; Zhang, Yu; Chen, Bo; Lin, Ye

2017-04-01

Extraction socket remodeling and ridge preservation strategies have been extensively explored. To evaluate the efficacy of applying a micro-titanium stent as a pressure bearing device on extraction socket remodeling of maxillary anterior tooth. Twenty-four patients with a extraction socket of maxillary incisor were treated with spontaneous healing (control group) or by applying a micro-titanium stent as a facial pressure bearing device over the facial bone wall (test group). Two virtual models obtained from cone beam computed tomography data before extraction and 4 months after healing were 3-dimenionally superimposed. Facial bone wall resorption, extraction socket remodeling features and ridge width preservation rate were determined and compared between the groups. Thin facial bone wall resulted in marked resorption in both groups. The greatest palatal shifting distance of facial bone located at the coronal level in the control group, but middle level in the test group. Compared with the original extraction socket, 87.61 ± 5.88% ridge width was preserved in the test group and 55.09 ± 14.46% in the control group. Due to the facial pressure bearing property, the rigid micro-titanium stent might preserve the ridge width and alter the resorption features of extraction socket. © 2016 Wiley Periodicals, Inc.

Changes in jawbones of male patients with chronic renal failure on digital panoramic radiographs.

PubMed

Dagistan, Saadettin; Miloglu, Ozkan; Caglayan, Fatma

2016-01-01

To compare the existence of gonial cortical bone thickness, antegonial index, mandibular canal bone resorption and gonial angle values and pathologies like ground-glass appearance in jawbones and brown tumor in male patients undergoing dialysis due to chronic renal failure and men from the healthy control group on panoramic radiographs. Panoramic radiographs were taken from 80 male individuals in total (40 normal and 40 dialysis patients). Values obtained from the right and left sides of the mandible were summed and their means were calculated. Gonial cortical thickness, antegonial index and gonial angle values were assessed with the Student's t-test, mandibular canal wall resorption with the Chi-square test, and pathologies such as ground-glass appearance and Brown tumor as "available" or "not available." Statistically significant differences were observed among the antegonial index (P < 0.001), gonial cortical bone thickness (P < 0.001), and gonial angle (P < 0.001) values of study and control groups. Besides, mandibular canal wall resorption (P < 0.001) was also statistically significant. In the study group, pathologies with ground-glass appearance were encountered in mandible, but no radiographic findings were observed similar to brown tumor. Compared to the control group, decreases were found in gonial cortical bone thicknesses, antegonial index values, mandibular canal wall resorption, and gonial angle values of the patients receiving dialysis treatment due to chronic renal failure. Although it is not statistically significant, pathology with ground-glass appearance was detected in a patient, but no pathologies like brown tumor were observed. These findings from patients with chronic renal failure must be evaluated in panoramic radiography.

Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein-Barr virus.

PubMed

Jakovljevic, A; Andric, M; Nikolic, N; Coric, V; Krezovic, S; Carkic, J; Knezevic, A; Beljic-Ivanovic, K; Pljesa-Ercegovac, M; Miletic, M; Soldatovic, I; Radosavljevic, T; Jovanovic, T; Simic, T; Ivanovic, V; Milasin, J

2018-06-01

To investigate whether apical periodontitis lesions infected by Epstein-Barr virus (EBV) exhibit higher levels of oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and oxidized glutathione (GSSG)] and bone resorption regulators [receptor activator of nuclear factor (NF-κB) ligand (RANKL) and osteoprotegerin (OPG)] compared to EBV-negative periapical lesions and healthy pulp tissues. The experimental group consisted of 30 EBV-positive and 30 EBV-negative periapical lesions collected in conjunction with apicoectomy. The pulp tissues of 20 impacted third molars were used as healthy controls. The qualitative and quantitative analysis of EBV was performed by nested and real-time polymerase chain reaction (PCR), respectively. The levels of RANKL and OPG were analysed by reverse transcriptase real-time PCR. The levels of 8-OHdG and GSSG were determined by enzyme-linked immunosorbent assay (ELISA). Mann-Whitney U-test and Spearman's correlation were used for statistical analysis. The levels of RANKL, OPG, 8-OHdG and GSSG were significantly higher in apical periodontitis lesions compared to healthy pulp controls (P = 0.001, P < 0.001, P < 0.001 and P < 0.05, respectively). RANKL and OPG mRNA expression was significantly higher in EBV-positive compared to EBV-negative periapical lesions (P < 0.05). There was no significant correlation between EBV copy numbers and levels of RANKL, OPG, 8OH-dG and GSSG in apical periodontitis. Levels of bone resorption regulators and oxidative stress biomarkers were increased in apical periodontitis compared to healthy pulp tissues. EBV-positive periapical lesions exhibited higher levels of RANKL and OPG compared to EBV-negative periapical lesions. EBV may contribute to progression of apical periodontitis via enhanced production of bone resorption regulators. © 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd.

Bone modelling at fresh extraction sockets: immediate implant placement versus spontaneous healing: an experimental study in the beagle dog.

PubMed

Vignoletti, Fabio; Discepoli, Nicola; Müller, Anna; de Sanctis, Massimo; Muñoz, Fernando; Sanz, Mariano

2012-01-01

The purpose of this investigation is to describe histologically the undisturbed healing of fresh extraction sockets when compared to immediate implant placement. In eight beagle dogs, after extraction of the 3P3 and 4P4, implants were inserted into the distal sockets of the premolars, while the mesial sockets were left to heal spontaneously. Each animal provided four socket sites (control) and four implant sites (test). After 6 weeks, animals were sacrificed and tissue blocks were dissected, prepared for ground sectioning. The relative vertical buccal bone resorption in relation to the lingual bone was similar in both test and control groups. At immediate implant sites, however, the absolute buccal bone loss observed was 2.32 (SD 0.36) mm, what may indicate that while an apical shift of both the buccal and lingual bone crest occurred at the implant sites, this may not happen in naturally healing sockets. The results from this investigation showed that after tooth extraction the buccal socket wall underwent bone resorption at both test and control sites. This resorption appeared to be more pronounced at the implant sites, although the limitations of the histological evaluation method utilized preclude a definite conclusion. © 2011 John Wiley & Sons A/S.

Is bone equally responsive to calcium and vitamin D intake from food vs. supplements? Use of 41calcium tracer kinetic model

DOE PAGES

Rogers, Tara S.; Garrod, Marjorie G.; Peerson, Janet M.; ...

2016-05-09

Few interventions directly compare equivalent calcium and vitamin D from dairy vs. supplements on the same bone outcomes. Here, the radioisotope calcium-41 ( 41Ca) holds promise as a tracer method to directly measure changes in bone resorption with differing dietary interventions.

Is bone equally responsive to calcium and vitamin D intake from food vs. supplements? Use of 41calcium tracer kinetic model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rogers, Tara S.; Garrod, Marjorie G.; Peerson, Janet M.

Few interventions directly compare equivalent calcium and vitamin D from dairy vs. supplements on the same bone outcomes. Here, the radioisotope calcium-41 ( 41Ca) holds promise as a tracer method to directly measure changes in bone resorption with differing dietary interventions.

A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis mediated through FoxP3+ CD8 T-cells

PubMed Central

Buchwald, Zachary S.; Yang, Chang; Nellore, Suman; Shashkova, Elena V.; Davis, Jennifer L.; Cline, Anna; Ko, Je; Novack, Deborah V.; DiPaolo, Richard; Aurora, Rajeev

2015-01-01

TNFα and IL-17 secreted by proinflammatory T-cells (TEFF) promote bone erosion by activating osteoclasts. We previously demonstrated that in addition to bone resorption, osteoclasts act as antigen presenting cells to induce FoxP3 in CD8 T-cells (TcREG). The osteoclast-induced regulatory CD8 T-cells limit bone resorption in ovariectomized mice (a murine model of postmenopausal osteoporosis). Here we show that while low-dose RANKL maximally induces TcREG via Notch signaling pathway to limit bone resorption, high-dose RANKL promotes bone resorption. In vitro, both TNFα and IL-17, cytokines that are abundant in ovariectomized animals, suppress TcREG induction by osteoclasts by repressing Notch ligand expression in osteoclasts but this effect can be counteracted by addition of RANKL. Ovariectomized mice treated with low-dose RANKL induced TcREG that suppressed bone resorption, decreased TEFF levels and increased bone formation. High dose RANKL had the expected osteolytic effect. Low dose RANKL administration in ovariectomized mice lacking CD8 T-cells was also osteolytic, confirming that TcREG mediate this bone anabolic effect. Our results show that while RANKL directly stimulates osteoclasts to resorb bone, it also controls the osteoclasts’ ability to induce regulatory T-cells, engaging an important negative feedback loop. In addition to the conceivable clinical relevance to treatment of osteoporosis, these observations have potential relevance to induction of tolerance and autoimmune diseases. PMID:25656537

Quantitative evaluation of bone resorption activity of osteoclast-like cells by measuring calcium phosphate resorbing area using incubator-facilitated and video-enhanced microscopy.

PubMed

Morimoto, Yoshitaka; Hoshino, Hironobu; Sakurai, Takashi; Terakawa, Susumu; Nagano, Akira

2009-04-01

Quantitative evaluation of the ability of bone resorption activity in live osteoclast-like cells (OCLs) has not yet been reported on. In this study, we observed the sequential morphological change of OCLs and measured the resorbing calcium phosphate (CP) area made by OCLs alone and with the addition of elcatonin utilizing incubator facilitated video-enhanced microscopy. OCLs, which were obtained from a coculture of ddy-mouse osteoblastic cells and bone marrow cells, were cultured on CP-coated quartz cover slips. The CP-free area increased constantly in the OCLs alone, whereas it did not increase after the addition of elcatonin. This study showed that analysis of the resorbed areas under the OCL body using this method enables the sequential quantitative evaluation of the bone resorption activity and the effect of several therapeutic agents on bone resorption in vitro.

Plasma fluctuation in estradiol-17β and bone resorption markers around parturition in dairy cows

PubMed Central

DEVKOTA, Bhuminad; TAKAHASHI, Masahiro; SATO, Saori; SASAKI, Kouya; UEKI, Atsushi; OSAWA, Takeshi; TAKAHASHI, Masahiro; YAMAGISHI, Norio

2015-01-01

Blood samples were obtained sequentially from 10 dairy cows around the time of parturition to assess plasma fluctuations in estradiol-17β (E2) levels in association with those of several bone resorption markers. Plasma E2 concentration increased sharply a few days prepartum and decreased quickly after parturition. In terms of bone resorption markers, the plasma level of tartrate-resistant acid phosphatase isoform 5b (TRAP5b) rose significantly, commencing 1 week prepartum, and was maintained at this level to a few days postpartum. The plasma concentration of carboxyterminal collagen cross-links of type-I collagen (CTx) increased significantly after parturition. These observations suggest that osteoclast-mediated bone resorption was activated after parturition when plasma E2 concentrations decreased. PMID:25755022

Plasma fluctuation in estradiol-17β and bone resorption markers around parturition in dairy cows.

PubMed

Devkota, Bhuminad; Takahashi, Masahiro; Sato, Saori; Sasaki, Kouya; Ueki, Atsushi; Osawa, Takeshi; Takahashi, Masahiro; Yamagishi, Norio

2015-07-01

Blood samples were obtained sequentially from 10 dairy cows around the time of parturition to assess plasma fluctuations in estradiol-17β (E2) levels in association with those of several bone resorption markers. Plasma E2 concentration increased sharply a few days prepartum and decreased quickly after parturition. In terms of bone resorption markers, the plasma level of tartrate-resistant acid phosphatase isoform 5b (TRAP5b) rose significantly, commencing 1 week prepartum, and was maintained at this level to a few days postpartum. The plasma concentration of carboxyterminal collagen cross-links of type-I collagen (CTx) increased significantly after parturition. These observations suggest that osteoclast-mediated bone resorption was activated after parturition when plasma E2 concentrations decreased.

Inhibitory effects of a bisphosphonate (risedronate) on experimental periodontitis in rats.

PubMed

Shoji, K; Horiuchi, H; Shinoda, H

1995-07-01

The present study was designed to examine whether systemic administration of a bisphosphonate, risedronate, could prevent alveolar bone resorption in rats with experimental periodontitis. On Day 1, an elastic ring was placed around the neck of the right mandibular 1st molar to induce inflammatory periodontitis. The animals were given daily injections of either 0.9% NaCl (control group), or 0.8, 1.6 or 3.2 mumoles/kg (s.c.) of risedronate (experimental groups) from Days 1 to 7, and were killed on Day 8. Histological examinations and determination of bone mineral density in the interdental area between the 1st and 2nd molars with an image analyzer revealed that the presence of the elastic ring induced a loss of attachment and bone resorption in the control group. Vigorous bone resorption, with appearance of a large number of osteoclasts, was observed in the interdental and bifurcation areas. In the experimental groups, however, the resorption of alveolar bone and the loss of bone mineral content in these areas were prevented in a dose-dependent fashion, especially at doses of 1.6 and 3.2 mumoles/kg. Many osteoclasts were detached from the surface of the alveolar bone and had degenerated appearances, such as rounded shapes, loss of polarity and pyknosis. These results suggest that administration of risedronate is effective in preventing bone resorption in periodontitis.

Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells.

PubMed

Streicher, Carmen; Heyny, Alexandra; Andrukhova, Olena; Haigl, Barbara; Slavic, Svetlana; Schüler, Christiane; Kollmann, Karoline; Kantner, Ingrid; Sexl, Veronika; Kleiter, Miriam; Hofbauer, Lorenz C; Kostenuik, Paul J; Erben, Reinhold G

2017-07-25

Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g. T and B-cell) and mesenchymal (osteoblast lineage, chondrocyte) cell types. The cellular mechanisms by which estrogen acts on bone are still a matter of controversy. By using murine reconstitution models that allow for selective deletion of estrogen receptor-alpha (ERα) or selective inhibition of RANKL in hematopoietic vs. mesenchymal cells, in conjunction with in situ expression profiling in bone cells, we identified bone lining cells as important gatekeepers of estrogen-controlled bone resorption. Our data indicate that the increase in bone resorption observed in states of estrogen deficiency in mice is mainly caused by lack of ERα-mediated suppression of RANKL expression in bone lining cells.

WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation.

PubMed

Matsuoka, Kazuhiko; Kohara, Yukihiro; Naoe, Yoshinori; Watanabe, Atsushi; Ito, Masako; Ikeda, Kyoji; Takeshita, Sunao

2018-04-06

The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCδ activation of MEK/ERK, suggesting a novel WAIF1/PKCδ/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage-specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCδ-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

[Therapeutic agents for disorders of bone and calcium metabolism--Parathyroid hormone in weekly subcutaneous injection].

PubMed

Uzawa, Toyonobu

2007-01-01

The parathyroid hormone (PTH) that is marketed outside Japan is for daily administration. It has been proven to increase bone mass and prevent fractures, and the effects are very strong. However, data suggest that daily administration of PTH increases bone resorption. By contrast, weekly administration of PTH, which is being developed in Japan, actually decreases bone resorption, and data suggest that this regimen maintains a good balance between bone formation (predominant) and bone resorption. Furthermore, it has been reported that weekly administration of PTH increases bone mass as much as every day administration of PTH, and as such, weekly administration of PTH has the potential to be a useful regimen with characteristics that are different from those of daily administration of PTH.

TRAF Family Member-Associated NF-κB Activator (TANK) Induced by RANKL Negatively Regulates Osteoclasts Survival and Function

PubMed Central

Wu, Mengrui; Wang, Yiping; Deng, Lianfu; Chen, Wei; Li, Yi-Ping

2012-01-01

Osteoclasts are the principle bone-resorbing cells. Precise control of balanced osteoclast activity is indispensable for bone homeostasis. Osteoclast activation mediated by RANK-TRAF6 axis has been clearly identified. However, a negative regulation-machinery in osteoclast remains unclear. TRAF family member-associated NF-κB activator (TANK) is induced by about 10 folds during osteoclastogenesis, according to a genome-wide analysis of gene expression before and after osteoclast maturation, and confirmed by western blot and quantitative RT-PCR. Bone marrow macrophages (BMMs) transduced with lentivirus carrying tank-shRNA were induced to form osteoclast in the presence of RANKL and M-CSF. Tank expression was downregulated by 90% by Tank-shRNA, which is confirmed by western blot. Compared with wild-type (WT) cells, osteoclastogenesis of Tank-silenced BMMs was increased, according to tartrate-resistant acid phosphatase (TRAP) stain on day 5 and day 7. Number of bone resorption pits by Tank-silenced osteoclasts was increased by 176% compared with WT cells, as shown by wheat germ agglutinin (WGA) stain and scanning electronic microscope (SEM) analysis. Survival rate of Tank-silenced mature osteoclast is also increased. However, acid production of Tank-knockdown cells was not changed compared with control cells. IκBα phosphorylation is increased in tank-silenced cells, indicating that TANK may negatively regulate NF-κB activity in osteoclast. In conclusion, Tank, whose expression is increased during osteoclastogenesis, inhibits osteoclast formation, activity and survival, by regulating NF-κB activity and c-FLIP expression. Tank enrolls itself in a negative feedback loop in bone resorption. These results may provide means for therapeutic intervention in diseases of excessive bone resorption. PMID:23139637

Omega 3 Fatty Acids Reduce Bone Resorption While Promoting Bone Generation in Rat Apical Periodontitis.

PubMed

Azuma, Mariane Maffei; Gomes-Filho, João Eduardo; Ervolino, Edilson; Pipa, Camila Barbosa; Cardoso, Carolina de Barros Morais; Andrada, Ana Cristina; Kawai, Toshihisa; Cintra, Luciano Tavares Angelo

2017-06-01

This study evaluated the effects of the dietary supplement omega 3 polyunsaturated fatty acids (ω-3 PUFAs) on pulp exposure-induced apical periodontitis (AP) in rats. Twenty-eight male rats were divided into groups: control untreated rats (C), control rats treated with ω-3 PUFAs alone (C-O), rats with pulp exposure-induced AP, and rats with pulp exposure-induced AP treated with ω-3 PUFAs (AP-O). The ω-3 PUFAs were administered orally, once a day, for 15 days before pulp exposure and, subsequently, 30 days after pulp exposure. Rats were killed 30 days after pulp exposure, and jaws were subjected to histologic and immunohistochemical analyses. Immunohistochemical analyses were performed to detect tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts on the bone surface of periapical area. Results were statistically evaluated by using analysis of variance and Tukey honestly significant difference, and P < .05 was considered statistically significant. The bone resorption lesion was significantly larger in the AP group compared with AP-O, C, and C-O groups (P < .05). The level of inflammatory cell infiltration was significantly elevated, and the number of tartrate-resistant acid phosphatase-positive osteoclasts was significantly higher in the periapical lesions of the AP group compared with AP-O, C, and C-O groups (P < .05). The number of osteocalcin-positive osteoblasts was significantly increased in the AP-O group compared with the AP group (P > .05). Supplementation with ω-3 PUFAs not only suppresses bone resorption but also promotes new bone formation in the periapical area of rats with AP in conjunction with downregulation of inflammatory cell infiltration into the lesion. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

TRAF family member-associated NF-κB activator (TANK) induced by RANKL negatively regulates osteoclasts survival and function.

PubMed

Wu, Mengrui; Wang, Yiping; Deng, Lianfu; Chen, Wei; Li, Yi-Ping

2012-01-01

Osteoclasts are the principle bone-resorbing cells. Precise control of balanced osteoclast activity is indispensable for bone homeostasis. Osteoclast activation mediated by RANK-TRAF6 axis has been clearly identified. However, a negative regulation-machinery in osteoclast remains unclear. TRAF family member-associated NF-κB activator (TANK) is induced by about 10 folds during osteoclastogenesis, according to a genome-wide analysis of gene expression before and after osteoclast maturation, and confirmed by western blot and quantitative RT-PCR. Bone marrow macrophages (BMMs) transduced with lentivirus carrying tank-shRNA were induced to form osteoclast in the presence of RANKL and M-CSF. Tank expression was downregulated by 90% by Tank-shRNA, which is confirmed by western blot. Compared with wild-type (WT) cells, osteoclastogenesis of Tank-silenced BMMs was increased, according to tartrate-resistant acid phosphatase (TRAP) stain on day 5 and day 7. Number of bone resorption pits by Tank-silenced osteoclasts was increased by 176% compared with WT cells, as shown by wheat germ agglutinin (WGA) stain and scanning electronic microscope (SEM) analysis. Survival rate of Tank-silenced mature osteoclast is also increased. However, acid production of Tank-knockdown cells was not changed compared with control cells. IκBα phosphorylation is increased in tank-silenced cells, indicating that TANK may negatively regulate NF-κB activity in osteoclast. In conclusion, Tank, whose expression is increased during osteoclastogenesis, inhibits osteoclast formation, activity and survival, by regulating NF-κB activity and c-FLIP expression. Tank enrolls itself in a negative feedback loop in bone resorption. These results may provide means for therapeutic intervention in diseases of excessive bone resorption.

Oral administration of vitamin C prevents alveolar bone resorption induced by high dietary cholesterol in rats.

PubMed

Sanbe, Toshihiro; Tomofuji, Takaaki; Ekuni, Daisuke; Azuma, Tetsuji; Tamaki, Naofumi; Yamamoto, Tatsuo

2007-11-01

A high-cholesterol diet stimulates alveolar bone resorption, which may be induced via tissue oxidative damage. Vitamin C reduces tissue oxidative damage by neutralizing free radicals and scavenging hydroxyl radicals, and its antioxidant effect may offer the clinical benefit of preventing alveolar bone resorption in cases of hyperlipidemia. We examined whether vitamin C could suppress alveolar bone resorption in rats fed a high-cholesterol diet. In this 12-week study, rats were divided into four groups: a control group (fed a regular diet) and three experimental groups (fed a high-cholesterol diet supplemented with 0, 1, or 2 g/l vitamin C). Vitamin C was provided by adding it to the drinking water. The bone mineral density of the alveolar bone was analyzed by microcomputerized tomography. As an index of tissue oxidative damage, the 8-hydroxydeoxyguanosine level in the periodontal tissue was determined using a competitive enzyme-linked immunosorbent assay. Hyperlipidemia, induced by a high-cholesterol diet, decreased rat alveolar bone density and increased the number of tartrate-resistant acid phosphatase-positive osteoclasts. The expression of 8-hydroxydeoxyguanosine was upregulated in the periodontal tissues. Intake of vitamin C reduced the effect of a high-cholesterol diet on alveolar bone density and osteoclast differentiation and decreased periodontal 8-hydroxydeoxyguanosine expression. In the rat model, vitamin C suppressed alveolar bone resorption, induced by high dietary cholesterol, by decreasing the oxidative damage of periodontal tissue.

Injectable bone substitute to preserve alveolar ridge resorption after tooth extraction: a study in dog.

PubMed

Boix, D; Weiss, P; Gauthier, O; Guicheux, J; Bouler, J-M; Pilet, P; Daculsi, G; Grimandi, G

2006-11-01

The aim of the present study was to assess the efficacy of a ready-to-use injectable bone substitute on the prevention of alveolar ridge resorption after tooth extraction. Maxillary and mandibular premolars were extracted from 3 Beagle dogs with preservation of alveolar bone. Thereafter, distal sockets were filled with an injectable bone substitute (IBS), obtained by combining a polymer solution and granules of a biphasic calcium phosphate (BCP) ceramic. As a control, the mesial sockets were left unfilled. After a 3 months healing period, specimens were removed and prepared for histomorphometric evaluation with image analysis. Histomorphometric study allowed to measure the mean and the maximal heights of alveolar crest modifications. Results always showed an alveolar bone resorption in unfilled sockets. Resorption in filled maxillary sites was significantly lower than in control sites. Interestingly, an alveolar ridge augmentation was measured in mandibular filled sockets including 30% of newly-formed bone. It was concluded that an injectable bone substitute composed of a polymeric carrier and calcium phosphate can significantly increase alveolar ridge preservation after tooth extraction.

Is bone equally responsive to calcium and vitamins D intake from food vs. supplements? Use of 41Ca tracer kinetic model

USDA-ARS?s Scientific Manuscript database

Background: Few interventions directly compare equivalent calcium and vitamin D from dairy vs. supplements on the same bone outcomes. The radioisotope calcium-41 (41Ca) holds promise as a tracer method to directly measure changes in bone resorption with differing dietary interventions. Objective: U...

Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis

PubMed Central

Huang, Jialiang; Wu, Chuanlong; Tian, Bo; Zhou, Xiao; Ma, Nian; Qian, Yufen

2016-01-01

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg−1∙day−1, respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis. PMID:27011174

Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity.

PubMed

Sowers, MaryFran R; Zheng, Huiyong; Greendale, Gail A; Neer, Robert M; Cauley, Jane A; Ellis, Jayne; Johnson, Sarah; Finkelstein, Joel S

2013-07-01

Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m² and smallest in women with BMI >30 kg/m². Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.

[An in vitro method for studying the metabolism of young bone matrix].

PubMed

Bonneton, C; Guest, M; Delbarre, F

1977-07-04

A method for studying in vitro bone resorption by the use of 35S labeled injection was investigated. Various substances (papaine) and hormones (calcitonin, vitamin D analogues) were tested and their effects on 35S and 45Ca metabolism were compared.

The potential of mangosteen (Garcinia mangostana) peel extract, combined with demineralized freeze-dried bovine bone xenograft, to reduce ridge resorption and alveolar bone regeneration in preserving the tooth extraction socket.

PubMed

Kresnoadi, Utari; Ariani, Maretaningtias Dwi; Djulaeha, Eha; Hendrijantini, Nike

2017-01-01

Following the extraction of a tooth, bone resorption can cause significant problems for a subsequent denture implant and restorative dentistry. Thus, the tooth extraction socket needs to be maintained to reduce the chance of any alveolar ridge bone resorption. The objective of this study is to determine whether the administration of mangosteen peel extracts (MPEs), combined with demineralized freeze-dried bovine bone xenograft (DFBBX) materials for tooth extraction socket preservation, could potentially reduce inflammation by decreased the expression of nuclear factor κβ (NfKb) and receptor activator of nuclear factor-κβ ligand (RANKL), to inhibit alveolar bone resorption, and increased of bone morphogenetic protein-2 (BMP2) expressions to accelerate alveolar bone regeneration. This study consists of several stages. First, a dosage of MPE combined with graft materials was applied to a preserved tooth extraction socket of a Cavia cobaya . Second, the C. cobaya was examined using immune histochemical expression of NfKb, RANKL, BMP2, as well as histology of osteoblasts and osteoclasts. The research was statistically analyzed, using an analysis of variance test and Tukey honest significant difference test. The results of this research were that it was determined that MPEs combined with graft materials on a preserved tooth extraction socket can reduce NfKb, RANK, and osteoclasts also increase of BMP2 and osteoblast. The induction of MPEs and DFBBX is effective in reducing inflammation, lowering osteoclasts, decreasing alveolar bone resorption, and also increasing BMP2 expression and alveolar bone regeneration.

A synthetic bioactive resorbable graft for predictable implant reconstruction: part one.

PubMed

Valen, Maurice; Ganz, Scott D

2002-01-01

Animal studies were conducted to evaluate the cell response and chemical potentiality of a synthetic bioactive resorbable graft (SBRG) made of nonceramic cluster particulate of low-temperature HA material. The study evaluated bone-bridging of the SBRG particulates in 1-mm wide implant channels of 5 x 8 mm long roughened titanium interface in 6 dogs and compared results to the same implant channels left empty as controls at 6- and 12-week intervals. Resorption rate capacity and cell response were evaluated with an assessment of the chemical characterization of the synthetic nonceramic material next to the titanium implant interfaces. Results of the animal studies were compared with human histologic biopsies of the SBRG for bone quality, density, and bone growth into defect sites concurrent with resorption time of the graft. One human biopsy consisted of a graft mixture of the SBRG and dense bovine-derived HA, compared under the electron microscope, including histology by H and E staining. Part 1 of this paper presents evidence of the predictability and efficacy of the SBRG osteoconductive, particulate chemical potentiality to aid in the regeneration of lost bone anatomy next to titanium implant interfaces. Recent technological innovations in computer hardware and software have given clinicians the tools to determine 3-dimensional quality and density of bone, including anatomical discrepancies, which can aid in the diagnosis and treatment planning for grafting procedures. When teeth are extracted, the surrounding bone and soft tissue are challenged as a result of the natural resorptive process. The diminished structural foundation for prosthetic reconstruction, with or without implants, can be compromised. A synthetic bioactive resorbable graft material having osteoconductive biochemical and biomechanical qualities similar to the host bone provides the means to improve compromised bone topography for ridge preservation, ridge augmentation, or to enhance the bony site for implant placement and subsequent prosthetic rehabilitation. Part two of this paper will demonstrate clinical applications of the SBRG material for purposes of implant placement and prosthetic reconstruction.

Overexpression of bone sialoprotein leads to an uncoupling of bone formation and bone resorption in mice.

PubMed

Valverde, Paloma; Zhang, Jin; Fix, Amanda; Zhu, Ji; Ma, Wenli; Tu, Qisheng; Chen, Jake

2008-11-01

The purpose of this study was to determine the effects of bone sialoprotein (BSP) overexpression in bone metabolism in vivo by using a homozygous transgenic mouse line that constitutively overexpresses mouse BSP cDNA driven by the cytomegalovirus (CMV) promoter. CMV-BSP transgenic (TG) mice and wildtype mice were weighed, and their length, BMD, and trabecular bone volume were measured. Serum levels of RANKL, osteocalcin, osteoprotegerin (OPG), TRACP5b, and PTH were determined. Bone histomorphometry, von Kossa staining, RT-PCR analysis, Western blot, MTS assay, in vitro mineralization assay, and TRACP staining were also performed to delineate phenotypes of this transgenic mouse line. Compared with wildtype mice, adult TG mice exhibit mild dwarfism, lower values of BMD, and lower trabecular bone volume. TG mice serum contained increased calcium levels and decreased PTH levels, whereas the levels of phosphorus and magnesium were within normal limits. TG mice serum also exhibited lower levels of osteoblast differentiation markers and higher levels of markers, indicating osteoclastic activity and bone resorption. H&E staining, TRACP staining, and bone histomorphometry showed that adult TG bones were thinner and the number of giant osteoclasts in TG mice was higher, whereas there were no significant alterations in osteoblast numbers between TG mice and WT mice. Furthermore, the vertical length of the hypertrophic zone in TG mice was slightly enlarged. Moreover, ex vivo experiments indicated that overexpression of BSP decreased osteoblast population and increased osteoclastic activity. Partly because of its effects in enhancing osteoclastic activity and decreasing osteoblast population, BSP overexpression leads to an uncoupling of bone formation and resorption, which in turn results in osteopenia and mild dwarfism in mice. These findings are expected to help the development of therapies to metabolic bone diseases characterized by high serum level of BSP.

Molecular and structural assessment of alveolar bone during tooth eruption and function in the miniature pig, Sus scrofa

PubMed Central

Yeh, Kuang-Dah; Popowics, Tracy

2011-01-01

Summary The development of alveolar bone adjacent to the tooth root during tooth eruption is not well understood. This study tested the hypothesis that predominantly woven bone forms adjacent to tooth roots during tooth eruption, but that this immature structure transitions to lamellar bone when the tooth comes into function. Additionally, bone resorption was predicted to play a key role in transitioning immature bone to more mature, load-bearing tissue. Miniature pigs were compared at two occlusal stages, 13 weeks (n=3), corresponding with the mucosal penetration stage of M1 tooth eruption, and 23 weeks (n=3), corresponding with early occlusion of M1/M1. Bone samples for RNA extraction and qRT-PCR analysis were harvested from the diastema and adjacent to M1 roots on one side. Following euthanasia, bone samples for hematoxylin and eosin and TRAP staining were harvested from these regions on the other side. In contrast to expectations, both erupting and functioning molars had reticular fibrolamellar structure in alveolar bone adjacent to M1. However, the woven bone matrix in older pigs was thicker and had denser primary osteons. Gene expression data and osteoclast cell counts showed a tendency for more bone resorptive activity near the molars than at distant sites, but no differences between eruptive stages. Thus, although resorption does occur, it is not a primary mechanism in the transition in alveolar bone from eruption to function. Incremental growth of existing woven bone and filling in of primary osteons within the mineralized scaffold generated the fortification necessary to support an erupted and functioning tooth. PMID:21434979

Modeling Calcium Loss from Bones During Space Flight

NASA Technical Reports Server (NTRS)

Wastney, Meryl E.; Morukov, Boris V.; Larina, Irina M.; Abrams, Steven A.; Nillen, Jeannie L.; Davis-Street, Janis E.; Lane, Helen W.; Smith, Scott M.; Paloski, W. H. (Technical Monitor)

1999-01-01

Calcium loss from bones during space flight creates a risk for astronauts who travel into space, and may prohibit space flights to other planets. The problem of calcium loss during space flight has been studied using animal models, bed rest (as a ground-based model), and humans in-flight. In-flight studies have typically documented bone loss by comparing bone mass before and after flight. To identify changes in metabolism leading to bone loss, we have performed kinetic studies using stable isotopes of calcium. Oral (Ca-43) and intravenous (Ca-46) tracers were administered to subjects (n=3), three-times before flight, once in-flight (after 110 days), and three times post-flight (on landing day, and 9 days and 3 months after flight). Samples of blood, saliva, urine, and feces were collected for up to 5 days after isotope administration, and were analyzed for tracer enrichment. Tracer data in tissues were analyzed using a compartmental model for calcium metabolism and the WinSAAM software. The model was used to: account for carryover of tracer between studies, fit data for all studies using the minimal number of changes between studies, and calculate calcium absorption, excretion, bone calcium deposition and bone calcium resorption. Results showed that fractional absorption decreased by 50% during flight and that bone resorption and urinary excretion increased by 50%. Results were supported by changes in biochemical markers of bone metabolism. Inflight bone loss of approximately 250 mg Ca/d resulted from decreased calcium absorption combined with increased bone resorption and excretion. Further studies will assess the time course of these changes during flight, and the effectiveness of countermeasures to mitigate flight-induced bone loss. The overall goal is to enable human travel beyond low-Earth orbit, and to allow for better understanding and treatment of bone diseases on Earth.

Bone Formation Rate in Experimental Disuse Osteoporosis in Monkeys

NASA Technical Reports Server (NTRS)

Cann, Christopher; Young, Donald R.

1976-01-01

Specific mechanisms underlying weightless and hypodynamic bone loss are obscure. A principal relationship which must be affected is the balance between bone formation and bone resorption rates. In order to better define the influence of those parameters on bone loss, and also to develop measurements in other species as a useful adjunct to human research, studies were undertaken with experimental monkeys. Tests were conducted with a total of 6 adult male monkeys, weighing 10-13 kg, and approximately 10-12 yrs. of age to evaluate specifically bone formation rate during the development of disuse osteoporosis and osteopenia. Three animals were restrained in a semi-recumbent position for six months; three animals served as normal caged controls. Food intake (Purina) was held relatively constant at 200g/day for each animal. Using a Norland Bone Mineral Analyzer, bone mineral losses of 3.5 to 6% were seen in the mid-shaft of the tibia and in the distal radius. Bone loss was confirmed radiographically, with observation of thinning of the proximal tibial cortex and trabeculae in the calcaneus. Bone formation rate was determined using standard Ca-47 kinetics under metabolic balance conditions. After six months of restraint, accretion was 7.2-13.2 mg Ca/kg/day, compared to 3.2-4.1 mg Ca/kg/day in caged controls and 3-8 mg Ca/kg/day in normal adult humans. Fecal and urine calcium was 25-40% higher in restrained animals than in controls. Dietary calcium absorption decreases during restraint, and calcium turnover increases, implying a rise in bone resorption rate concommitant with the observed rise in bone accretion rate. Further studies dealing specifically with bone resorption are underway to define this more fully.

Astronaut Bones: Stable Calcium Isotopes in Urine as a Biomarker of Bone Mineral Balance

NASA Astrophysics Data System (ADS)

Skulan, J.; Gordon, G. W.; Romaniello, S. J.; Anbar, A. D.; Smith, S. M.; Zwart, S.

2016-12-01

Bone loss is a common health concern, in conditions ranging from osteoporosis to cancer. Bone loss due to unloading is also an important health issue for astronauts. We demonstrate stable calcium isotopes, a tool developed in geochemistry, are capable of detecting real-time quantitative changes in net bone mineral balance (BMB) using serum and urine [1]. We validated this technique by comparing with DEXA and biomarker data in subjects during bed rest, a ground-based analog of space flight effects [2-4]. We now apply this tool to assess changes in astronauts' BMB before, during and after 4-6 month space missions. There is stable isotope fractionation asymmetry between bone formation and resorption. During bone formation there is a mass-dependent preference for "lighter" calcium isotopes to be removed from serum and incorporated into bone mineral. During bone resorption, there is no measurable isotopic discrimination between serum and bone. Hence, when bone formation rates exceed that of resorption, serum and urine become isotopically "heavy" due to the sequestration of "light" calcium in bone. Conversely, when bone resorption exceeds bone formation, serum and urine become isotopically "light" due to the release of the sequestered light calcium from bone. We measured Ca isotopes in urine of thirty International Space Station astronauts. Average Ca isotope values in astronauts' urine shift isotopically lighter during microgravity, consistent with negative net BMB. Within a month of return to Earth, astronauts returned to within error of their δ44Ca value prior to departure. Urine samples from astronauts testing bone loss countermeasures showed bisphosphonates provide a viable pharmacological countermeasure. Some, but not all, individuals appear able to resist bone loss through diet and intensive resistive exercise alone. This is a promising new technique for monitoring BMB in astronauts, and hopefully someday on the way to/from Mars, this also has important clinical applications for human health and terrestrial medicine [5]. REFERENCES [1] Morgan, J.L. et al (2011) Anal Chem 83, 6956-6962. [2] Skulan, J.L. et al. (2007) Clin Chem 53, 1155-1158. [3] Morgan, J.L. et al (2012) PNAS 109, 9989-9994. [4] Channon, M.B. et al (2015) Bone 77, 69-74. [5] Gordon, G.W. et al (2014) Leukemia 28, 2112-2115.

Changes in markers of bone formation and resorption in a bed rest model of weightlessness

NASA Technical Reports Server (NTRS)

Lueken, S. A.; Arnaud, S. B.; Taylor, A. K.; Baylink, D. J.

1993-01-01

To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.

Novel antiosteoclastogenic activity of phloretin antagonizing RANKL-induced osteoclast differentiation of murine macrophages.

PubMed

Kim, Jung-Lye; Kang, Min-Kyung; Gong, Ju-Hyun; Park, Sin-Hye; Han, Seon-Young; Kang, Young-Hee

2012-08-01

Bone-remodeling imbalance resulting in more bone resorption than bone formation is known to cause skeletal diseases such as osteoporosis. Phloretin, a natural dihydrochalcone compound largely present in apple peels, possesses antiphotoaging, and antiinflammatory activity. Phloretin inhibited receptor activator of NF-κB ligand (RANKL)-induced formation of multinucleated osteoclasts and diminished bone resorption area produced during the osteoclast differentiation process. It was also found that ≥ 10 μM phloretin reduced RANKL-enhanced tartrate-resistance acid phosphatase activity and matrix metalloproteinase-9 secretion in a dose-dependent manner. The phloretin treatment retarded RANKL-induced expression of carbonic anhydrase II, vacuolar-type H(+) -ATPase D2 and β3 integrin, all involved in the bone resorption. Furthermore, submicromolar phloretin diminished the expression and secretion of cathepsin K elevated by RANKL, being concurrent with inhibition of TRAF6 induction and NF-κB activation. RANKL-induced activation of nuclear factor of activated T cells c1 (NFATc1) and microphthalmia-associated transcription factor was also suppressed by phloretin. These results demonstrate that the inhibition of osteoclast differentiation and bone resorption by phloretin entail a disturbance of TRAF6-NFATc1-NF-κB pathway triggered by RANKL. Therefore, phloretin may be a potential therapeutic agent targeting osteoclast differentiation and bone resorption in skeletal diseases such as osteoporosis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Long-term effects of local pretreatment with alendronate on healing of replanted rat teeth.

PubMed

Komatsu, K; Shimada, A; Shibata, T; Shimoda, S; Oida, S; Kawasaki, K; Nifuji, A

2008-04-01

Our previous study showed that topical alendronate, an inhibitor of bone resorption, reduces root resorption and ankylosis for 21 d after replantation of rat teeth. The aim of the present study was to evaluate the long-term inhibitory effects of topical alendronate in the replanted teeth. The rat maxillary first molars were extracted, placed in saline containing 1 mm alendronate (alendronate group) or saline (saline group) for 5 min and then replanted. The maxillae were dissected at 60 and 120 d. Microcomputed tomography horizontal sections at three root levels were analyzed for root and bone resorption, ankylosis and pulp mineralization. In the alendronate group at 60 and 120 d, the frequencies of resorption of roots and bone were lower than those in the saline group. The p values show statistical significances of lower frequencies in the alendronate group than in the saline group by chi-square test (see Table 1). Ankylosis and pulp mineralization occurred in the alendronate and saline groups. Bone marrow spaces were narrowed in conjunction with bone tissue expansion around the replanted teeth in the alendronate group. The inhibitory effects of topical alendronate were retained on root and bone resorption, but not on ankylosis and pulp mineralization, in the replanted teeth for 4 mo. Alendronate might also stimulate bone formation around the rat replanted teeth.

Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis.

PubMed

Yamaguchi, Masayoshi

2006-11-01

Aging induces a decrease in bone mass, and osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public health problem. Bone loss with increasing age may be due to decreased bone formation and increased bone resorption. Pharmacologic and nutritional factors may prevent bone loss with aging, although chemical compounds in food and plants which act on bone metabolism are poorly understood. We have found that isoflavones (including genistein and daidzein), which are contained in soybeans, have a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption, thereby increasing bone mass. Menaquinone-7, an analogue of vitamin K(2) which is abundant in fermented soybeans, has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption. Of various carotenoids, beta-cryptoxanthin, which is abundant in Satsuma mandarin (Citrus unchiu MARC), has a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption. The supplementation of these factors has a preventive effect on bone loss induced by ovariectomy in rats, which are an animal model of osteoporosis, and their intake has been shown to have a stimulatory effect on bone mass in humans. Factors with an anabolic effect on bone metabolism were found in extracts obtained from wasabi leafstalk (Wasabi japonica MATSUM), the marine alga Sargassum horneri, and bee pollen Cistus ladaniferus. Phytocomponent p-hydroxycinnamic acid was also found to have an anabolic effect on bone metabolism. Food chemical factors thus play a role in bone health and may be important in the prevention of bone loss with increasing age.

Sanguiin H-6, a constituent of Rubus parvifolius L., inhibits receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorption in vitro and prevents tumor necrosis factor-α-induced osteoclast formation in vivo.

PubMed

Sakai, Eiko; Aoki, Yuri; Yoshimatsu, Masako; Nishishita, Kazuhisa; Iwatake, Mayumi; Fukuma, Yutaka; Okamoto, Kuniaki; Tanaka, Takashi; Tsukuba, Takayuki

2016-07-15

Osteoclasts are multinucleated bone-resorbing cells that differentiate in response to receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). Enhanced osteoclastogenesis contributes to bone diseases, such as osteoporosis and rheumatoid arthritis. Rubus parvifolius L. is traditionally used as an herbal medicine for rheumatism; however, its detailed chemical composition and the molecular mechanisms responsible for its biological action have not been elucidated. To investigate the mechanisms by which R. parvifolius L. extract and its major constituent sanguiin H-6, inhibit osteoclastogenesis and bone resorption. Cell proliferation, cell differentiation, and bone resorption were detected in vitro. Inhibition of signaling pathways, marker protein expression, and protein nuclear translocation were evaluated by western blot analysis. Tumor necrosis factor-α (TNF-α)-mediated osteoclastogenesis was examined in vivo. R. parvifolius L. extract inhibited the bone-resorption activity of osteoclasts. In addition, sanguiin H-6 markedly inhibited RANKL-induced osteoclast differentiation and bone resorption, reduced reactive oxygen species production, and inhibited the phosphorylation of inhibitor of NF-κB alpha (IκBα) and p38 mitogen-activated protein kinase. Sanguiin H-6 also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), cathepsin K, and c-Src. Moreover, sanguiin H-6 inhibited the nuclear translocation of NFATc1, c-Fos, and NF-κB in vitro, as well as TNF-α-mediated osteoclastogenesis in vivo. Our data revealed that R. parvifolius L. has anti-bone resorption activity and suggest that its constituent, sanguiin H-6, can potentially be used for the prevention and treatment of bone diseases associated with excessive osteoclast formation and subsequent bone destruction. Copyright © 2016 Elsevier GmbH. All rights reserved.

A study of changes in bone metabolism in cases of gender identity disorder.

PubMed

Miyajima, Tsuyoshi; Kim, Yoon Taek; Oda, Hiromi

2012-07-01

The aim of this study was to determine the effect of increasing estrogen and decreasing androgen in males and increasing androgen and decreasing estrogen in females on bone metabolism in patients with gender identity disorder (GID). We measured and examined bone mineral density (BMD) and bone metabolism markers retrospectively in GID patients who were treated in our hospital. In addition, we studied the effects of treatment on those who had osteoporosis. Patients who underwent a change from male to female (MtF) showed inhibition of bone resorption and increased L2-4 BMD whereas those who underwent a change from female to male (FtM) had increased bone resorption and decreased L2-4 BMD. Six months after administration of risedronate to FtM patients with osteoporosis, L2-4 BMD increased and bone resorption markers decreased. These results indicate that estrogen is an important element with regard to bone metabolism in males.

Bone histomorphometry in de novo renal transplant recipients indicates a further decline in bone resorption 1 year posttransplantation.

PubMed

Evenepoel, Pieter; Behets, Geert J; Viaene, Liesbeth; D'Haese, Patrick C

2017-02-01

Renal transplantation is believed to have a major impact on bone health. The present prospective observational bone biopsy study aimed to define the natural history of bone histomorphometry parameters in contemporaneous de novo renal transplant recipients. Paired bone biopsies were performed at the time of transplantation and at one-year posttransplantation in an unselected cohort of 36 patients referred for deceased kidney replacement. Parameters of mineral metabolism and circulating bone turnover markers were monitored as well. Static parameters of bone formation and especially bone resorption being already low-normal in the majority of patients at the time of renal transplantation, further declined during the first posttransplant year. However, interindividual variation was substantial, and significance was reached only for bone resorption parameters. Bone mineralization and trabecular bone volume were within the normal range at the time of transplantation (83.3% and 91.7% of graft recipients, respectively) and showed little change one-year posttransplantation. Changes in osteoclast number were paralleled by changes in circulating tartrate-resistant acid phosphatase 5b levels. Finally, cumulative glucocorticoid dose, but not the posttransplantation parathyroid hormone level, associated with trabecular bone loss. Thus, the impact of renal transplantation on bone histomorphometry is limited with only bone resorption, being already low at the time of transplantation, showing a further decline. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression.

PubMed

Siebelt, M; Waarsing, J H; Groen, H C; Müller, C; Koelewijn, S J; de Blois, E; Verhaar, J A N; de Jong, M; Weinans, H

2014-09-01

Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12weeks with in vivo μCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12weeks with ex vivo contrast enhanced μCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness. ALN treatment successfully inhibited subchondral bone remodeling. As a result we found less subchondral plate porosity and reduced osteophytosis. ALN treatment did not reduce subchondral sclerosis. However, after the OA induction phase, ALN treatment protected cartilage ECM from degradation and reduced synovial macrophage activation. Surprisingly, ALN treatment also improved sGAG content of tibia cartilage in healthy joints. Our data was consistent with the hypothesis that osteoclastic bone resorption might play an important role in OA and may be a driving force for progression of the disease. However, our study suggest that this effect might not solely be effects on osteoclastic activity, since ALN treatment also influenced macrophage functioning. Additionally, ALN treatment and physical activity exercised a positive effect in healthy control joints, which increased cartilage sGAG content. More research on this topic might lead to novel insights as to improve cartilage quality. Copyright © 2014 Elsevier Inc. All rights reserved.

Differences in responses to X-ray exposure between osteoclast and osteoblast cells

PubMed Central

Zhang, Jian; Wang, Ziyang; Wu, Anqing; Nie, Jing; Pei, Hailong; Hu, Wentao; Wang, Bing; Shang, Peng; Li, Bingyan

2017-01-01

Abstract Radiation-induced bone loss is a potential health concern for cancer patients undergoing radiotherapy. Enhanced bone resorption by osteoclasts and decreased bone formation by osteoblasts were thought to be the main reasons. In this study, we showed that both pre-differentiating and differentiating osteoclasts were relatively sensitive to X-rays compared with osteoblasts. X-rays decreased cell viability to a greater degree in RAW264.7 cells and in differentiating cells than than in osteoblastic MC3T3-E1 cells. X-rays at up to 8 Gy had little effects on osteoblast mineralization. In contrast, X-rays at 1 Gy induced enhanced osteoclastogenesis by enhanced cell fusion, but had no effects on bone resorption. A higher dose of X-rays at 8 Gy, however, had an inhibitory effect on bone resorption. In addition, actin ring formation was disrupted by 8 Gy of X-rays and reorganized into clusters. An increased activity of Caspase 3 was found after X-ray exposure. Actin disorganization and increased apoptosis may be the potential effects of X-rays at high doses, by inhibiting osteoclast differentiation. Taken together, our data indicate high radiosensitivity of osteoclasts. X-ray irradiation at relatively low doses can activate osteoclastogenesis, but not osteogenic differentiation. The radiosensitive osteoclasts are the potentially responsive cells for X-ray-induced bone loss. PMID:28541506

Basic research and clinical application of beta-tricalcium phosphate (β-TCP).

PubMed

Tanaka, T; Komaki, H; Chazono, M; Kitasato, S; Kakuta, A; Akiyama, S; Marumo, K

2017-09-01

The mechanism of bone substitute resorption involves two processes: solution-mediated and cell-mediated disintegration. In our previous animal studies, the main resorption process of beta-tricalcium phosphate (β-TCP) was considered to be cell-mediated disintegration by TRAP-positive cells. Thus, osteoclast-mediated resorption of β-TCP is important for enabling bone formation. We also report the results of treatment with β-TCP graft in patients since 1989. Two to three weeks after implantation, resorption of β-TCP occurred from the periphery, and then continued toward the center over time. Complete or nearly complete bone healing was achieved in most cases within a few years and was dependent upon the amount of implanted material, the patient's age, and the type of bone (cortical or cancellous). We have previously reported that an injectable complex of β-TCP granules and collagen supplemented with rhFGF-2 enabled cortical bone regeneration of rabbit tibiae. Based on the experimental results, we applied this technique to the patients with femoral and humeral fractures in elderly patients, and obtained bone union. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

OSTEOCLAST-INDUCED FOXP3+ CD8 T-CELLS LIMIT BONE LOSS IN MICE

PubMed Central

Buchwald, Zachary S.; Kiesel, Jennifer R.; Yang, Chang; DiPaolo, Richard; Novack, Deborah V.; Aurora, Rajeev

2014-01-01

Osteoimmunology is the crosstalk between the skeletal and immune system. We have previously shown in vitro that osteoclasts (OC) crosspresent antigens to induce FoxP3 in CD8 T-cells (OCiTcREG), which then suppress osteoclast activity. Here we assessed the ability of OC-iTcREG to limit bone resorption in vivo. Mice lacking CD8 T-cells lose more bone in response to RANKL (Tnfsf11) administration. Using adoptive transfer experiments we demonstrate that FoxP3+ CD8 T-cells limit bone loss by RANKL administration. In ovariectomized mice, a murine model of postmenopausal osteoporosis, OC-iTcREG limited bone loss and increased bone density as assessed by serum markers, micro computed tomography (μCT) and histomorphometry. Indeed, OC-iTcREG—treated ovariectomized mice had decreased levels of effector T-cells in the bone marrow compared to untreated mice, and increased bone formation rates relative to bisphosphonate-treated mice. Our results provide the first in vivo evidence that OC-iTcREG have anti-resorptive activity and repress the immune system, thus extending the purview of osteoimmunology. PMID:23756229

Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang

Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiationmore » and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases.« less

Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com; O'Shea, Patrick J.; Fagura, Malbinder

Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitorsmore » caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis and mineralisation produced by GSK-3 inhibition. • In rats, 3 GSK-3 inhibitors produced a unique serum bone turnover biomarker profile. • Enhanced bone formation was seen within 7 to 14 days of compound treatment in rats.« less

Rapidly Assessing Changes in Bone Mineral Balance Using Natural Stable Calcium Isotopes

NASA Technical Reports Server (NTRS)

Morgan, J. L. L.; Gordon, G. W.; Romaniello, S. J.; Skulan, J. L.; Smith, S. M.; Anbar, A. D.

2011-01-01

We demonstrate that variations in the Ca isotope ratios in urine rapidly and quantitatively reflect changes in bone mineral balance. This variation occurs because bone formation depletes soft tissue of light Ca isotopes, while bone resorption releases that isotopically light Ca back into soft tissue. In a study of 12 individuals confined to bed rest, a condition known to induce bone resorption, we show that Ca isotope ratios shift in a direction consistent with net bone loss after just 7 days, long before detectible changes in bone density occur. Consistent with this interpretation, the Ca isotope variations track changes observed in N-teleopeptide, a bone resorption biomarker, while bone-specific alkaline phosphatase, a bone formation biomarker, is unchanged. Ca isotopes can in principle be used to quantify net changes in bone mass. Ca isotopes indicate an average loss of 0.62 +/- 0.16 % in bone mass over the course of this 30-day study. The Ca isotope technique should accelerate the pace of discovery of new treatments for bone disease and provide novel insights into the dynamics of bone metabolism.

Relationship between serum leptin concentrations and bone mineral density as well as biochemical markers of bone turnover in women with postmenopausal osteoporosis.

PubMed

Shaarawy, Mohamed; Abassi, Asmaa Farid; Hassan, Hany; Salem, Mahmoud E

2003-04-01

To determine whether leptin is involved in bone remodeling in patients with postmenopausal osteoporosis. Cross-sectional study. Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University. Ninety postmenopausal osteoporotic women (37 obese and 53 nonobese) and 30 healthy premenopausal women from the same clinic served as controls. Lumbar spine bone mineral density (LS-BMD) of osteoporotic patients was more than 2.5 SD below the normal mean of healthy premenopausal women. Serum levels of leptin, osteocalcin (OC), bone alkaline phosphatase (B-ALP), urinary deoxypyridinoline (DPyr), and N-telopeptide of type 1 collagen (NTX) as well as LS-BMD using dual energy X-ray absorptiometry (DEXA). The serum leptin level in obese postmenopausal osteoporotic patients was significantly increased compared with nonobese osteoporotic patients. There were no significant differences of bone formation markers (B-ALP, OC), bone resorption markers (DPyr, NTX), or LS-BMD between the obese and nonobese groups. There were no significant correlations between serum leptin and any biomarkers of bone turnover and BMD. In postmenopausal osteoporotic patients with increased bone turnover, serum leptin concentration is not correlated with BMD or with the biomarkers of bone formation or bone resorption.

Bone metastasis target redox-responsive micell for the treatment of lung cancer bone metastasis and anti-bone resorption.

PubMed

Ye, Wei-Liang; Zhao, Yi-Pu; Cheng, Ying; Liu, Dao-Zhou; Cui, Han; Liu, Miao; Zhang, Bang-Le; Mei, Qi-Bing; Zhou, Si-Yuan

2018-01-16

In order to inhibit the growth of lung cancer bone metastasis and reduce the bone resorption at bone metastasis sites, a bone metastasis target micelle DOX@DBMs-ALN was prepared. The size and the zeta potential of DOX@DBNs-ALN were about 60 nm and -15 mV, respectively. DOX@DBMs-ALN exhibited high binding affinity with hydroxyapatite and released DOX in redox-responsive manner. DOX@DBMs-ALN was effectively up taken by A549 cells and delivered DOX to the nucleus of A549 cells, which resulted in strong cytotoxicity on A549 cells. The in vivo experimental results indicated that DOX@DBMs-ALN specifically delivered DOX to bone metastasis site and obviously prolonged the retention time of DOX in bone metastasis site. Moreover, DOX@DBMs-ALN not only significantly inhibited the growth of bone metastasis tumour but also obviously reduced the bone resorption at bone metastasis sites without causing marked systemic toxicity. Thus, DOX@DBMs-ALN has great potential in the treatment of lung cancer bone metastasis.

Smad4 is required to inhibit osteoclastogenesis and maintain bone mass.

PubMed

Morita, Mayu; Yoshida, Shigeyuki; Iwasaki, Ryotaro; Yasui, Tetsuro; Sato, Yuiko; Kobayashi, Tami; Watanabe, Ryuichi; Oike, Takatsugu; Miyamoto, Kana; Takami, Masamichi; Ozato, Keiko; Deng, Chu-Xia; Aburatani, Hiroyuki; Tanaka, Sakae; Yoshimura, Akihiko; Toyama, Yoshiaki; Matsumoto, Morio; Nakamura, Masaya; Kawana, Hiromasa; Nakagawa, Taneaki; Miyamoto, Takeshi

2016-10-12

Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFβs inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFβ1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGFβ1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGFβ1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGFβ1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption.

Increased bone density in mice lacking the proton receptor, OGR1

PubMed Central

Krieger, Nancy S.; Yao, Zhenqiang; Kyker-Snowman, Kelly; Kim, Min Ho; Boyce, Brendan F.; Bushinsky, David A.

2016-01-01

Chronic metabolic acidosis stimulates cell-mediated calcium efflux from bone through osteoblastic prostaglandin E2-induced stimulation of RANKL leading to increased osteoclastic bone resorption. Osteoblasts express the proton-sensing G-protein coupled receptor, OGR1, which activates IP3-mediated intracellular calcium. Proton-induced osteoblastic intracellular calcium signaling requires OGR1, suggesting OGR1 is the sensor activated during acidosis to cause bone resorption. Growing mice produce large amounts of metabolic acids which must be buffered, primarily by bone, prior to excretion by the kidney. Here we tested whether lack of OGR1 inhibits proton-induced bone resorption by measuring bone mineral density by μCT and histomorphometry in 8 week old male OGR1−/− and C57/Bl6 wild type mice. OGR1−/− mice have normal skeletal development with no atypical gross phenotype. Trabecular and cortical bone volume was increased in tibiae and vertebrae from OGR1−/−. There were increased osteoblast numbers on the cortical and trabecular surfaces of tibiae from OGR1−/− mice, increased endocortical and trabecular bone formation rates, and osteoblastic gene expression. Osteoclast numbers and surface were increased in tibiae of OGR1−/− mice. Thus, in rapidly growing mice, lack of OGR1 leads to increased bone mass with increased bone turnover and a greater increase in bone formation than resorption. This supports the important role of the proton receptor, OGR1, in the response of bone to protons. PMID:26880453

Circulating osteoprotegerin and sRANKL concentrations in the perinatal period at term. The impact of intrauterine growth restriction.

PubMed

Briana, Despina D; Boutsikou, Maria; Baka, Stavroula; Hassiakos, Demetrios; Gourgiotis, Demetrios; Malamitsi-Puchner, Ariadne

2009-01-01

Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are main determinants of bone resorption. To investigate OPG and soluble RANKL (sRANKL) concentrations in maternal, fetal and neonatal serum of IUGR patients and appropriate for gestational age (AGA) pregnancies. Additionally, plasma intact parathormone (PTH) concentrations were evaluated. Circulating OPG, sRANKL and PTH concentrations were measured in 40 mothers and their singleton full-term fetuses-neonates (AGA: n = 20, and IUGR: n =20) on postnatal days 1 (N1) and 4 (N4). No significant differences in OPG, sRANKL or PTH concentrations were observed between AGA and IUGR groups. In both groups, maternal OPG concentrations were elevated compared with fetal, and N1 and N4 concentrations (p < or = 0.045 in all cases). N4 sRANKL concentrations were elevated compared with maternal, fetal and N1 ones (p < or = 0.01 in all cases). Fetal and N1 sRANKL concentrations correlated positively with PTH levels (r = 0.642, p = 0.024 and r = 0.584, p = 0.046, respectively). The lack of a difference in circulating OPG, sRANKL or PTH concentrations between IUGR cases and AGA controls suggests that the low bone mass of IUGR infants may not be related to higher bone resorption rates. The increased maternal, compared with fetal/neonatal, OPG concentrations may suggest their placental origin. The lower OPG and higher sRANKL concentrations in fetuses and neonates could represent high bone resorption rates. Copyright 2009 S. Karger AG, Basel.

Inhibition of osteoclast bone resorption activity through osteoprotegerin-induced damage of the sealing zone.

PubMed

Song, Ruilong; Gu, Jianhong; Liu, Xuezhong; Zhu, Jiaqiao; Wang, Qichao; Gao, Qian; Zhang, Jiaming; Cheng, Laiyang; Tong, Xishuai; Qi, Xinyi; Yuan, Yan; Liu, Zongping

2014-09-01

Bone remodeling is dependent on the dynamic equilibrium between osteoclast-mediated bone resorption and osteoblast-mediated osteogenesis. The sealing zone is an osteoclast-specific cytoskeletal structure, the integrity of which is critical for osteoclast-mediated bone resorption. To date, studies have focused mainly on the osteoprotegerin (OPG)‑induced inhibition of osteoclast differentiation through the OPG/receptor activator of the nuclear factor kappa-B ligand (RANKL)/RANK system, which affects the bone resorption of osteoclasts. However, the effects of OPG on the sealing zone have not been reported to date. In this study, the formation of the sealing zone was observed by Hoffman modulation contrast (HMC) microscopy and confocal laser scanning microscopy. The effects of OPG on the existing sealing zone and osteoclast-mediated bone resorption activity, as well as the regulatory role of genes involved in the formation of the sealing zone were examined by immunofluorescence staining, HMC microscopy, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blot analysis and scanning electron microscopy. The sealing zone was formed on day 5, with belt-like protuberances at the cell edge and scattered distribution of cell nuclei, but no filopodia. The sealing zone was intact in the untreated control group. However, defects in the sealing zone were observed in the OPG-treated group (20 ng/ml) and the structure was absent in the groups treated with 40 and 80 ng/ml OPG. The podosomes showed a scattered or clustered distribution between the basal surface of the osteoclasts and the well surface. Furthermore, resorption lacunae were not detected in the 20 ng/ml OPG-treated group, indicating the loss of osteoclast-mediated bone resorption activity. Treatment with OPG resulted in a significant decrease in the expression of Arhgef8/Net1 and DOCK5 Rho guanine nucleotide exchange factors (RhoGEFs), 10 of 18 RhoGTPases (RhoA, RhoB, cdc42v1, cdc42v2, RhoU/Wrch1, RhoF/Rif, Rac2, RhoG, Rnd1 and RhoBTB1), ROCK1 and ROCK2. In conclusion, podosome distribution was affected by the OPG-induced inhibition of the expression of genes in the RhoGTPase signaling pathway. This resulted in damage to or destruction of the sealing zone, thus inhibiting osteoclast-mediated bone resorption activity.

Bone augmentation of the osteo-odonto alveolar lamina in MOOKP--will it delay laminar resorption?

PubMed

Iyer, Geetha; Srinivasan, Bhaskar; Agarwal, Shweta; Rishi, Ekta; Rishi, Pukhraj; Rajan, Gunaseelan; Shanmugasundaram, Shanmugasundaram

2015-07-01

We aimed to describe a new technique and analyse the early outcomes of augmenting the canine tooth using a mandibular bone graft in an attempt to delay or retard the process of laminar resorption following the modified osteo odonto keratoprosthesis (MOOKP) procedure. This was a retrospective case series. Eyes that underwent the bone augmentation procedure between December 2012 and February 2014 were retrospectively analysed. The procedure, performed by the oromaxillofacial surgeon, involved securing a mandibular bone graft beneath the periosteum on the labial aspect of the canine tooth chosen to be harvested for the MOOKP procedure. This procedure was performed simultaneously with the Stage 1 A of the MOOKP. Three months later, the tooth was harvested and fashioned into the osteo-odonto alveolar lamina similar to the method described in the Rome-Vienna Protocol. The bone augmentation procedure was performed in 11 eyes (five SJS/ six chemical injuries). The mean follow-up after Stage 2 of MOOKP procedure in these eyes was 7.45 months (2 to 20 months). Complications noted were peripheral laminar exposure (three eyes-SJS) and bone graft exposure and necrosis in the mouth (nine-SJS). No evidence of clinical laminar resorption was noted in any of the eyes. Laminar resorption in MOOKP can lead to vision and globe threatening complications due to the consequent cylinder instability and chances of extrusion. Augmenting the bone on the labial aspect of the canine tooth might have a role to play in delaying or preventing laminar resorption.

Tibial plateau fracture after anterior cruciate ligament reconstruction: Role of the interference screw resorption in the stress riser effect.

PubMed

Thaunat, Mathieu; Nourissat, Geoffroy; Gaudin, Pascal; Beaufils, Philippe

2006-06-01

We report a case of tibial plateau fracture after previous anterior cruciate ligament (ACL) reconstruction using patellar tendon autograft and bioabsorbable screws 4 years previously. The fracture occurred through the tibial tunnel. The interference screw had undergone complete resorption and the tunnel widening had increased. The resorption of the interference screw did not simultaneously promote and foster the growth of surrounding bone tissue. Therefore, the area of reactive tissue left by the screw resorption in an enlarged bone tunnel may lead to vulnerability of the tibial plateau. Stress risers would occur following ACL reconstruction if either resorption is not complete or bony integration is not complete.

Grizzly bears (Ursus arctos horribilis) and black bears (Ursus americanus) prevent trabecular bone loss during disuse (hibernation).

PubMed

McGee-Lawrence, Meghan E; Wojda, Samantha J; Barlow, Lindsay N; Drummer, Thomas D; Castillo, Alesha B; Kennedy, Oran; Condon, Keith W; Auger, Janene; Black, Hal L; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

2009-12-01

Disuse typically causes an imbalance in bone formation and bone resorption, leading to losses of cortical and trabecular bone. In contrast, bears maintain balanced intracortical remodeling and prevent cortical bone loss during disuse (hibernation). Trabecular bone, however, is more detrimentally affected than cortical bone in other animal models of disuse. Here we investigated the effects of hibernation on bone remodeling, architectural properties, and mineral density of grizzly bear (Ursus arctos horribilis) and black bear (Ursus americanus) trabecular bone in several skeletal locations. There were no differences in bone volume fraction or tissue mineral density between hibernating and active bears or between pre- and post-hibernation bears in the ilium, distal femur, or calcaneus. Though indices of cellular activity level (mineral apposition rate, osteoid thickness) decreased, trabecular bone resorption and formation indices remained balanced in hibernating grizzly bears. These data suggest that bears prevent bone loss during disuse by maintaining a balance between bone formation and bone resorption, which consequently preserves bone structure and strength. Further investigation of bone metabolism in hibernating bears may lead to the translation of mechanisms preventing disuse-induced bone loss in bears into novel treatments for osteoporosis.

Grizzly bears (Ursus arctos horribilis) and black bears (Ursus americanus) prevent trabecular bone loss during disuse (hibernation)

PubMed Central

McGee-Lawrence, Meghan E.; Wojda, Samantha J.; Barlow, Lindsay N.; Drummer, Thomas D.; Castillo, Alesha B.; Kennedy, Oran; Condon, Keith W.; Auger, Janene; Black, Hal L.; Nelson, O. Lynne; Robbins, Charles T.; Donahue, Seth W.

2009-01-01

Disuse typically causes an imbalance in bone formation and bone resorption, leading to losses of cortical and trabecular bone. In contrast, bears maintain balanced intracortical remodeling and prevent cortical bone loss during disuse (hibernation). Trabecular bone, however, is more detrimentally affected than cortical bone in other animal models of disuse. Here we investigated the effects of hibernation on bone remodeling, architectural properties, and mineral density of grizzly bear (Ursus arctos horribilis) and black bear (Ursus americanus) trabecular bone in several skeletal locations. There were no differences in bone volume fraction or tissue mineral density between hibernating and active bears or between pre- and post-hibernation bears in the ilium, distal femur, or calcaneus. Though indices of cellular activity level (mineral apposition rate, osteoid thickness) decreased, trabecular bone resorption and formation indices remained balanced in hibernating grizzly bears. These data suggest that bears prevent bone loss during disuse by maintaining a balance between bone formation and bone resorption, which consequently preserves bone structure and strength. Further investigation of bone metabolism in hibernating bears may lead to the translation of mechanisms preventing disuse induced bone loss in bears into novel treatments for osteoporosis. PMID:19703606

Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice.

PubMed

Matsumoto, Shigeru; Tominari, Tsukasa; Matsumoto, Chiho; Yoshinouchi, Shosei; Ichimaru, Ryota; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2018-01-20

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.

Reduction of Dietary Acid Load as a Potential Countermeasure for Bone Loss Associated with Spaceflight

NASA Technical Reports Server (NTRS)

Zwart, S. R.; Watts, S. M.; Sams, C. F.; Whitson, P. A.; Smith, S. M.

2006-01-01

In several studies we tested the concepts that diet can alter acid-base balance and that reducing the dietary acid load has a positive effect on maintenance of bone. In study 1, (n = 11, 60-90 d bed rest), the renal acid load of the diet was estimated from its chemical composition, and was positively correlated with urinary markers of bone resorption (P less than 0.05); that is, the greater the acid load, the greater the excretion of bone resorption markers. In study 2, in males (n = 8, 30 d bed rest), an estimate of the ratio of nonvolatile acid precursors to base precursors in the diet was positively correlated (P less than 0.05) with markers of bone resorption. In study 3, for 28 d subjects received either a placebo (n = 6) or an essential amino acid supplement (n = 7) that included methionine, a known acid precursor. During bed rest (28 d), urinary calcium was greater than baseline levels in the supplemented group but not the control group (P less than 0.05), and in the supplemented group, urinary pH decreased (P less than 0.05). In study 4, less bone resorption occurred in space crew members who received potassium citrate (n = 6) during spaceflight of 4-6 months than in crew members who received placebo or were not in the study (n = 8) (P less than 0.05). Reducing acid load has the potential to mitigate increased bone resorption during spaceflight, and may serve as a bone loss countermeasure.

MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover - a systematic review and meta-analysis.

PubMed

Hygum, Katrine; Starup-Linde, Jakob; Harsløf, Torben; Vestergaard, Peter; Langdahl, Bente L

2017-03-01

To investigate the differences in bone turnover between diabetic patients and controls. A systematic review and meta-analysis. A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers. A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (-0.10 ng/mL (-0.12, -0.08)) and the bone formation markers osteocalcin (-2.51 ng/mL (-3.01, -2.01)) and procollagen type 1 amino terminal propeptide (-10.80 ng/mL (-12.83, -8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (-0.31 U/L (-0.56, -0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)). Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this. © 2017 European Society of Endocrinology.

Activity restriction increases deoxypyridinoline excretion in hospitalized high-risk pregnant women.

PubMed

Vanderspank, Dana; Bernier, Suzanne M; Sopper, Maggie M; Watson, Patricia; Mottola, Michelle F

2014-01-01

Activity restriction (AR), one of the most common interventions used in high-risk pregnancies, may exacerbate loss of bone mass. The purpose of this study was to determine changes over time in bone resorption in hospitalized AR women during late pregnancy. This was a short-term prospective study conducted in two tertiary-care obstetric hospitals. We measured urinary deoxypyridinoline (Dpd) excretion, a marker of bone resorption, once per week in a convenience sample of 14 hospitalized AR women in the third trimester and compared values at 28-31 and 34-36 weeks' gestation to those of 11 ambulatory control women. Both groups completed a bone-loading questionnaire, 3-day food intake record, and pedometer step counts at the same gestational age. Urinary Dpd excretion increased from Days 1-7 (2.60 ± 0.32 nmol/mmol creatinine) to Days 22-28 (5.36 ± 0.83 nmol/mmol creatinine; p ≤ .05). Dpd excretion was higher in AR women (4.51 ± 0.31 nmol/mmol creatinine) than ambulatory women (2.72 ± 0.39 nmol/mmol creatinine) at 34-36 weeks' gestation (p ≤ .05). Energy intake between ambulatory and AR women was not different (p ≥ .05). All women met the daily requirements for calcium and vitamin D intake during pregnancy. Average daily pedometer steps for the AR women were significantly less compared to controls (1,329 ± 936 and 8,024 ± 1,890 steps/day, respectively; p ≤ .05). AR leads to increased bone resorption in hospitalized pregnant women, which may impact future risk of developing osteopenia and osteoporosis.

Eldecalcitol improves mechanical strength of cortical bones by stimulating the periosteal bone formation in the senescence-accelerated SAM/P6 mice - a comparison with alfacalcidol.

PubMed

Shiraishi, Ayako; Sakai, Sadaoki; Saito, Hitoshi; Takahashi, Fumiaki

2014-10-01

Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25(OH)2D3, is a potent inhibitor of bone resorption that has demonstrated a greater effect at reducing the risk of fracture in osteoporotic patients than alfacalcidol (ALF). In the present study, we used the senescence-accelerated mouse strain P6 (SAM/P6), which has low bone mass caused by osteoblast dysfunction, to evaluate the effect of ELD on cortical bone in comparison with ALF. Four-month-old SAM/P6 mice were given either ELD (0.025 or 0.05μg/kg) or ALF (0.2 or 0.4μg/kg) by oral gavage 5 times/week for 6 weeks. Both ELD and ALF increased serum calcium (Ca) in a dose-dependent manner. Serum Ca levels in the ELD 0.05μg/kg group were comparable to those of the ALF 0.2μg/kg group. ELD 0.05μg/kg significantly improved the bone biomechanical properties of the femur compared with the vehicle control group (p<0.001) and the ALF 0.2μg/kg group (p<0.05) evaluated by 3-point bending test. The cortical area of the mid-femur in the ELD 0.05μg/kg group but not the ALF 0.2μg/kg group was significantly higher than those of the vehicle control group (p<0.001). Bone histomorphometry revealed that in the femoral endocortical surface, the suppression of bone resorption parameters (N.Oc/BS) and bone formation parameters (MS/BS) by ELD (0.05μg/kg) was greater than that by ALF (0.2μg/kg). In contrast, in the femoral periosteal surface, ELD 0.05μg/kg significantly increased bone formation parameters (BFR/BS, MS/BS) compared with the vehicle control group (p<0.05, p<0.01, respectively), whereas ALF 0.2μg/kg did not alter these parameters. These results indicate that ELD improved the biomechanical properties of femoral cortical bone not only by inhibiting endocortical bone resorption but also by stimulating the periosteal bone formation in SAM/P6 mice. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Does the cortical bone resorption rate change due to 90Sr-radiation exposure? Analysis of data from Techa Riverside residents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tolstykh, E I; Shagina, N B; Degteva, M O

2011-08-01

The Mayak Production Association released large amounts of 90Sr into the Techa River (Southern Urals, Russia) with peak amounts in 1950-1951. Techa Riverside residents ingested an average of about 3,000 kBq of 90Sr. The 90Sr-body burden of approximately 15,000 individuals has been measured in the Urals Research Center for Radiation Medicine in 1974-1997 with use of a special whole-body counter (WBC). Strontium-90 had mainly deposited in the cortical part of the skeleton by 25 years following intake, and 90Sr elimination occurs as a result of cortical bone resorption. The effect of 90Sr-radiation exposure on the rate of cortical bone resorptionmore » was studied. Data on 2,022 WBC measurements were selected for 207 adult persons, who were measured three or more times before they were 50-55 years old. The individual-resorption rates were calculated with the rate of strontium recirculation evaluated as 0.0018 year -1. Individual absorbed doses in red bone marrow (RBM) and bone surface (BS) were also calculated. Statistically significant negative relationships of cortical bone resorption rate were discovered related to 90Sr-body burden and dose absorbed in the RBM or the BS. The response appears to have a threshold of about 1.5-Gy RBM dose. The radiation induced decrease in bone resorption rate may not be significant in terms of health. However, a decrease in bone remodeling rate can be among several causes of an increased level of degenerative dystrophic bone pathology in exposed persons.« less

Peculiarities of the bone tissue resorption under microgravity conditions

NASA Astrophysics Data System (ADS)

Rodionova, N.; Oganov, V.; Polkovenko, O.; Nitsevich, T.

The actual problem - peculiarities of resorptive processes in the spongiose of thingbones - we studied with the use of tranmissive electron microscopy in experiments on rats (American space station SLS-2) and on monkeys Macaca mulatt? (BION-11). Animals were onboard during 2 weeks. There was established, that the resorption happen with osteoclasts participation. They can create groups of cells. In the osteoclasts population we indicated not typical for the control (ground experiment) "giant" cells, which have on ultrathin sections 5-6 nuclei, many lysosomes, well developed "light" zone and "brush-border". The destruction of minera lized matrix in bone lacunas also happens by the way of osteolytic activity of osteocytes. Lysosome ferments of osteocytes are secreted by the eczocytosis. The osteocytic osteolysis, as well as the osteoclastic one can be seen as a physiological, gormon-dependent mechanism of resorption. The presence of a considerable number of neutrophiles, which enter in some zones of resorption is also typical. When these neutrophiles destruct, they release lysosomic ferments that dissolve the bone matrix. In some zones of resorption we noted the presence of the row from collagen fibrils, which loosed crystals , on mineralized matrix borders. The cell detritus is noted in zones of surface dissolving among crystallic conglomerates. It certificates the processes of osteogenic cells destruction that happen here. So, under the microgravity conditions in zones of adaptive remodeling of the spongiose the processes of the bone tissue resorption happen by some ways, namely: by the functional activization of osteoclasts; by the osteocytic osteolysis increasing; as a result of hydrolytic activity of neutrophiles, entering in these zones, and also by the local demineralization and further destruction of bone matrix surface zones.

Hypergravity suppresses bone resorption in ovariectomized rats

NASA Astrophysics Data System (ADS)

Ikawa, Tesshu; Kawaguchi, Amu; Okabe, Takahiro; Ninomiya, Tadashi; Nakamichi, Yuko; Nakamura, Midori; Uehara, Shunsuke; Nakamura, Hiroaki; Udagawa, Nobuyuki; Takahashi, Naoyuki; Nakamura, Hiroaki; Wakitani, Shigeyuki

2011-04-01

The effects of gravity on bone metabolism are unclear, and little has been reported about the effects of hypergravity on the mature skeleton. Since low gravity has been shown to decrease bone volume, we hypothesized that hypergravity increases bone volume. To clarify this hypothesis, adult female rats were ovariectomized and exposed to hypergravity (2.9G) using a centrifugation system. The rats were killed 28 days after the start of loading, and the distal femoral metaphysis of the rats was studied. Bone architecture was assessed by micro-computed tomography (micro-CT) and bone mineral density was measured using peripheral quantitative CT (pQCT). Hypergravity increased the trabecular bone volume of ovariectomized rats. Histomorphometric analyses revealed that hypergravity suppressed both bone formation and resorption and increased bone volume in ovariectomized rats. Further, the cell morphology, activity, proliferation, and differentiation of osteoclasts and osteoblasts exposed to hypergravity were evaluated in vitro. Hypergravity inhibited actin ring formation in mature osteoclasts, which suggested that the osteoclast activity was suppressed. However, hypergravity had no effect on osteoblasts. These results suggest that hypergravity can stimulate an increase in bone volume by suppressing bone resorption in ovariectomized rats.

Vitamin D status and bone turnover in women with acute hip fracture.

PubMed

Nuti, Ranuccio; Martini, Giuseppe; Valenti, Roberto; Gambera, Dario; Gennari, Luigi; Salvadori, Stefania; Avanzati, Annalisa

2004-05-01

Hypovitaminosis D is common in elderly women. Few data are available on vitamin D status and bone turnover in women with acute hip fracture. The aims of this study were to determine whether elderly Italian women with an acute hip fracture also had low vitamin D levels and an increase of bone turnover compared with elderly women with osteoporosis but without fractures. Seventy-four women with acute osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were studied. All women were self-sufficient and had adequate sunlight exposure. To exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen as indices of bone formation and bone resorption), blood samples were drawn within 24 hours of the fracture. Current data indicated that in our patients the prevalence of hypovitaminosis D is common although to a lesser extent than in women who are housebound. Women with acute hip fractures had a higher prevalence of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12 ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture did not influence the rate of bone formation, whereas the increase in bone resorption could be attributed to an older age of women with acute hip fracture because of similar values of parathyroid hormone levels in the two groups.

Various selected vegetables, fruits, mushrooms and red wine residue inhibit bone resorption in rats.

PubMed

Mühlbauer, Roman C; Lozano, Annemarie; Reinli, Andreas; Wetli, Herbert

2003-11-01

To make a broad survey of the effect of components of the human diet on bone resorption, a few items from the following categories were added to rat diets: vegetables, fruits, beans, nuts and seeds, mushrooms, carbohydrate sources and beverages. The effect on bone resorption was measured by the urinary excretion of tritium released from bones of 9-wk-old rats prelabeled with tritiated tetracycline from weeks 1 to 6. The number of rats per experiment was 26--6, 5, 5, 5 and 5 in the untreated control group fed the plain semipurified diet, the positive control group fed onions and three groups fed one of the newly investigated items, respectively. New experiments were added until 10 rats were fed each item in each of two separate experiments. The results for each item were compared to those for the untreated control group (n = 12) investigated simultaneously. We found that feeding rats 1 g/d of dry fennel, celeriac, oranges, prunes, French beans and farmed and wild mushrooms (Agaricus hortensis and Boletus edulis) as well as the freeze-dried residue from red wine significantly (P < 0.05 or lower) inhibited bone resorption. Eighteen items had no significant effect. To date we have found 25/53 items that exhibit inhibitory activity. Activity appears to be restricted to the following categories: vegetables, salads, herbs, mushrooms, fruits and red wine residue (25/36 items effective). Furthermore, as assessed in a similar experimental design with various doses of a mixture of active items, we determined the minimum effective dose of the dry items to be 170 mg/d. These results open the possibility for targeted interventions in humans.

Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair.

PubMed

Paiva, Katiucia B S; Granjeiro, José M

2017-01-01

Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering. © 2017 Elsevier Inc. All rights reserved.

Impact of bone lead and bone resorption on plasma and whole blood lead levels during pregnancy.

PubMed

Téllez-Rojo, Martha María; Hernández-Avila, Mauricio; Lamadrid-Figueroa, Héctor; Smith, Donald; Hernández-Cadena, Leticia; Mercado, Adriana; Aro, Antonio; Schwartz, Joel; Hu, Howard

2004-10-01

The authors tested the hypotheses that maternal bone lead burden is associated with increasing maternal whole blood and plasma lead levels over the course of pregnancy and that this association is modified by rates of maternal bone resorption. A total of 193 Mexican women were evaluated (1997-1999) in the first, second, and third trimesters of pregnancy. Whole blood lead and plasma lead levels were measured in each trimester. Urine was analyzed for cross-linked N-telopeptides (NTx) of type I collagen, a biomarker of bone resorption. Patella and tibia lead levels were measured at 4 weeks postpartum. The relation between whole blood, plasma, and bone lead and NTx was assessed using mixed models. Plasma lead concentrations followed a U-shape, while NTx levels increased significantly during pregnancy. In a multivariate model, the authors observed a significant and positive interaction between NTx and bone lead when plasma lead was used as the outcome variable. Dietary calcium intake was inversely associated with plasma lead. Results for whole blood lead were similar but less pronounced. These results confirm previous evidence that bone resorption increases during pregnancy, with a consequential significant release of lead from bone, constituting an endogenous source of prenatal exposure. They also provide a rationale for testing strategies (e.g., nutritional supplementation with calcium) aimed at decreasing prenatal lead exposure.

Impaired rib bone mass and quality in end-stage cystic fibrosis patients.

PubMed

Mailhot, Geneviève; Dion, Natalie; Farlay, Delphine; Rizzo, Sébastien; Bureau, Nathalie J; Jomphe, Valérie; Sankhe, Safiétou; Boivin, Georges; Lands, Larry C; Ferraro, Pasquale; Ste-Marie, Louis-Georges

2017-05-01

Advancements in research and clinical care have considerably extended the life expectancy of cystic fibrosis (CF) patients. However, with this extended survival come comorbidities. One of the leading co-morbidities is CF-related bone disease (CFBD), which progresses with disease severity and places patients at high risk for fractures, particularly of the ribs and vertebrae. Evidence that CF patients with vertebral fractures had higher bone mineral density (BMD) than the nonfracture group led us to postulate that bone quality is impaired in these patients. We therefore examined rib specimens resected at the time of lung transplant in CF patients to measure parameters of bone quantity and quality. In this exploratory study, we analysed 19 end-stage CF and 13 control rib specimens resected from otherwise healthy lung donors. BMD, bone microarchitecture, static parameters of bone formation and resorption and microcrack density of rib specimens were quantified by imaging, histomorphometric and histological methods. Variables reflecting the mineralization of ribs were assessed by digitized microradiography. The degree of bone mineralization (g/cm 3 ) and the heterogeneity index of the mineralization (g/cm 3 ) were calculated for trabecular and cortical bone. Compared to controls, CF ribs exhibited lower areal and trabecular volumetric BMD, decreased trabecular thickness and osteoid parameters, and increased microcrack density, that was particularly pronounced in specimens from patients with CF-related diabetes. Static parameters of bone resorption were similar in both groups. Degree of mineralization of total bone, but not heterogeneity index, was increased in CF specimens. The combination of reduced bone mass, altered microarchitecture, imbalanced bone remodeling (maintained bone resorption but decreased formation), increased microdamage and a small increase of the degree of mineralization, may lead to decreased bone strength, which, when coupled with chronic coughing and chest physical therapy, may provide an explanation for the increased incidence of rib fractures previously reported in this population. Copyright © 2017 Elsevier Inc. All rights reserved.

Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease.

PubMed

Sato, Yoshihiro; Honda, Yoshiaki; Iwamoto, Jun

2007-03-20

There is a high incidence of hip fractures in patients with Parkinson disease (PD). Bone mineral density (BMD) is decreased in patients with PD, correlating with the immobilization-induced bone resorption and hypovitaminosis D with compensatory hyperparathyroidism. To evaluate the effectiveness of risedronate, an inhibitor of bone resorption, on osteoporosis and the risk of hip fractures in elderly men with PD. This was a 2-year, randomized, double-blind, placebo-controlled trial. In a prospective study of patients with PD, 121 patients received a daily dose of 2.5 mg risedronate and vitamin D2 1,000 IU for 2 years, and the remaining 121 received placebo and vitamin D2 1,000 IU. Incidence of hip fractures was compared between the two groups. Nine patients sustained hip fractures in the placebo group, and three hip fractures occurred in the risedronate group. The relative risk of a hip fracture in the risedronate group vs the placebo group was 0.33 (95% CI, 0.09 to 1.20). BMD increased by 2.2% in the risedronate group and decreased by 2.9% in the placebo group (p < 0.0001). Urinary deoxypyridinoline, a bone resorption marker, decreased by 46.7% in the risedronate group and by 33.0% in the placebo group. Treatment with risedronate and vitamin D2 increases bone mineral density in elderly men with Parkinson disease and reduces the risk of hip fractures.

Histomorphometric Study of New Bone Formation Comparing Defect Healing with Three Bone Grafting Materials: The Effect of Osteoporosis on Graft Consolidation.

PubMed

Zhang, Qiao; Jing, Dai; Zhang, Yufeng; Miron, Richard J

Bone grafting materials are frequently utilized in oral surgery and periodontology to fill bone defects and augment lost or missing bone. The purpose of this study was to compare new bone formation in bone defects created in both normal and osteoporotic animals loaded with three types of bone grafts from different origins. Forty-eight female Wistar rats were equally divided into control normal and ovariectomized animals. Bilateral 2.5-mm femur defects were created and filled with an equal weight of (1) natural bone mineral (NBM, BioOss) of bovine origin, (2) demineralized freeze-dried bone allograft (DFDBA, LifeNet), or (3) biphasic calcium phosphate (BCP, Vivoss). Following 3 and 6 weeks of healing, hematoxylin and eosin and TRAP staining was performed to determine new bone formation, material degradation, and osteoclast activity. All bone substitutes demonstrated osteoconductive potential at 3 and 6 weeks with higher osteoclast numbers observed in all ovariectomized animals. NBM displayed continual new bone formation with little to no sign of particle degradation, even in osteoporotic animals. DFDBA particles showed similar levels of new bone formation but rapid particle degradation rates with lower levels of mineralized tissue. BCP bone grafts demonstrated significantly higher new bone formation when compared with both NBM and DFDBA particles; however, the material was associated with higher osteoclast activity and particle degradation. Interestingly, in osteoporotic animals, BCP displayed synergistically and markedly more rapid rates of particle degradation. Recent modifications to synthetically fabricated materials were shown to be equally or more osteopromotive than NBM and DFDBA. However, the current BCP utilized demonstrated much faster resorption properties in osteoporotic animals associated with a decrease in total bone volume when compared with the slowly/nonresorbing NBM. The results from this study point to the clinical relevance of minimizing fast-resorbing bone grafting materials in osteoporotic phenotypes due to the higher osteoclastic activity and greater material resorption.

Osteoinductive effect of bone bank allografts on human osteoblasts in culture.

PubMed

de la Piedra, Concepción; Vicario, Carlos; de Acuña, Lucrecia Rodríguez; García-Moreno, Carmen; Traba, Maria Luisa; Arlandis, Santiago; Marco, Fernando; López-Durán, Luis

2008-02-01

Incorporation of a human bone allograft requires osteoclast activity and growth of recipient osteoblasts. The aim of this work was to study the effects produced by autoclavated and -80 degrees C frozen bone allografts on osteoblast proliferation and synthesis of interleukin 6 (IL6), activator of bone resorption, aminoterminal propeptide of procollagen I (PINP), marker of bone matrix formation, and osteoprotegerin (OPG), inhibitor of osteoclast activity and differentiation. Allografts were obtained from human femoral heads. Human osteoblasts were cultured in the presence (problem group) or in the absence (control group) of allografts during 15 days. Allografts produced a decrease in osteoblast proliferation in the first week of the experiment, and an increase in IL6 mRNA, both at 3 h and 2 days, and an increase in the IL6 released to the culture medium the second day of the experiment. We found a decrease in OPG released to the culture on the 2nd and fourth days. These results suggest an increase in bone resorption and a decrease in bone formation in the first week of the experiment. In the second week, allografts produced an increase in osteoblast proliferation and PINP release to the culture medium, indicating an increase in bone formation; an increase in OPG released to the culture medium, which would indicate a decrease in bone resorption; and a decrease in IL6, indicating a decrease in bone resorption stimulation. These results demonstrate that autoclavated and -80 degrees C frozen bone allografts produce in bone environment changes that regulate their own incorporation to the recipient bone.

Pharmacological management of osteogenesis

PubMed Central

Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

2014-01-01

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

Role of RANKL in bone diseases.

PubMed

Anandarajah, Allen P

2009-03-01

Bone remodeling is a tightly regulated process of osteoclast-mediated bone resorption, balanced by osteoblast-mediated bone formation. Disruption of this balance can lead to increased bone turnover, resulting in excessive bone loss or extra bone formation and consequent skeletal disease. The receptor activator of nuclear factor kappaB ligand (RANKL) (along with its receptor), the receptor activator of nuclear factor kappaB and its natural decoy receptor, osteoprotegerin, are the final effector proteins of osteoclastic bone resorption. Here, I provide an overview of recent studies that highlight the key role of RANKL in the pathophysiology of several bone diseases and discuss the novel therapeutic approaches afforded by the modulation of RANKL.

iNOS-Derived Nitric Oxide Stimulates Osteoclast Activity and Alveolar Bone Loss in Ligature-Induced Periodontitis in Rats

PubMed Central

Herrera, Bruno S.; Martins-Porto, Rodrigo; Maia-Dantas, Aline; Campi, Paula; Spolidorio, Luis C.; Costa, Soraia K.P.; Van Dyke, Thomas E.; Gyurko, Robert; Muscara, Marcelo N.

2012-01-01

Background Inflammatory stimuli activate inducible nitric oxide synthase (iNOS) in a variety of cell types, including osteoclasts (OC) and osteoblasts, resulting in sustained NO production. In this study, we evaluate the alveolar bone loss in rats with periodontitis under long-term iNOS inhibition, and the differentiation and activity of OC from iNOS-knockout (KO) mice in vitro. Methods Oral aminoguanidine (an iNOS inhibitor) or water treatment was started 2 weeks before induction of periodontitis. Rats were sacrificed 3, 7, or 14 days after ligature placement, and alveolar bone loss was evaluated. In vitro OC culture experiments were also performed to study the differentiation of freshly isolated bone marrow cells from both iNOS KO and wild-type C57BL/6 mice. OC were counted 6 days later after tartrate-resistant acid phosphatase staining (a marker of osteoclast identity), and bone resorption activity was assessed by counting the number of resorption pits on dentin disks. Results Rats with ligature showed progressive and significant alveolar bone loss compared to sham animals, and aminoguanidine treatment significantly inhibited ligature-induced bone loss at 7 and 14 days after the induction. In comparison to bone marrow cells from wild-type mice, cells from iNOS KO mice showed decreased OC growth and the resulting OC covered a smaller culture dish area and generated fewer resorption pit counts. Conclusion Our results demonstrate that iNOS inhibition prevents alveolar bone loss in a rat model of ligature-induced periodontitis, thus confirming that iNOS-derived NO plays a crucial role in the pathogenesis of periodontitis, probably by stimulating OC differentiation and activity. PMID:21417589

Immunolocalization of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in Meckel's cartilage compared with developing endochondral bones in mice

PubMed Central

Sakakura, Yasunori; Tsuruga, Eichi; Irie, Kazuharu; Hosokawa, Yoichiro; Nakamura, Hiroaki; Yajima, Toshiniko

2005-01-01

We examined the immunolocalization of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in areas of resorption caused by osteoclasts/chondroclasts on embryonic days 14–16 (E14–16) in Meckel's cartilage, and compared the results with those in endochondral bones in mice. Intense RANKL and OPG immunoreactivity was detected in the chondrocytes in Meckel's cartilage. On E15, when the incisor teeth were closest to the middle portion of Meckel's cartilage, tartrate-resistant acid phosphatase (TRAP)-positive cells appeared on the lateral side of the cartilage. Furthermore, the dental follicle showed moderate immunoreactivity for RANKL and OPG, whereas osteoblasts derived from perichondral cells were immunonegative for RANKL and OPG in that area. On E16, cartilage resorption by TRAP-positive cells had progressed at the differential position, and intensely immunoreactive products of RANKL were overlapped on and found to exist next to TRAP-positive cells in the resorption area. In developing metatarsal tissue, OPG immunoreactivity was intense in periosteal osteoblasts, whereas RANKL was only faintly seen in some of the periosteal cells. In epiphyseal chondrocytes of the developing femur, RANKL immunoreactivity was moderate, and OPG scarcely detected. These results indicate a peculiarity of RANKL and OPG immunolocalization in resorption of Meckel's cartilage. Growth of the incisor teeth may be involved in the time- and position-specific resorption of Meckel's cartilage through local regulation of the RANKL/OPG system in dental follicular cells and periosteal osteoblasts, whereas RANKL and OPG in chondrocytes seem to contribute to resorption through regulation of the chondroclast function. PMID:16191162

A Comprehensive Mixture of Tobacco Smoke Components Retards Orthodontic Tooth Movement via the Inhibition of Osteoclastogenesis in a Rat Model

PubMed Central

Nagaie, Maya; Nishiura, Aki; Honda, Yoshitomo; Fujiwara, Shin-Ichi; Matsumoto, Naoyuki

2014-01-01

Tobacco smoke is a complex mixture of numerous components. Nevertheless, most experiments have examined the effects of individual chemicals in tobacco smoke. The comprehensive effects of components on tooth movement and bone resorption remain unexplored. Here, we have shown that a comprehensive mixture of tobacco smoke components (TSCs) attenuated bone resorption through osteoclastogenesis inhibition, thereby retarding experimental tooth movement in a rat model. An elastic power chain (PC) inserted between the first and second maxillary molars robustly yielded experimental tooth movement within 10 days. TSC administration effectively retarded tooth movement since day 4. Histological evaluation disclosed that tooth movement induced bone resorption at two sites: in the bone marrow and the peripheral bone near the root. TSC administration significantly reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclastic cells in the bone marrow cavity of the PC-treated dentition. An in vitro study indicated that the inhibitory effects of TSCs on osteoclastogenesis seemed directed more toward preosteoclasts than osteoblasts. These results indicate that the comprehensive mixture of TSCs might be a useful tool for detailed verification of the adverse effects of tobacco smoke, possibly contributing to the development of reliable treatments in various fields associated with bone resorption. PMID:25322153

Multiscale design and multiobjective optimization of orthopedic hip implants with functionally graded cellular material.

PubMed

Arabnejad Khanoki, Sajad; Pasini, Damiano

2012-03-01

Revision surgeries of total hip arthroplasty are often caused by a deficient structural compatibility of the implant. Two main culprits, among others, are bone-implant interface instability and bone resorption. To address these issues, in this paper we propose a novel type of implant, which, in contrast to current hip replacement implants made of either a fully solid or a foam material, consists of a lattice microstructure with nonhomogeneous distribution of material properties. A methodology based on multiscale mechanics and design optimization is introduced to synthesize a graded cellular implant that can minimize concurrently bone resorption and implant interface failure. The procedure is applied to the design of a 2D left implanted femur with optimized gradients of relative density. To assess the manufacturability of the graded cellular microstructure, a proof-of-concept is fabricated by using rapid prototyping. The results from the analysis are used to compare the optimized cellular implant with a fully dense titanium implant and a homogeneous foam implant with a relative density of 50%. The bone resorption and the maximum value of interface stress of the cellular implant are found to be over 70% and 50% less than the titanium implant while being 53% and 65% less than the foam implant.

Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling.

PubMed

Mishina, Yuji; Starbuck, Michael W; Gentile, Michael A; Fukuda, Tomokazu; Kasparcova, Viera; Seedor, J Gregory; Hanks, Mark C; Amling, Michael; Pinero, Gerald J; Harada, Shun-ichi; Behringer, Richard R

2004-06-25

Bone morphogenetic proteins (BMPs) function during various aspects of embryonic development including skeletogenesis. However, their biological functions after birth are less understood. To investigate the role of BMPs during bone remodeling, we generated a postnatal osteoblast-specific disruption of Bmpr1a that encodes the type IA receptor for BMPs in mice. Mutant mice were smaller than controls up to 6 months after birth. Irregular calcification and low bone mass were observed, but there were normal numbers of osteoblasts. The ability of the mutant osteoblasts to form mineralized nodules in culture was severely reduced. Interestingly, bone mass was increased in aged mutant mice due to reduced bone resorption evidenced by reduced bone turnover. The mutant mice lost more bone after ovariectomy likely resulting from decreased osteoblast function which could not overcome ovariectomy-induced bone resorption. In organ culture of bones from aged mice, ablation of the Bmpr1a gene by adenoviral Cre recombinase abolished the stimulatory effects of BMP4 on the expression of lysosomal enzymes essential for osteoclastic bone resorption. These results demonstrate essential and age-dependent roles for BMP signaling mediated by BMPRIA (a type IA receptor for BMP) in osteoblasts for bone remodeling.

The cell biology and role of resorptive cells in diseases: A review.

PubMed

Babaji, Prashant; Devanna, Raghu; Jagtap, Kiran; Chaurasia, Vishwajit Rampratap; Jerry, Jeethu John; Choudhury, Basanta Kumar; Duhan, Dinesh

2017-01-01

Resorptive cells are responsible for the resorption of mineralized matrix of hard tissues. Bone-resorbing cells are called osteoclasts; however, they can resorb mineralized dental tissues or calcified cartilage and then they are called odontoclasts and chondroclasts, respectively. Resorptive cells form when mononuclear precursors derived from a monocyte-macrophage cell lineage are attracted to certain mineralized surfaces and subsequently fuse and adhere onto them for exerting their resorbing activity. These cells are responsible for degradation of calcified extracellular matrix composed of organic molecules and hydroxyapatite. The activity of these cells can be observed in both physiological and pathological processes throughout life and their activity is mainly required in bone turnover and growth, spontaneous and induced (orthodontic) tooth movement, tooth eruption, and bone fracture healing, as well as in pathological conditions such as osteoporosis, osteoarthritis, and bone metastasis. In addition, they are responsible for daily control of calcium homeostasis. Clastic cells also resorb the primary teeth for shedding before the permanent teeth erupt into the oral cavity.

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins.

PubMed

Zwart, Sara R; Hargens, Alan R; Lee, Stuart M C; Macias, Brandon R; Watenpaugh, Donald E; Tse, Kevin; Smith, Scott M

2007-02-01

Supine weight-bearing exercise within lower body negative pressure (LBNP) alleviates some of the skeletal deconditioning induced by simulated weightlessness in men. We examined this potential beneficial effect in women. Because dietary acid load affected the degree of bone resorption in men during bed rest, we also investigated this variable in women. Subjects were 7 pairs of female identical twins assigned at random to 2 groups, sedentary bed rest (control) or bed rest with supine treadmill exercise within LBNP. Dietary intake was controlled and monitored. Urinary calcium and markers of bone resorption were measured before bed rest and on bed rest days 5/6, 12/13, 19/20, and 26/27. Bone mineral content was assessed by dual-energy X-ray absorptiometry before and after bed rest. Data were analyzed by repeated-measures two-way analysis of variance. Pearson correlation coefficients were used to define the relationships between diet and markers of bone metabolism and to estimate heritability of markers. During bed rest, all markers of bone resorption and urinary calcium and phosphorus increased (P<0.001); parathyroid hormone (P=0.06), bone-specific alkaline phosphatase (P=0.06), and 1,25-dihydroxyvitamin D (P=0.09) tended to decrease. LBNP exercise tended to mitigate bone density loss. The ratio of dietary animal protein to potassium was positively correlated with urinary calcium excretion for all weeks of bed rest in the control group, but only during weeks 1 and 3 in the exercise group. Pre-bed rest data suggested that many markers of bone metabolism have strong genetic determinants. Treadmill exercise within LBNP had less of a protective effect on bone resorption during bed rest in women than previously published results had shown for its effect in men, but the same trends were observed for both sexes. Dietary acid load of these female subjects was significantly correlated with calcium excretion but not with other bone resorption markers.

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

PubMed Central

Zwart, Sara R.; Hargens, Alan R.; Lee, Stuart M. C.; Macias, Brandon R.; Watenpaugh, Donald E.; Tse, Kevin; Smith, Scott M.

2007-01-01

Supine weight-bearing exercise within lower body negative pressure (LBNP) alleviates some of the skeletal deconditioning induced by simulated weightlessness in men. We examined the potential beneficial effect in women. Because dietary acid load affected the degree of bone resorption in men during bed rest, we also investigated this variable in women. Subjects were 7 pairs of female identical twins assigned at random to 2 groups, sedentary bed rest (control) or bed rest with supine treadmill exercise within LBNP. Dietary intake was controlled and monitored. Urinary calcium and markers of bone resorption were measured before bed rest (BR) and on BR days 5/6, 12/13, 19/20, and 26/27. Bone mineral content was assessed by dual-energy X-ray absorptiometry before and after bed rest. Data were analyzed by repeated measures two-way analysis of variance. Pearson correlation coefficients were used to define the relationships between diet and markers of bone metabolism, and to estimate heritability of markers. During bed rest, all markers of bone resorption and urinary calcium and phosphorus increased (P < 0.001); parathyroid hormone (P = 0.06), bone-specific alkaline phosphatase (P = 0.06), and 1,25-dihydroxyvitamin D (P = 0.09) tended to decrease. LBNP exercise tended to mitigate bone density loss. The ratio of dietary animal protein to potassium was positively correlated with urinary calcium excretion for all weeks of bed rest in the control group, but only during weeks 1 and 3 for the exercise group. Pre-bed rest data suggested that many markers of bone metabolism have strong genetic determinants. Treadmill exercise within LBNP had less of a protective effect on bone resorption during bed rest in women than previously-published results had shown for its effect in men, but the same trends were observed for both sexes. Dietary acid load of these female subjects was significantly correlated with calcium excretion but not with other bone resorption markers. PMID:17070743

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption.

PubMed

Canalis, Ernesto; Schilling, Lauren; Yee, Siu-Pok; Lee, Sun-Kyeong; Zanotti, Stefano

2016-01-22

Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C→T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2(Q2319X) heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2(Q2319X) cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor κB ligand in vitro were increased in Notch2(Q2319X) mutants. These effects were suppressed by the γ-secretase inhibitor LY450139. In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

PubMed Central

van't Hof, R. J.; Armour, K. J.; Smith, L. M.; Armour, K. E.; Wei, X. Q.; Liew, F. Y.; Ralston, S. H.

2000-01-01

Nitric oxide has been suggested to be involved in the regulation of bone turnover, especially in pathological conditions characterized by release of bone-resorbing cytokines. The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic bone resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role that the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 by studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciotropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Immunohistochemical studies and electrophoretic mobility shift assays performed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NFκB and in NFκB-DNA binding, which were reversed by treatment with the NO donor S-nitroso-acetyl penicillamine. These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFκB in osteoclast precursors. PMID:10869429

Inhibition of experimental bone resorption and osteoclast formation and survival by 2-aminoethanesulphonic acid.

PubMed

Koide, M; Okahashi, N; Tanaka, R; Kazuno, K; Shibasaki, K; Yamazaki, Y; Kaneko, K; Ueda, N; Ohguchi, M; Ishihara, Y; Noguchi, T; Nishihara, T

1999-09-01

It is known that bone resorption is mediated by osteoclasts, and lipopolysaccharide (LPS) and inflammatory mediators such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2) induce osteoclast differentiation from haemopoietic cells, 2-aminoethanesulphonic acid, which is known as taurine, is an important nutrient and is added to most synthetic human infant milk formulas. In this study, it was found that 2-aminoethanesulphonic acid inhibits the stimulation of bone resorption mediated by LPS of the periodontopathic microorganism Actinobacillus actinomycetemcomitans Y4 in organ cultures of newborn mouse calvaria. The effect of 2-aminoethanesulphonic acid on the development and survival of osteoclast-like multinucleated cells produced in a mouse bone-marrow culture system was also examined. 2-aminoethanesulphonic acid (100 microg/ml) suppressed the formation of these osteoclast-like cells in the presence of LPS of A. actinomycetemcomitans Y4, IL-1alpha or PGE2 in mouse marrow cultures. On the other hand, 2-aminoethanesulphonic acid did not inhibit 1alpha, 25-dihydroxyvitamin D3-mediated osteoclast differentiation. Although IL-1alpha elongated the survival of the osteoclast-like cells, 2-aminoethanesulphonic acid blocked the supportive effect of IL-1alpha on osteoclast survival. 2-aminoethanesulphonic acid showed no effect on the growth of mouse osteoblasts. Finally, it was found that 2-aminoethanesulphonic acid inhibited alveolar bone resorption in experimental periodontitis in hamsters. These results suggest that 2-aminoethanesulphonic acid is an effective agent in preventing inflammatory bone resorption in periodontal diseases.

Relationship between fluoride exposure and osteoclast markers during RANKL-induced osteoclast differentiation.

PubMed

Junrui, Pei; Bingyun, Li; Yanhui, Gao; Xu, Jiaxun; Darko, Gottfried M; Dianjun, Sun

2016-09-01

Skeletal fluorosis is a metabolic bone disease caused by excessive accumulation of fluoride. Although the cause of this disease is known, the mechanism by which fluoride accumulates on the bone has not been clearly defined, thus there are no markers that can be used for screening skeletal fluorosis in epidemiology. In this study, osteoclasts were formed from bone marrow cells of C57BL/6 mice-treated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand. The mRNA expression of tartrate-resistant acid phosphatase 5b (TRAP5b), osteoclast-associated receptor (OSCAR), calcitonin receptor (CTR), matrix metalloproteinase 9 (MMP9) and cathepsin K (CK) were detected using real-time PCR (RT-PCR). Results showed that fluoride between 0.5 and 8mg/l had no effect on osteoclast formation. However fluoride at 0.5mg/l level significantly decreased the activity of osteoclast bone resorption. Fluoride concentration was negatively correlated with the activity of osteoclast bone resorption. On day 5 of osteoclast differentiation maturity, MMP9 and CK mRNA expression were not only negatively correlated with fluoride concentration, but directly correlated with the activity of osteoclast bone resorption. TRAP5b, CTR and OSCAR mRNA expression were positively correlated with the number of osteoclast and they had no correlation with the activity of osteoclast bone resorption. Thus, it can be seen that MMP9 and CK may reflect the change of activity of bone resorption as well the degree of fluoride exposure. TRAP5b, CTR and OSCAR can represent the change of number of osteoclast formed. Copyright © 2016 Elsevier B.V. All rights reserved.

[MECHANISMS OF OSTEOPENIC SYNDROME IMPLEMENTATION IN PATIENTS WITH COMORBIDITY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CHRONIC PANCREATITIS].

PubMed

Zhelezniakova, N

2016-10-01

Objective -to identify mechanisms of osteopenic syndrome implementation in patients with comorbid course of COPD and chronic pancreatitis (CP). 51 patients with comorbidity of CP and COPD (main group), 47 - with isolated COPD (compared group) have been examined. Assessment of excretory function of the pancreas was performed by determination of elastase-1 in the feces. Concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α were determined by ELISA. It has been found out that patients with comorbid pathology are characterized by the significant decrease of bone mineral density than in the compared group. The progression of pancreatic dysfunction exacerbates the processes of bone resorption. It was estimated that increasing of proinflammatory cytokines concentration leads to considerable enhancement of osteopenic processes. The presence of concomitant chronic pancreatitis in patients with COPD brings in an aggravation of resorptive processes in bone tissue, the severity of which depends on the degree of excretory pancreatic insufficiency and expressivity of proinflammatory cytokine cascade.

Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass

NASA Technical Reports Server (NTRS)

Elefteriou, Florent; Takeda, Shu; Liu, Xiuyun; Armstrong, Dawna; Karsenty, Gerard

2003-01-01

Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice

PubMed Central

Valverde, Paloma; Zhang, Jin; Fix, Amanda; Zhu, Ji; Ma, Wenli; Tu, Qisheng; Chen, Jake

2008-01-01

The purpose of this study was to determine the effects of bone sialoprotein (BSP) overexpression in bone metabolism in vivo by using a homozygous transgenic mouse line that constitutively overexpresses mouse BSP cDNA driven by the cytomegalovirus (CMV) promoter. CMV-BSP transgenic (TG) mice and wildtype mice were weighed, and their length, BMD, and trabecular bone volume were measured. Serum levels of RANKL, osteocalcin, osteoprotegerin (OPG), TRACP5b, and PTH were determined. Bone histomorphometry, von Kossa staining, RT-PCR analysis, Western blot, MTS assay, in vitro mineralization assay, and TRACP staining were also performed to delineate phenotypes of this transgenic mouse line. Compared with wildtype mice, adult TG mice exhibit mild dwarfism, lower values of BMD, and lower trabecular bone volume. TG mice serum contained increased calcium levels and decreased PTH levels, whereas the levels of phosphorus and magnesium were within normal limits. TG mice serum also exhibited lower levels of osteoblast differentiation markers and higher levels of markers, indicating osteoclastic activity and bone resorption. H&E staining, TRACP staining, and bone histomorphometry showed that adult TG bones were thinner and the number of giant osteoclasts in TG mice was higher, whereas there were no significant alterations in osteoblast numbers between TG mice and WT mice. Furthermore, the vertical length of the hypertrophic zone in TG mice was slightly enlarged. Moreover, ex vivo experiments indicated that overexpression of BSP decreased osteoblast population and increased osteoclastic activity. Partly because of its effects in enhancing osteoclastic activity and decreasing osteoblast population, BSP overexpression leads to an uncoupling of bone formation and resorption, which in turn results in osteopenia and mild dwarfism in mice. These findings are expected to help the development of therapies to metabolic bone diseases characterized by high serum level of BSP. PMID:18597627

Polar bears (Ursus maritimus), the most evolutionary advanced hibernators, avoid significant bone loss during hibernation.

PubMed

Lennox, Alanda R; Goodship, Allen E

2008-02-01

Some hibernating animals are known to reduce muscle and bone loss associated with mechanical unloading during prolonged immobilisation,compared to humans. However, here we show that wild pregnant polar bears (Ursus maritimus) are the first known animals to avoid significant bone loss altogether, despite six months of continuous hibernation. Using serum biochemical markers of bone turnover, we showed that concentrations for bone resorption are not significantly increased as a consequence of hibernation in wild polar bears. This is in sharp contrast to previous studies on other hibernating species, where for example, black bears (Ursus americanus), show a 3-4 fold increase in serum bone resorption concentrations posthibernation,and must compensate for this loss through rapid bone recovery on remobilisation, to avoid the risk of fracture. In further contrast to black bears, serum concentrations of bone formation markers were highly significantly increased in pregnant female polar bears compared to non-pregnant,thus non-hibernating females both prior to and after hibernation. However, bone formation concentrations in new mothers were significantly reduced compared to pre-hibernation concentrations. The de-coupling of bone turnover in favour of bone formation prior to hibernation, suggests that wild polar bears may posses a unique physiological mechanism for building bone in protective preparation against expected osteopenia associated with disuse,starvation, and hormonal drives to mobilise calcium for reproduction, during hibernation. Understanding this physiological mechanism could have profound implications for a natural solution for the prevention of osteoporosis in animals subjected to captivity with inadequate space for exercise,humans subjected to prolonged bed rest while recovering from illness, or astronauts exposed to antigravity during spaceflight.© 2008 Elsevier Inc. All rights reserved.

Rabbiteye blueberry prevents osteoporosis in ovariectomized rats.

PubMed

Li, Tao; Wu, Shou-Mian; Xu, Zhi-Yuan; Ou-Yang, Sheng

2014-08-08

It has been forecasted that the rabbiteye blueberry could inhibit osteoporosis. However, the inhibition and prevention of osteoporosis via rabbiteye blueberry are still elusive. This study was aim to evaluate the anti-osteoporosis effects of rabbiteye blueberry in ovariectomized rats. Thirty rats were randomly divided into three groups of ten rats each as follows: sham-operated group (SG), ovariectomized model control group (OMG), and ovariectomized rabbiteye blueberry treatment group (OBG). The blood mineral levels, the alkaline phosphatase (ALP) activity, and osteoprotegerin (OPG) level were determined. The expression analyses of type I collagen, integrin-β1, and focal adhesion kinase (FAK) were performed. Besides, the bone mineral density (BMD) and bone histomorphometry (BH) were measured. The ALP activity in SG and OBG was significantly lower than that in OMG. For the OPG level, the significant increase of OPG level in OBG was indicated compared with the other groups. The mRNA expression levels of type I collagen, integrin-β1, and FAK in OMG were significantly lower than those in other groups. The BMD in OMG were all significantly lower than those in SG and OBG. For BH, blueberry significantly improved the trabecular bone volume fraction, trabecular thickness, mean trabecular bone number, and bone formation rate, and decreased the trabecular separation, the percent of bone resorption perimeter, and mean osteoclast number in OBG compared with OMG. The rabbiteye blueberries had an effective inhibition in bone resorption, bone loss, and reduction of bone strength of ovariectomized rats and could improve the BMD, osteogenic activity, and trabecular bone structure.

The Effect of Systemic Delivery of Aminoguanidine versus Doxycycline on the Resorptive Phase of Alveolar Bone Following modified Widman Flap in Diabetic Rats: A Histopathological and Scanning Electron Microscope (SEM) study.

PubMed

Tella, E; Aldahlawi, S; Eldeeb, A; El Gazaerly, H

2014-07-01

Aminoguanidine (guanylhydrazinehydrochloride) is a drug that prevents many of the classical systemic complications of diabetes including diabetic osteopenia through its inhibitory activity on the accumulation of advanced glycation end -products (AGEs). The aim of the present study was to evaluate the effectiveness of aminoguanidine versus doxycycline in reducing alveolar bone resorption following mucoperiosteal flap in diabetic rats, using the conventional histopathology and scanning electron microscope (SEM). Twenty-seven male albino rats were used in this study. Periodontal defects were induced experimentally on lower anterior teeth. All rats were subjected to induction of diabetes, by IV injection of the pancreatic B-cells toxin alloxan monohydrate. After eight weeks following the establishment of periodontal defects in all rats, the ligation was removed and 3 rats were scarified as negative control (group 1). The remaining animals were divided into three group based on treatment applied following mucoperiosteal flap surgery. Group 2 received saline treatment only, group 3 received doxycycline periostat (1.5 mg/kg/day) for 3 weeks, and group 4 received aminoguanidine (7.3 mmol/kg) for 3 weeks. The fasting glucose level was measured weekly post operatively. After 21 days all rats were sacrificed. Three anterior parts of the mandible of each group was prepared for histopathological examination and two parts were prepared for SEM. Aminoguanidine treated group (group 4) showed statistically significant increased new bone formation, higher number of osteoblasts and decrease osteoclasts number, resorptive lacunae and existing inflammatory cell infiltration as compared to positive control group (group 2) (P<0.05). Doxycycline was also effective in reducing bone loss as documental by histopathological study. The present study showed that aminoguanidine was significantly effective in reducing alveolar bone loss and can modify the detrimental effects of diabetes in alveolar bone resorption.

[Naringin reduced polymethylmethacrylate-induced osteolysis in the mouse air sacs model].

PubMed

Li, Nian-Hu; Xu, Zhan-wang

2015-04-01

To evaluate the influence of naringin on PMMA-induced osteoclastic bone resorption using the mouse air sacs model. Total 48 female Balb/c mices with the age of 8 to 10 weeks were chosen in the study. Air were injected into the back in 32 mices and formed the air sacs, 6 d later, the skulls (originated from other 16 mices) were implanted to the air sacs. Thirty-two animals were divided into naringin treatment group (with 2 concentrations of 150 mg/kg and 30 mg/ kg) , DMSO group and PBS blank group, 8 animals in each group. Polymethylmethacrylate (PMMA) particles were injected into the air sacs in naringin treatment groups and DMSO group so as to irritate inflammatory reaction. Naringin with 2 concentrations of 150 mg/kg and 30 mg/kg were dissolved in DMSO of 0.2 ml, and were injected into air sacs, respectively. In PBS black group, no stimulation with PMMA particles, only injected PBS, and in DMSO group, injected DMSO without naringin. Tartrate resistant acid phosphatase (TRAP), Ca2+ release, modified Masson stain and histological analysis were performed on the 7th day after stimulation. Compared with DMSO group, naringin treatment group's cellular infiltration decreased (P < 0.01); concentration of 150 mg/kg was better than that of concentrations of 30 mg/kg (8.90 ± 1.75 vs 15.23 ± 1.86). Naringin can decrease calcium release in the lavage of the air sacs bone resorption model, especially obvious in naringin with concentration of 150 mg/kg. Naringin can ameliorate the inflammatory reaction and the subsequent bone resorption (including bone collagen loss, TRAP positive cells amount and so on) in air sacs with bone implant and PMMA particles. Naringin with concentration of 150 mg/kg appeared to be an optimal dosage to deliver the therapeutic effects. Naringin inhibits PMMA-induced osteoclastogenesis and ameliorates the PMMA-associated inflammatory reaction and the subsequent bone resorption.

Feasibility of simultaneous measurement of bone formation and bone resorption markers to assess bone turnover rate in postmenopausal women: an EPOLOS study.

PubMed

Łukaszkiewicz, Jacek; Karczmarewicz, Elzbieta; Płudowski, Paweł; Jaworski, Maciej; Czerwiński, Edward; Lewiński, Andrzej; Marcinowska-Suchowierska, Ewa; Milewicz, Andrzej; Spaczyński, Marek; Lorenc, Roman S

2008-12-01

One of the most important risk factors for osteoporotic fractures in postmenopausal women is elevated bone turnover (EBT), occurring in 25-30% of this population. This study's aim was to find a correlation between bone resorption and bone formation markers to assess bone turnover rate and qualify an individual postmenopausal woman as a possible EBT subject. Three hundred twenty postmenopausal women (> or = one year after the last menstruation, < or = 70 years old) were enrolled at seven clinical sites in this cross-sectional observational study conducted within the EPOLOS. The group was a random sample of the population. The study was performed in a referral center involved in the diagnosis and treatment of osteoporosis. The exclusion criteria included pregnancy, cancer, fracture in the last year, and overweight (> 100 kg). Bone mineral density (BMD) measurements of the lumbar spine, total hip, trochanter, and femoral neck regions were performed. Bone resorption and formation rates were evaluated by serum levels of C-terminal telopeptide of type I collagen (CTX) and osteocalcin (OC), respectively. Using logistic regression to correlate the concentrations of CTX and OC it was possible not only to distinguish the EBT subgroup, but also to construct a simple nomogram for easy classification of individual patients as possible EBT subjects. EBT patients showed generally decreased BMD values and increased bone formation and resorption rates. Evaluation of both CTX and OC levels enables a more proper indication for EBT. The proposed nomogram may assist in evaluating outcome from the two markers of bone turnover.

Postmenopausal women with osteoarthritis and osteoporosis show different ultrastructural characteristics of trabecular bone of the femoral head.

PubMed

Shen, Yun; Zhang, Zi-Ming; Jiang, Sheng-Dan; Jiang, Lei-Sheng; Dai, Li-Yang

2009-04-09

Osteoporosis (OP) and osteoarthritis (OA) are public health diseases affecting the quality of life of the elderly, and bring about a heavy burden to the society and family of patients. It has been debated whether or not there is an inverse relationship between these two disorders. To compare the exact difference in bone tissue structure between osteoporosis and osteoarthritis, we observed the ultrastructure of trabecular bone from the femoral heads using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A total of 15 femoral head specimens from postmenopausal women were collected during the procedures of total or hemi hip replacement (OP, n = 8; OA, n = 7). The morphologic structure of the trabecular bone, collagen fibers, resorption lacuna and osteoblasts were observed. Under SEM, osteoporotic trabeculae appeared to be thinning, tapering, breaking and perforating. A number of resorption lacunae of various shapes were seen on the surface of the trabeculum. The collagen fibers of lacuna were resorbed. On occasion, naked granular bone crystals could be found. In the OA group, the trabecular bone looked thick with integrated structure. Reticular and granular new bone could be found. The trabeculum was covered by well-arranged collagen fibers around the resorption lacuna. In the OP group, under TEM, marginal collagen fibers were observed to be aligned loosely with enlarged spaces. A few inactive osteoblasts and no inflammatory cells were seen. In the OA group, the collagen fibers inside the trabeculum were arranged in a dense manner with many active osteoblasts and inflammatory cells infiltrating the matrix. We found significant differences in the trabecular bone, collagen fibers, lacunae and osteoblasts between postmenopausal women with OP and OA. These findings support the hypothesis that there is an inverse relationship between OP and OA.

Postmenopausal women with osteoarthritis and osteoporosis show different ultrastructural characteristics of trabecular bone of the femoral head

PubMed Central

Shen, Yun; Zhang, Zi-Ming; Jiang, Sheng-Dan; Jiang, Lei-Sheng; Dai, Li-Yang

2009-01-01

Background Osteoporosis (OP) and osteoarthritis (OA) are public health diseases affecting the quality of life of the elderly, and bring about a heavy burden to the society and family of patients. It has been debated whether or not there is an inverse relationship between these two disorders. Methods To compare the exact difference in bone tissue structure between osteoporosis and osteoarthritis, we observed the ultrastructure of trabecular bone from the femoral heads using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A total of 15 femoral head specimens from postmenopausal women were collected during the procedures of total or hemi hip replacement (OP, n = 8; OA, n = 7). The morphologic structure of the trabecular bone, collagen fibers, resorption lacuna and osteoblasts were observed. Results Under SEM, osteoporotic trabeculae appeared to be thinning, tapering, breaking and perforating. A number of resorption lacunae of various shapes were seen on the surface of the trabeculum. The collagen fibers of lacuna were resorbed. On occasion, naked granular bone crystals could be found. In the OA group, the trabecular bone looked thick with integrated structure. Reticular and granular new bone could be found. The trabeculum was covered by well-arranged collagen fibers around the resorption lacuna. In the OP group, under TEM, marginal collagen fibers were observed to be aligned loosely with enlarged spaces. A few inactive osteoblasts and no inflammatory cells were seen. In the OA group, the collagen fibers inside the trabeculum were arranged in a dense manner with many active osteoblasts and inflammatory cells infiltrating the matrix. Conclusion We found significant differences in the trabecular bone, collagen fibers, lacunae and osteoblasts between postmenopausal women with OP and OA. These findings support the hypothesis that there is an inverse relationship between OP and OA. PMID:19356253

Socket preservation.

PubMed

Fee, L

2017-04-21

Socket preservation maintains bone volume post-extraction in anticipation of an implant placement or fixed partial denture pontic site. This procedure helps compensate for the resorption of the facial bone wall. Socket preservation should be considered when implant placement needs to be delayed for patient or site-related reasons. The ideal healing time before implant placement is six months. Socket preservation can reduce the need for later bone augmentation. By reducing bone resorption and accelerating bone formation it increases implant success and survival. Biomaterials for socket grafting including autograft, allograft, xenograft and alloplast. A bone substitute with a low substitution rate is recommended.

Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency

PubMed Central

Xiong, Jinhu; Piemontese, Marilina; Thostenson, Jeff D.; Weinstein, Robert S.; Manolagas, Stavros C.; O’Brien, Charles A.

2014-01-01

Parathyroid hormone (PTH) excess stimulates bone resorption. This effect is associated with increased expression of the osteoclastogenic cytokine receptor activator of nuclear factor кB ligand (RANKL) in bone. However, several different cell types, including bone marrow stromal cells, osteocytes, and T lymphocytes, express both RANKL and the PTH receptor and it is unclear whether RANKL expression by any of these cell types is required for PTH-induced bone loss. Here we have used mice lacking the RANKL gene in osteocytes to determine whether RANKL produced by this cell type is required for the bone loss caused by secondary hyperparathyroidism induced by dietary calcium deficiency in adult mice. Thirty days of dietary calcium deficiency caused bone loss in control mice, but this effect was blunted in mice lacking RANKL in osteocytes. The increase in RANKL expression in bone and the increase in osteoclast number caused by dietary calcium deficiency were also blunted in mice lacking RANKL in osteocytes. These results demonstrate that RANKL produced by osteocytes contributes to the increased bone resorption and the bone loss caused by secondary hyperparathyroidism, strengthening the evidence that osteocytes are an important target cell for hormonal control of bone remodeling. PMID:24933342

Subchondral pre-solidified chitosan/blood implants elicit reproducible early osteochondral wound-repair responses including neutrophil and stromal cell chemotaxis, bone resorption and repair, enhanced repair tissue integration and delayed matrix deposition

PubMed Central

2013-01-01

Background In this study we evaluated a novel approach to guide the bone marrow-driven articular cartilage repair response in skeletally aged rabbits. We hypothesized that dispersed chitosan particles implanted close to the bone marrow degrade in situ in a molecular mass-dependent manner, and attract more stromal cells to the site in aged rabbits compared to the blood clot in untreated controls. Methods Three microdrill hole defects, 1.4 mm diameter and 2 mm deep, were created in both knee trochlea of 30 month-old New Zealand White rabbits. Each of 3 isotonic chitosan solutions (150, 40, 10 kDa, 80% degree of deaceylation, with fluorescent chitosan tracer) was mixed with autologous rabbit whole blood, clotted with Tissue Factor to form cylindrical implants, and press-fit in drill holes in the left knee while contralateral holes received Tissue Factor or no treatment. At day 1 or day 21 post-operative, defects were analyzed by micro-computed tomography, histomorphometry and stereology for bone and soft tissue repair. Results All 3 implants filled the top of defects at day 1 and were partly degraded in situ at 21 days post-operative. All implants attracted neutrophils, osteoclasts and abundant bone marrow-derived stromal cells, stimulated bone resorption followed by new woven bone repair (bone remodeling) and promoted repair tissue-bone integration. 150 kDa chitosan implant was less degraded, and elicited more apoptotic neutrophils and bone resorption than 10 kDa chitosan implant. Drilled controls elicited a poorly integrated fibrous or fibrocartilaginous tissue. Conclusions Pre-solidified implants elicit stromal cells and vigorous bone plate remodeling through a phase involving neutrophil chemotaxis. Pre-solidified chitosan implants are tunable by molecular mass, and could be beneficial for augmented marrow stimulation therapy if the recruited stromal cells can progress to bone and cartilage repair. PMID:23324433

Mineral trioxide aggregate repair of a perforating internal resorption in a mandibular molar.

PubMed

Meire, Maarten; De Moor, Roeland

2008-02-01

Internal resorption is a rare condition in permanent teeth that poses difficulties for treatment. The challenge is complicated further if the resorption extends beyond the confines of the root. This article describes treatment of a perforating internal resorption in the mesial root of a second lower molar, with adjacent destruction of the alveolar bone. After cleaning the root canal space and the resorption lacuna by mechanical instrumentation, irrigation, and interim calcium hydroxide dressing, the defect was filled with mineral trioxide aggregate, and the canals were obturated conventionally with gutta percha and epoxy resin sealer. At a 2-year follow-up examination, no clinical abnormalities were found, and complete resolution of the alveolar bone lesion and establishment of a new periodontal ligament were observed.

In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption.

PubMed

Dong, X Neil; Qin, An; Xu, Jiake; Wang, Xiaodu

2011-08-01

Advanced glycation end products (AGEs) have been observed to accumulate in bone with increasing age and may impose effects on bone resorption activities. However, the underlying mechanism of AGEs accumulation in bone is still poorly understood. In this study, human cortical bone specimens from young (31±6years old), middle-aged (51±3years old) and elderly (76±4years old) groups were examined to determine the spatial-temporal distribution of AGEs in bone matrix and its effect on bone resorption activities by directly culturing osteoclastic cells on bone slices. The results of this study indicated that the fluorescence intensity (excitation wave length 360nm and emission wave length 470±40nm) could be used to estimate the relative distribution of AGEs in bone (pentosidine as its marker) under an epifluorescence microscope. Using the fluorescence intensity as the relative measure of AGEs concentration, it was found that the concentration of AGEs varied with biological tissue ages, showing the greatest amount in the interstitial tissue, followed by the old osteons, and the least amount in newly formed osteons. In addition, AGEs accumulation was found to be dependent on donor ages, suggesting that the younger the donor the less AGEs were accumulated in the tissue. Most interestingly, AGEs accumulation appeared to initiate from the region of cement lines, and spread diffusively to the other parts as the tissue aged. Finally, it was observed that the bone resorption activities of osteoclasts were positively correlated with the in situ concentration of AGEs and such an effect was enhanced with increasing donor age. These findings may help elucidate the mechanism of AGEs accumulation in bone and its association with bone remodeling process. Copyright © 2011 Elsevier Inc. All rights reserved.

IN SITU ACCUMULATION OF ADVANCED GLYCATION ENDPRODUCTS (AGES) IN BONE MATRIX AND ITS CORRELATION WITH OSTEOCLASTIC BONE RESORPTION

PubMed Central

Dong, X. Neil; Qin, An; Xu, Jiake; Wang, Xiaodu

2011-01-01

Advanced glycation end products (AGEs) have been observed to accumulate in bone with increasing age and may impose effects on bone resorption activities. However, the underlying mechanism of AGEs accumulation in bone is still poorly understood. In this study, human cortical bone specimens from young (31±6 years old), middle-aged (51±3 years old) and elderly (76±4 years old) groups were examined to determine the spatial-temporal distribution of AGEs in bone matrix and its effect on bone resorption activities by directly culturing osteoclastic cells on bone slices. The results of this study indicated that the fluorescence intensity (excitation wave length 360 nm and emission wave length 470±40 nm) could be used to estimate the relative distribution of AGEs in bone (pentosidine as its marker) under an epifluorescence microscope. Using the fluorescence intensity as the relative measure of AGEs concentration, it was found that the concentration of AGEs varied with biological tissue ages, showing the greatest amount in the interstitial tissue, followed by the old osteons, and the least amount in newly formed osteons. In addition, AGEs accumulation was found to be dependent on donor ages, suggesting that the younger the donor the less AGEs were accumulated in the tissue. Most interestingly, AGEs accumulation appeared to initiate from the region of cement lines, and spread diffusively to the other parts as the tissue aged. Finally, it was observed that the bone resorption activities of osteoclasts were positively correlated with the in situ concentration of AGEs and such an effect was enhanced with increasing donor age. These findings may help elucidate the mechanism of AGEs accumulation in bone and its association with bone remodeling process. PMID:21530698

Conservative Socket Regeneration with Buccal Wall Defect Using Guided Tissue.

PubMed

Al-Juboori, Mohammed Jasim

2016-01-01

Progressive alveolar bone resorption after tooth extraction may lead to surgical and prosthetic-driven difficulties, especially when deciding to use a dental implant to replace the extracted tooth. This case report discusses an irreparable lower left second premolar tooth with a periodontal lesion on the buccal side. A preservative tooth extraction was performed. Then, the socket was grafted with bovine bone, a collagen membrane was placed between the buccal bone and the attached gingiva, covering the bone dehiscence buccally, and the socket without a flap was raised. After a 6-month healing period, there was minimal socket width resorption and a shallow buccal vestibule. The implant was placed with high primary stability and sufficient buccal plate thickness. In conclusion, this guided tissue regeneration technique can minimize alveolar bone resorption in a socket with buccal dehiscence, but technical difficulties and shallowing of the buccal vestibule still exist.

Inhalation of diesel engine exhaust increases bone mineral concentrations in growing rats.

PubMed

Watanabe, N; Nakamura, T

1996-03-01

Experiments were conducted to determine whether diesel engine exhaust affects bone metabolism in growing rats. The rats were assigned to three groups: those exposed to total diesel engine exhaust with 5.63 mg/m3 particulate matter, 4.10 ppm nitrogen dioxide, 8.10 ppm nitrogen monoxide; those exposed to filtered exhaust without particulate matter; and those exposed to clean air. Dosing experiments were performed for 3 months beginning at birth (6 h/day for 5 days/week). Bone mineral content (BMC) values in lumbar vertebral bone were significantly increased in both groups exposed to diesel exhaust (P < 0.01) compared to that of rats exposed to clean air. Bone mineral density (BMD) values were also significantly increased in both exposed groups, total exhaust (P < 0.01) and filtered exhaust (P < 0.001), compared to that of rats exposed to clean air. BMD values in the mid-femur were also significantly greater in animals exposed to diesel exhaust, total exhaust (P < 0.05), and filtered exhaust (P < 0.01), compared to that of those exposed to clean air. Urinary excretion of deoxypyridinolines, a biochemical marker for bone resorption, was significantly reduced in animals exposed to total diesel exhaust and filtered exhaust (P < 0.001, P < 0.01) compared to control. There was also a significant difference between the two exposure groups of diesel exhaust (P < 0.05). Since these effects were not inhibited by filtration, the gaseous phase of the exhaust was considered more responsible than particulate matter for reducing bone resorption.

Carbon fibre versus metal framework in full-arch immediate loading rehabilitations of the maxilla - a cohort clinical study.

PubMed

Pera, F; Pesce, P; Solimano, F; Tealdo, T; Pera, P; Menini, M

2017-05-01

Frameworks made of carbon fibre-reinforced composites (CFRC) seem to be a viable alternative to traditional metal frameworks in implant prosthodontics. CFRC provide stiffness, rigidity and optimal biocompatibility. The aim of the present prospective study was to compare carbon fibre frameworks versus metal frameworks used to rigidly splint implants in full-arch immediate loading rehabilitations. Forty-two patients (test group) were rehabilitated with full-arch immediate loading rehabilitations of the upper jaw (total: 170 implants) following the Columbus Bridge Protocol with four to six implants with distal tilted implants. All patients were treated with resin screw-retained full-arch prostheses endowed with carbon fibre frameworks. The mean follow-up was 22 months (range: 18-24). Differences in the absolute change of bone resorption over time between the two implant sides (mesial and distal) were assessed performing a Mann-Whitney U-test. The outcomes were statistically compared with those of patients rehabilitated following the same protocol but using metal frameworks (control group: 34 patients with 163 implants - data reported in Tealdo, Menini, Bevilacqua, Pera, Pesce, Signori, Pera, Int J Prosthodont, 27, 2014, 207). Ten implants failed in the control group (6·1%); none failed in the test group (P = 0·002). A statistically significant difference in the absolute change of bone resorption around the implants was found between the two groups (P = 0·004), with greater mean peri-implant bone resorption in the control group (1 mm) compared to the test group (0·8 mm). Carbon fibre frameworks may be considered as a viable alternative to the metal ones and showed less marginal bone loss around implants and a greater implant survival rate during the observation period. © 2017 John Wiley & Sons Ltd.

The influence of implant design on periprosthetic bone remodelling of two types of uncemented HA-coated hip stems. A two-year follow-up study using DEXA.

PubMed

Van der Wal, B C H; Rahmy, A I A; Grimm, B; Blake, G M; Heyligers, I C; Tonino, A J

2006-01-01

Proximal bone resorption and an increased fracture rate in the ABG-I stem has been shown. For these reasons the ABG-I stem design was changed to the ABG-II. In this study periprosthetic bone loss around the ABG-I vs ABG-II is compared to verify if the design changes resulted in improved proximal bone preservation. 51 patients were randomised to either the ABG-I or ABG-II hip prosthesis. Periprosthetic BMD change at various time points was measured using DEXA. Between the two groups (age, gender, weight etc.) no statistical difference was encountered. Compared to the baseline at two years the ABG-II preserved bone better proximally (e.g. zone 7: ABG-II: -3.7%, ABG-I: -11.9%, p=0.05) than the ABG-I. Distally, the trend was opposite and less bone loss was measured for the ABG-I than the ABG-II in zones 3, 4 and 5 (n.s.). this study confirms the philosophy behind the design changes from the ABG-I to ABG-II stem where increased elasticity, more proximal HA-coating, a shorter and distally polished stem, were meant to reduce proximal bone resorption. In future this may lead to fewer periprosthetic fractures and to less complicated revision surgery.

Three-dimensional Characterization of Resorption Cavity Size and Location in Human Vertebral Trabecular Bone

PubMed Central

Goff, M.G.; Slyfield, C.R.; Kummari, S.R.; Tkachenko, E.V.; Fischer, S. E.; Yi, Y.H.; Jekir, M.; Keaveny, T.M.; Hernandez, C.J.

2012-01-01

The number and size of resorption cavities in cancellous bone are believed to influence rates of bone loss, local tissue stress and strain and potentially whole bone strength. Traditional two-dimensional approaches to measuring resorption cavities in cancellous bone report the percent of the bone surface covered by cavities or osteoclasts, but cannot measure cavity number or size. Here we use three-dimensional imaging (voxel size 0.7 × 0.7 × 5.0 μm) to characterize resorption cavity location, number and size in human vertebral cancellous bone from nine elderly donors (7 male, 2 female, ages 47–80 years). Cavities were 30.10 ± 8.56 μm in maximum depth, 80.60 ± 22.23 *103 μm2 in surface area and 614.16 ± 311.93 *103 μm3 in volume (mean ± SD). The average number of cavities per unit tissue volume (N.Cv/TV) was 1.25 ± 0.77 mm−3. The ratio of maximum cavity depth to local trabecular thickness was 30.46 ± 7.03 % and maximum cavity depth was greater on thicker trabeculae (p < 0.05, r2 = 0.14). Half of the resorption cavities were located entirely on nodes (the intersection of two or more trabeculae) within the trabecular structure. Cavities that were not entirely on nodes were predominately on plate-like trabeculae oriented in the cranial-caudal (longitudinal) direction. Cavities on plate-like trabeculae were larger in maximum cavity depth, cavity surface area and cavity volume than cavities on rod-like trabeculae (p < 0.05). We conclude from these findings that cavity size and location are related to local trabecular microarchitecture. PMID:22507299

Towards the optimal design of an uncemented acetabular component using genetic algorithms

NASA Astrophysics Data System (ADS)

Ghosh, Rajesh; Pratihar, Dilip Kumar; Gupta, Sanjay

2015-12-01

Aseptic loosening of the acetabular component (hemispherical socket of the pelvic bone) has been mainly attributed to bone resorption and excessive generation of wear particle debris. The aim of this study was to determine optimal design parameters for the acetabular component that would minimize bone resorption and volumetric wear. Three-dimensional finite element models of intact and implanted pelvises were developed using data from computed tomography scans. A multi-objective optimization problem was formulated and solved using a genetic algorithm. A combination of suitable implant material and corresponding set of optimal thicknesses of the component was obtained from the Pareto-optimal front of solutions. The ultra-high-molecular-weight polyethylene (UHMWPE) component generated considerably greater volumetric wear but lower bone density loss compared to carbon-fibre reinforced polyetheretherketone (CFR-PEEK) and ceramic. CFR-PEEK was located in the range between ceramic and UHMWPE. Although ceramic appeared to be a viable alternative to cobalt-chromium-molybdenum alloy, CFR-PEEK seems to be the most promising alternative material.

Efficacy of Oral Etidronate for Skeletal Diseases in Japan

PubMed Central

Takeda, Tsuyoshi; Sato, Yoshihiro

2005-01-01

Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400 mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects. PMID:15988801

Improved bone metabolism in female elite athletes after vitamin K supplementation.

PubMed

Craciun, A M; Wolf, J; Knapen, M H; Brouns, F; Vermeer, C

1998-10-01

In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives. All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20-25% decrease of bone resorption markers. This shift is suggestive for an improved balance between bone formation and resorption.

Bone Balance within a Cortical BMU: Local Controls of Bone Resorption and Formation

PubMed Central

Smith, David W.; Gardiner, Bruce S.; Dunstan, Colin

2012-01-01

Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short-term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the ‘integration of information’ occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors. PMID:22844401

Dietary Supplement Attenuates Radiation-Induced Osteoclastogenic and Oxidative Stress-Related Responses and Protects Adult Mice from Radiation-Induced Bone Loss

NASA Technical Reports Server (NTRS)

Globus, Ruth; Schreurs, Ann-Sofie; Tahimic, Candice; Shirazi-Fard, Yasaman; Alwood, Joshua; Shahnazari, Mohammed; Halloran, Bernard

2015-01-01

Our central hypothesis is that oxidative stress plays a key role in cell dysfunction and progressive bone loss caused by radiation exposure during spaceflight. In animal studies, excess free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. We previously reported that exposure to low or high-LET radiation rapidly increases expression levels of pro-osteoclastogenic and oxidative stress-related genes in bone and marrow, followed by pathological changes in skeletal structure. To screen various antioxidants for radioprotective effects on bone, 4 month old, male C57Bl6/J mice were treated with a dietary antioxidant cocktail, injectable alpha-lipoic acid, or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs total body radiation and one day later marrow cells were collected and the relevant genes analyzed for expression levels. Of the candidates tested, DP was most effective in reducing bone resorption-related gene expression. Microcomputed tomography revealed that DP also prevented the radiation-induced deterioration of skeletal microarchitecture, as indicated by percent bone volume, trabecular spacing and trabecular number. DP had similar protective effects on skeletal structure after sequential exposure to protons (0.5 Gy, 150MeV/n) and 56Fe 0.5Gy, 600 MeV/n). When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerted pro-osteogenic effects apart from previously identified anti-resorptive actions, which may contribute to radioprotection of skeletal tissue. In conclusion, a diet enriched in certain types of antioxidants and polyphenols such as DP may be useful as an intervention to protect tissues from degenerative effects of ionizing radiation.

Implant angulation: 2-year retrospective analysis on the influence of dental implant angle insertion on marginal bone resorption in maxillary and mandibular osseous onlay grafts.

PubMed

Ramaglia, Luca; Toti, Paolo; Sbordone, Carolina; Guidetti, Franco; Martuscelli, Ranieri; Sbordone, Ludovico

2015-05-01

The purpose of this study was to determine the existence of correlations between marginal peri-implant linear bone loss and the angulation of implants in maxillary and mandibular augmented areas over the course of a 2-year survey. Dependent variables described the sample of the present retrospective chart review. By using three-dimensional radiographs, input variables, describing the implant angulation (buccal-lingual angle [φ] and mesial-distal angle [θ]) were measured; outcome variables described survival rate and marginal bone resorption (MBR) around dental implants in autogenous grafts (10 maxillae and 14 mandibles). Pairwise comparisons and linear correlation coefficient were computed. The peri-implant MBR in maxillary buccal and palatal areas appeared less intensive in the presence of an increased angulation of an implant towards the palatal side. Minor MBR was recorded around mandibular dental implants positioned at a right angle and slightly angulated towards the mesial. Resorption in buccal areas may be less intensive as the angulation of placed implants increases towards the palatal area in the maxilla, whereas for the mandible, a greater inclination towards the lingual area could be negative. In the mandibular group, when the implant was slightly angulated in the direction of the distal area, bone resorption seemed to be more marked in the buccal area. In the planning of dental implant placement in reconstructed alveolar bone with autograft, the extremely unfavourable resorption at the buccal aspect should be considered; this marginal bone loss seemed to be very sensitive to the angulation of the dental implant.

Stimulation of fibroblast growth factor 23 by metabolic acidosis requires osteoblastic intracellular calcium signaling and prostaglandin synthesis.

PubMed

Krieger, Nancy S; Bushinsky, David A

2017-10-01

Serum fibroblast growth factor 23 (FGF23) increases progressively in chronic kidney disease (CKD) and is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the factors regulating its production are not clear. Patients with CKD have decreased renal acid excretion leading to metabolic acidosis (MET). During MET, acid is buffered by bone with release of mineral calcium (Ca) and phosphate (P). MET increases intracellular Ca signaling and cyclooxygenase 2 (COX2)-induced prostaglandin production in the osteoblast, leading to decreased bone formation and increased bone resorption. We found that MET directly stimulates FGF23 in mouse bone organ cultures and primary osteoblasts. We hypothesized that MET increases FGF23 through similar pathways that lead to bone resorption. Neonatal mouse calvariae were incubated in neutral (NTL, pH = 7.44, Pco 2 = 38 mmHg, [HCO 3 - ] = 27 mM) or acid (MET, pH = 7.18, Pco 2 = 37 mmHg, [HCO 3 - ] = 13 mM) medium without or with 2-APB (50 μM), an inhibitor of intracellular Ca signaling or NS-398 (1 μM), an inhibitor of COX2. Each agent significantly inhibited MET stimulation of medium FGF23 protein and calvarial FGF23 RNA as well as bone resorption at 48 h. To exclude the potential contribution of MET-induced bone P release, we utilized primary calvarial osteoblasts. In these cells each agent inhibited MET stimulation of FGF23 RNA expression at 6 h. Thus stimulation of FGF23 by MET in mouse osteoblasts utilizes the same initial signaling pathways as MET-induced bone resorption. Therapeutic interventions directed toward correction of MET, especially in CKD, have the potential to not only prevent bone resorption but also lower FGF23 and perhaps decrease mortality. Copyright © 2017 the American Physiological Society.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2002-01-01

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Ergonomic task reduction prevents bone osteopenia in a rat model of upper extremity overuse

PubMed Central

BARBE, Mary F.; JAIN, Nisha X.; MASSICOTTE, Vicky S.; POPOFF, Steven N.; BARR-GILLESPIE, Ann E.

2015-01-01

We evaluated the effectiveness of ergonomic workload reduction of switching rats from a high repetition high force (HRHF) lever pulling task to a reduced force and reach rate task for preventing task-induced osteopenic changes in distal forelimb bones. Distal radius and ulna trabecular structure was examined in young adult rats performing one of three handle-pulling tasks for 12 wk: 1) HRHF, 2) low repetition low force (LRLF); or 3) HRHF for 4 wk and than LRLF thereafter (HRHF-to-LRLF). Results were compared to age-matched controls rats. Distal forelimb bones of 12-wk HRHF rats showed increased trabecular resorption and decreased volume, as control rats. HRHF-to-LRLF rats had similar trabecular bone quality as control rats; and decreased bone resorption (decreased trabecular bone volume and serum CTX1), increased bone formation (increased mineral apposition, bone formation rate, and serum osteocalcin), and decreased osteoclasts and inflammatory cytokines, than HRHF rats. Thus, an ergonomic intervention of HRHF-to-LRLF prevented loss of trabecular bone volume occurring with prolonged performance of a repetitive upper extremity task. These findings support the idea of reduced workload as an effective approach to management of work-related musculoskeletal disorders, and begin to define reach rate and load level boundaries for such interventions. PMID:25739896

Antiosteoclastic activity of milk thistle extract after ovariectomy to suppress estrogen deficiency-induced osteoporosis.

PubMed

Kim, Jung-Lye; Kim, Yun-Ho; Kang, Min-Kyung; Gong, Ju-Hyun; Han, Seoung-Jun; Kang, Young-Hee

2013-01-01

Bone integrity abnormality and imbalance between bone formation by osteoblasts and bone resorption by osteoclasts are known to result in metabolic bone diseases such as osteoporosis. Silymarin-rich milk thistle extract (MTE) and its component silibinin enhanced alkaline phosphatase activity of osteoblasts but reduced tartrate-resistant acid phosphatase (TRAP) activity of osteoclasts. The osteoprotective effects of MTE were comparable to those of estrogenic isoflavone. Low-dose combination of MTE and isoflavone had a pharmacological synergy that may be useful for osteogenic activity. This study attempted to reveal the suppressive effects of MTE on bone loss. C57BL/6 female mice were ovariectomized (OVX) as a model for postmenopausal osteopenia and orally administered 10 mg/kg MTE or silibinin for 8 weeks. The sham-operated mice served as estrogen controls. The treatment of ovariectomized mice with nontoxic MTE and silibinin improved femoral bone mineral density and serum receptor activator of nuclear factor- κB ligand/osteoprotegerin ratio, an index of osteoclastogenic stimulus. In addition, the administration of MTE or silibinin inhibited femoral bone loss induced by ovariectomy and suppressed femoral TRAP activity and cathepsin K induction responsible for osteoclastogenesis and bone resorption. Collectively, oral dosage of MTE containing silibinin in the preclinical setting is effective in preventing estrogen deficiency-induced bone loss.

Antiosteoclastic Activity of Milk Thistle Extract after Ovariectomy to Suppress Estrogen Deficiency-Induced Osteoporosis

PubMed Central

Kim, Jung-Lye; Kim, Yun-Ho; Kang, Min-Kyung; Gong, Ju-Hyun; Han, Seoung-Jun; Kang, Young-Hee

2013-01-01

Bone integrity abnormality and imbalance between bone formation by osteoblasts and bone resorption by osteoclasts are known to result in metabolic bone diseases such as osteoporosis. Silymarin-rich milk thistle extract (MTE) and its component silibinin enhanced alkaline phosphatase activity of osteoblasts but reduced tartrate-resistant acid phosphatase (TRAP) activity of osteoclasts. The osteoprotective effects of MTE were comparable to those of estrogenic isoflavone. Low-dose combination of MTE and isoflavone had a pharmacological synergy that may be useful for osteogenic activity. This study attempted to reveal the suppressive effects of MTE on bone loss. C57BL/6 female mice were ovariectomized (OVX) as a model for postmenopausal osteopenia and orally administered 10 mg/kg MTE or silibinin for 8 weeks. The sham-operated mice served as estrogen controls. The treatment of ovariectomized mice with nontoxic MTE and silibinin improved femoral bone mineral density and serum receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, an index of osteoclastogenic stimulus. In addition, the administration of MTE or silibinin inhibited femoral bone loss induced by ovariectomy and suppressed femoral TRAP activity and cathepsin K induction responsible for osteoclastogenesis and bone resorption. Collectively, oral dosage of MTE containing silibinin in the preclinical setting is effective in preventing estrogen deficiency-induced bone loss. PMID:23781510

Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation.

PubMed

Heervä, Eetu; Alanne, Maria H; Peltonen, Sirkku; Kuorilehto, Tommi; Hentunen, Teuvo; Väänänen, Kalervo; Peltonen, Juha

2010-09-01

Neurofibromatosis 1 syndrome (NF1) presents with skeletal involvement suggesting that altered bone dynamics is associated with NF1. Histological analysis of three cases of NF1-related pseudarthrosis revealed numerous osteoclasts in contact with adjacent bone, and within the pseudarthrosis tissue itself. These findings prompted us to evaluate the differentiation and resorption capacity of NF1-osteoclast like cells (OLCs) in vitro. Osteoclast progenitors were isolated from peripheral blood of 17 patients with NF1 and allowed to differentiate into OLCs on bone slices. The following differences were found between NF1 and control samples: samples from NF1 patients resulted in a higher number of resorbing OLCs; NF1 OLCs were larger in size; their nuclei were more numerous; actin rings were more frequent; and the resorption pits in NF1 samples were more numerous and larger. Bone resorption markers revealed that the resorption activity in NF1 OLC cultures was approximately two times higher than in controls. Following deprivation from serum, the number of NF1 OLCs remained essentially the same during 24h, whereas the number of control OLCs was dramatically reduced during the same time. Three patients had NF1-related lytic bone lesions, and their in vitro results differed from those of other patients. Our results demonstrate that OLCs derived from blood of patients with NF1 display elevated resorption activity under conditions isolated from microenvironment operative in vivo. Thus, increased osteoclast activity may be a phenotypic property of the NF1 syndrome, and at least in part explain selected skeletal findings in NF1, such as osteoporosis/osteopenia. Copyright 2010 Elsevier Inc. All rights reserved.

Gallium modulates osteoclastic bone resorption in vitro without affecting osteoblasts

PubMed Central

Verron, Elise; Masson, Martial; Khoshniat, Solmaz; Duplomb, Laurence; Wittrant, Yohann; Baud'huin, Marc; Badran, Zahi; Bujoli, Bruno; Janvier, Pascal; Scimeca, Jean-Claude; Bouler, Jean-Michel; Guicheux, Jérôme

2010-01-01

Background and purpose: Gallium (Ga) has been shown to be effective in the treatment of disorders associated with accelerated bone loss, including cancer-related hypercalcemia and Paget's disease. These clinical applications suggest that Ga could reduce bone resorption. However, few studies have studied the effects of Ga on osteoclastic resorption. Here, we have explored the effects of Ga on bone cells in vitro. Experimental approach: In different osteoclastic models [osteoclasts isolated from long bones of neonatal rabbits (RBC), murine RAW 264.7 cells and human CD14-positive cells], we have performed resorption activity tests, staining for tartrate resistant acid phosphatase (TRAP), real-time polymerase chain reaction analysis, viability and apoptotic assays. We also evaluated the effect of Ga on osteoblasts in terms of proliferation, viability and activity by using an osteoblastic cell line (MC3T3-E1) and primary mouse osteoblasts. Key results: Gallium dose-dependently (0–100 µM) inhibited the in vitro resorption activity of RBC and induced a significant decrease in the expression level of transcripts coding for osteoclastic markers in RAW 264.7 cells. Ga also dramatically reduced the formation of TRAP-positive multinucleated cells. Ga down-regulated in a dose-dependant manner the expression of the transcription factor NFATc1. However, Ga did not affect the viability or activity of primary and MC3T3-E1 osteoblasts. Conclusions and implications: Gallium exhibits a dose-dependent anti-osteoclastic effect by reducing in vitro osteoclastic resorption, differentiation and formation without negatively affecting osteoblasts. We provide evidence that this inhibitory mechanism involves down-regulation of NFATc1 expression, a master regulator of RANK-induced osteoclastic differentiation. PMID:20397300

An essential role for the association of CD47 to SHPS-1 in skeletal remodeling.

PubMed

Maile, Laura A; DeMambro, Victoria E; Wai, Christine; Lotinun, Sutada; Aday, Ariel W; Capps, Byron E; Beamer, Wesley G; Rosen, Clifford J; Clemmons, David R

2011-09-01

Integrin-associated protein (IAP/CD47) has been implicated in macrophage-macrophage fusion. To understand the actions of CD47 on skeletal remodeling, we compared Cd47(-/-) mice with Cd47(+/+) controls. Cd47(-/-) mice weighed less and had decreased areal bone mineral density compared with controls. Cd47(-/-) femurs were shorter in length with thinner cortices and exhibited lower trabecular bone volume owing to decreased trabecular number and thickness. Histomorphometry revealed reduced bone-formation and mineral apposition rates, accompanied by decreased osteoblast numbers. No differences in osteoclast number were observed despite a nonsignificant but 40% decrease in eroded surface/bone surface in Cd47(-/-) mice. In vitro, the number of functional osteoclasts formed by differentiating Cd47(-/-) bone marrow cells was significantly decreased compared with wild-type cultures and was associated with a decrease in bone-resorption capacity. Furthermore, by disrupting the CD47-SHPS-1 association, we found that osteoclastogenesis was markedly impaired. Assays for markers of osteoclast maturation suggested that the defect was at the point of fusion and not differentiation and was associated with a lack of SHPS-1 phosphorylation, SHP-1 phosphatase recruitment, and subsequent dephosphorylation of non-muscle cell myosin IIA. We also demonstrated a significant decrease in osteoblastogenesis in bone marrow stromal cells derived from Cd47(-/-) mice. Our finding of cell-autonomous defects in Cd47(-/-) osteoblast and osteoclast differentiation coupled with the pronounced skeletal phenotype of Cd47(-/-) mice support the conclusion that CD47 plays an important role in regulating skeletal acquisition and maintenance through its actions on both bone formation and bone resorption. Copyright © 2011 American Society for Bone and Mineral Research.

New mechanisms and targets in the treatment of bone fragility.

PubMed

Martin, T John; Seeman, Ego

2007-01-01

Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1-34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with other pathways in determining bone formation, is likely to lead to new therapeutic developments. The recent discovery through mouse genetics that PTHrP (PTH-related protein) is a crucial bone-derived paracrine regulator of remodelling offers new and interesting therapeutic targets.

The role of lipopolysaccharide in infectious bone resorption of periapical lesion.

PubMed

Hong, Chi-Yuan; Lin, Sze-Kwan; Kok, Sang-Heng; Cheng, Shih-Jung; Lee, Ming-Shu; Wang, Tong-Mei; Chen, Chuan-Shuo; Lin, Li-Deh; Wang, Juo-Song

2004-03-01

The role of lipopolysaccharide (LPS) in periapical lesion-induced bone resorption was investigated. Polymyxin B (PMB), a specific inhibitor of LPS, was evaluated to treat the apical lesion. Lipopolysaccharide isolated from two common endodontic pathogens, Fusobacterium nucleatum and Porphyromonas endodontalis, stimulated mouse macrophage (J774) to release interleukin-1alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) in a time-dependent manner. Combination of LPS further enhanced the stimulation. PMB inhibited these effects significantly. LPS also stimulated matrix metalloproteinase-1 (MMP-1) gene expression in J774, whereas anti-IL-1 alpha and anti-TNF-alpha antibodies, as well as PMB, diminished this effect. A disease model of periapical lesion was established in Wistar rat. Administration of PMB reduced the extent of lesion-associated bone resorption by 76% to approximately 80%, and simultaneously reduced the numbers of MMP-1-producing macrophages. It is suggested that LPS released from the infected root canal triggers the synthesis of IL-1 alpha and TNF-alpha from macrophages. These pro-inflammatory cytokines up-regulate the production of MMP-1 by macrophages to promote periapical bone resorption.

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

PubMed

Otero, Jesse E; Stevens, Jeff W; Malandra, Allison E; Fredericks, Douglas C; Odgren, Paul R; Buckwalter, Joseph A; Morcuende, Jose

2014-12-01

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

An evaluation of the effect of age and the peri-parturient period on bone metabolism in dairy cows as measured by serum bone-specific alkaline phosphatase activity and urinary deoxypyridinoline concentration.

PubMed

Sato, Reiichiro; Onda, Ken; Kato, Hajime; Ochiai, Hideharu; Kawai, Kazuhiro; Iriki, Tsunenori; Kaneko, Kazuyuki; Yamazaki, Yukio; Wada, Yasunori

2013-08-01

Various biochemical markers help to evaluate the state of bone turnover in humans and could be used during the peri-parturient period in dairy cows when calcium (Ca) metabolism changes dramatically. To investigate this, the peri-partum characteristics of serum bone-specific alkaline phosphatase (BAP) and urinary deoxypyridinoline (DPD) were investigated. Both serum BAP activity and urinary DPD concentrations were increased and demonstrated wide variability in younger animals, and these findings were consistent with other bone turnover markers. Around the time of parturition, serum Ca concentration and serum BAP activity in multiparous cows were significantly lower than in primiparous cows, but urinary DPD concentration was unchanged. The use of BAP as a bone formation marker appears to be valuable for evaluating bone remodelling status in cows, but the specificity of the test needs to be confirmed. The DPD/BAP ratio around parturition demonstrated a clear difference in bone turnover status between the two parity groups with multiparous cows demonstrating increased signs of bone resorption compared with primiparous cows, corresponding to the Ca requirement for milk production. In future studies, the applicability of the ratio of bone resorption marker to bone formation marker should be evaluated for bone turnover assessment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Periprosthetic bone loss in total hip arthroplasty. Polyethylene wear debris and the concept of the effective joint space.

PubMed

Schmalzried, T P; Jasty, M; Harris, W H

1992-07-01

Thirty-four hips in which there had been prosthetic replacement were selected for study because of the presence of linear (diffuse) or lytic (localized) areas of periprosthetic bone loss. In all hips, there was careful documentation of the anatomical location of the material that had been obtained for histological analysis, and the specific purpose of the removal of the tissue was for examination to determine the cause of the resorption of bone. Specimens from twenty-three hips were retrieved during an operation and from eleven hips, at autopsy. The area of bone loss was linear only in sixteen hips, lytic only in thirteen, and both linear and lytic in five. In all thirty-four hips, intracellular particulate debris was found in the macrophages that were present in the area of bone resorption. All thirty-four had intracellular particles of polyethylene, many of which were less than one micrometer in size. Thirty-one hips had extracellular particles of polyethylene as well. Twenty-two of the thirty-four hips had intracellular metallic debris; in ten, metallic debris was found extracellularly as well. Ten of the sixteen cemented specimens had intracellular and extracellular polymethylmethacrylate debris. In the mechanically stable prostheses--cemented and uncemented--polyethylene wear debris was identified in areas of bone resorption far from the articular surfaces. The number of macrophages in a microscopic field was directly related to the amount of particulate polyethylene debris that was visible by light microscopy. Although the gross radiographic appearances of linear bone loss and lytic bone loss were different, the histological appearance of the regions in which there was active bone resorption was similar. Regardless of the radiographic appearance and anatomical origin of the specimen, bone resorption was found to occur in association with macrophages that were laden with polyethylene debris. In general, the number of macrophages present had a direct relationship to the degree of bone resorption that was seen. We believe that these findings indicate that joint fluid penetrates far more extensively than previously thought, even in a well fixed component, along the interface between the prosthesis and bone and in the periprosthetic tissues; it is often more extensive than is shown by arthrography. We therefore suggest the concept of the effective joint space to include all periprosthetic regions that are accessible to joint fluid and thus accessible to particulate debris.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Resorption Increases as Early as the Second Day in Head- Down Bed Rest

NASA Astrophysics Data System (ADS)

Heer, M.; Kamps, N.; Mika, C.; Boese, A.; Gerzer, R.

Long-term bed rest and space mission studies have shown that immobilization as well as microgravity induce increased bone resorption while bone formation tends to decrease. In order to analyze the kinetics of short-term changes in bone turnover we studied in a randomized, strictly controlled crossover design the effects of 6 days 6° head-down tilt bed rest (HDT) in 8 male healthy subjects (mean body weight (BW): 70.1 +/- 1.88 kg; mean age: 25.5 +/- 1.04 years) in our metabolic ward. Two days before arriving in the metabolic ward the subjects started with a diet consisting of an energy content of 10 MJ/d, 2000 mg Calcium/d, 400 i.U. Vitamin D, 200 mEq Na+ and 50 ml water/kg BW/d. The diet was continued in the metabolic ward. The metabolic ward period (11days) was divided into 3 parts: 4 ambulatory days, 6 days either HDT or control and 1 recovery day. Continuous urine collection started on the first day in the metabolic ward to analyze calcium excretion and bone resorption markers, namely C-telopeptide (CTX) and N-telopeptide (NTX). On the 2nd ambulatory day in the metabolic ward and on the 5th day in HDT or control blood was drawn to analyze serum calcium, parathyroid hormone, and bone formation markers (bone Alkaline Phosphatase (bAP), Procollagen-I-Propeptide (P-I-CP). Both study phases were identical with respect to environmental conditions, study protocol and diet. Urinary calcium excretion was as early as the first day in immobilization increased (p<0.01). CTX- and NTX-excretion stayed unchanged the first 24 hours in HDT compared to the control. But, already on the 2nd day of immobilization both bone resorption markers significantly increased. NTX-excretion was increased by 28.7 +/- 14.0% (p<0.05), while CTX-excretion rose by 17.8 +/- 8.3% (p<0.01). Both, the CTX- excretion as well as the calcium excretion keep the significantly higher level during the HDT period, and even continued through the first day of recovery. However, NTX excretion, descended from day three until the end of HDT. But, the level of NTX excretion during HDT was always higher than during control. In contrast to the bone resorption markers, the formation marker P-I-CP tended to decrease as early as the fifth day of immobilization (p<0.10). Serum calcium-, parathyroid hormone-, as well as bAP concentrations were unchanged. We conclude from these results of a pronounced rise of bone resorption markers that already 24 hours of immobilization induce a significant rise in osteoclast activity in healthy subjects. Thus, it appears possible to use short-term bed rest studies for the development of countermeasures to immobilization osteoporosis and to avoid long-term studies, which presently impose major detectable changes on the health status of healthy human subjects. Further studies are mandatory to investigate the underlying mechanisms and respective countermeasures.

Nanocrystallinity effects on osteoblast and osteoclast response to silicon substituted hydroxyapatite.

PubMed

Casarrubios, Laura; Matesanz, María Concepción; Sánchez-Salcedo, Sandra; Arcos, Daniel; Vallet-Regí, María; Portolés, María Teresa

2016-11-15

Silicon substituted hydroxyapatites (SiHA) are highly crystalline bioceramics treated at high temperatures (about 1200°C) which have been approved for clinical use with spinal, orthopedic, periodontal, oral and craniomaxillofacial applications. The preparation of SiHA with lower temperature methods (about 700°C) provides nanocrystalline SiHA (nano-SiHA) with enhanced bioreactivity due to higher surface area and smaller crystal size. The aim of this study has been to know the nanocrystallinity effects on the response of both osteoblasts and osteoclasts (the two main cell types involved in bone remodelling) to silicon substituted hydroxyapatite. Saos-2 osteoblasts and osteoclast-like cells (differentiated from RAW-264.7 macrophages) have been cultured on the surface of nano-SiHA and SiHA disks and different cell parameters have been evaluated: cell adhesion, proliferation, viability, intracellular content of reactive oxygen species, cell cycle phases, apoptosis, cell morphology, osteoclast-like cell differentiation and resorptive activity. This comparative in vitro study evidences that nanocrystallinity of SiHA affects the cell/biomaterial interface inducing bone cell apoptosis by loss of cell anchorage (anoikis), delaying osteoclast-like cell differentiation and decreasing the resorptive activity of this cell type. These results suggest the potential use of nano-SiHA biomaterial for preventing bone resorption in treatment of osteoporotic bone. Copyright © 2016 Elsevier Inc. All rights reserved.

Otosclerosis: Temporal Bone Pathology.

PubMed

Quesnel, Alicia M; Ishai, Reuven; McKenna, Michael J

2018-04-01

Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

Bone metabolism and renal stone risk during International Space Station missions.

PubMed

Smith, Scott M; Heer, Martina; Shackelford, Linda C; Sibonga, Jean D; Spatz, Jordan; Pietrzyk, Robert A; Hudson, Edgar K; Zwart, Sara R

2015-12-01

Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p<0.06). IGF-1, which regulates bone growth and formation, increased during flight in all 3 groups (p<0.001). Our results are consistent with the growing body of literature showing that the hyper-resorptive state of bone that is brought on by spaceflight can be countered pharmacologically or mitigated through an exercise-induced increase in bone formation, with nutritional support. Key questions remain about the effect of exercise-induced alterations in bone metabolism on bone strength and fracture risk. Published by Elsevier Inc.

A bone-resorption surface-targeting nanoparticle to deliver anti-miR214 for osteoporosis therapy

PubMed Central

Zhang, Shufan; Liu, Jiafan; Sun, Yao; Wang, Xiaogang

2017-01-01

With increasing fracture risks due to fragility, osteoporosis is a global health problem threatening postmenopausal women. In these patients, osteoclasts play leading roles in bone loss and fracture. How to inhibit osteoclast activity is the key issue for osteoporosis treatment. In recent years, miRNA-based gene therapy through gene regulation has been considered a potential therapeutic method. However, in light of the side effects, the use of therapeutic miRNAs in osteoporosis treatment is still limited by the lack of tissue/cell-specific delivery systems. Here, we developed polyurethane (PU) nanomicelles modified by the acidic peptide Asp8. Our data showed that without overt toxicity or eliciting an immune response, this delivery system encapsulated and selectively deliver miRNAs to OSCAR+ osteoclasts at bone-resorption surface in vivo. With the Asp8-PU delivery system, anti-miR214 was delivered to osteoclasts, and bone microarchitecture and bone mass were improved in ovariectomized osteoporosis mice. Therefore, Asp8-PU could be a useful bone-resorption surface-targeting delivery system for treatment of osteoclast-induced bone diseases and aging-related osteoporosis. PMID:29075114

Osteoclastic differentiation and resorption is modulated by bioactive metal ions Co2+, Cu2+ and Cr3+ incorporated into calcium phosphate bone cements.

PubMed

Bernhardt, Anne; Schamel, Martha; Gbureck, Uwe; Gelinsky, Michael

2017-01-01

Biologically active metal ions in low doses have the potential to accelerate bone defect healing. For successful remodelling the interaction of bone graft materials with both bone-forming osteoblasts and bone resorbing osteoclasts is crucial. In the present study brushite forming calcium phosphate cements (CPC) were doped with Co2+, Cu2+ and Cr3+ and the influence of these materials on osteoclast differentiation and activity was examined. Human osteoclasts were differentiated from human peripheral blood mononuclear cells (PBMC) both on the surface and in indirect contact to the materials on dentin discs. Release of calcium, phosphate and bioactive metal ions was determined using ICP-MS both in the presence and absence of the cells. While Co2+ and Cu2+ showed a burst release, Cr3+ was released steadily at very low concentrations (below 1 μM) and both calcium and phosphate release of the cements was considerably changed in the Cr3+ modified samples. Direct cultivation of PBMC/osteoclasts on Co2+ cements showed lower attached cell number compared to the reference but high activity of osteoclast specific enzymes tartrate resistant acid phosphatase (TRAP), carbonic anhydrase II (CAII) and cathepsin K (CTSK) and significantly increased gene expression of vitronectin receptor. Indirect cultivation with diluted Co2+ cement extracts revealed highest resorbed area compared to all other modifications and the reference. Cu2+ cements had cytotoxic effect on PBMC/osteoclasts during direct cultivation, while indirect cultivation with diluted extracts from Cu2+ cements did not provoke cytotoxic effects but a strictly inhibited resorption. Cr3+ doped cements did not show cytotoxic effects at all. Gene expression and enzyme activity of CTSK was significantly increased in direct culture. Indirect cultivation with Cr3+ doped cements revealed significantly higher resorbed area compared to the reference. In conclusion Cr3+ doped calcium phosphate cements are an innovative cement modification because of their high cytocompatibility and support of active resorption by osteoclasts.

Reduced proliferation and osteocalcin expression in osteoblasts of male idiopathic osteoporosis.

PubMed

Ruiz-Gaspà, Sílvia; Blanch-Rubió, Josep; Ciria-Recasens, Manuel; Monfort, Jordi; Tío, Laura; Garcia-Giralt, Natàlia; Nogués, Xavier; Monllau, Joan C; Carbonell-Abelló, Jordi; Pérez-Edo, Lluis

2010-03-01

Osteoporosis is characterized by low bone mineral density (BMD), resulting in increasing susceptibility to bone fractures. In men, it has been related to some diseases and toxic habits, but in some instances the cause of the primary--or idiopathic--osteoporosis is not apparent. In a previous study, our group compared histomorphometric measurements in cortical and cancellous bones from male idiopathic osteoporosis (MIO) patients to those of control subjects and found reduced bone formation without major differences in bone resorption. To confirm these results, this study analyzed the etiology of this pathology, examining the osteoblast behavior in vitro. We compared two parameters of osteoblast activity in MIO patients and controls: osteoblastic proliferation and gene expression of COL1A1 and osteocalcin, in basal conditions and with vitamin D(3) added. All these experiments were performed from a first-passage osteoblastic culture, obtained from osteoblasts that had migrated from the transiliac explants to the plate. The results suggested that the MIO osteoblast has a slower proliferation rate and decreased expression of genes related to matrix formation, probably due to a lesser or slower response to some stimulus. We concluded that, contrary to female osteoporosis, in which loss of BMD is predominantly due to increased resorption, low BMD in MIO seems to be due to an osteoblastic defect.

Responds of Bone Cells to Microgravity: Ground-Based Research

NASA Astrophysics Data System (ADS)

Zhang, Jian; Li, Jingbao; Xu, Huiyun; Yang, Pengfei; Xie, Li; Qian, Airong; Zhao, Yong; Shang, Peng

2015-11-01

Severe loss of bone occurs due to long-duration spaceflight. Mechanical loading stimulates bone formation, while bone degradation happens under mechanical unloading. Bone remodeling is a dynamic process in which bone formation and bone resorption are tightly coupled. Increased bone resorption and decreased bone formation caused by reduced mechanical loading, generally result in disrupted bone remodeling. Bone remodeling is orchestrated by multiple bone cells including osteoblast, osteocyte, osteoclast and mesenchymal stem cell. It is yet not clear that how these bone cells sense altered gravity, translate physical stimulus into biochemical signals, and then regulate themselves structurally and functionally. In this paper, studies elucidating the bioeffects of microgravity on bone cells (osteoblast, osteocyte, osteoclast, mesenchymal stem cell) using various platforms including spaceflight and ground-based simulated microgravity were summarized. Promising gravity-sensitive signaling pathways and protein molecules were proposed.

Novel bioactivity of phosvitin in connective tissue and bone organogenesis revealed by live calvarial bone organ culture models.

PubMed

Liu, Jess; Czernick, Drew; Lin, Shih-Chun; Alasmari, Abeer; Serge, Dibart; Salih, Erdjan

2013-09-01

Egg yolk phosvitin is one of the most highly phosphorylated extracellular matrix proteins known in nature with unique physico-chemical properties deemed to be critical during ex-vivo egg embryo development. We have utilized our unique live mouse calvarial bone organ culture models under conditions which dissociates the two bone remodeling stages, viz., resorption by osteoclasts and formation by osteoblasts, to highlight important and to date unknown critical biological functions of egg phosvitin. In our resorption model live bone cultures were grown in the absence of ascorbate and were stimulated by parathyroid hormone (PTH) to undergo rapid osteoclast formation/differentiation with bone resorption. In this resorption model native phosvitin potently inhibited PTH-induced osteoclastic bone resorption with simultaneous new osteoid/bone formation in the absence of ascorbate (vitamin C). These surprising and critical observations were extended using the bone formation model in the absence of ascorbate and in the presence of phosvitin which supported the above results. The results were corroborated by analyses for calcium release or uptake, tartrate-resistant acid phosphatase activity (marker for osteoclasts), alkaline phosphatase activity (marker for osteoblasts), collagen and hydroxyproline composition, and histological and quantitative histomorphometric evaluations. The data revealed that the discovered bioactivity of phosvitin mirrors that of ascorbate during collagen synthesis and the formation of new osteoid/bone. Complementing those studies use of the synthetic collagen peptide analog and cultured calvarial osteoblasts in conjunction with mass spectrometric analysis provided results that augmented the bone organ culture work and confirmed the capacity of phosvitin to stimulate differentiation of osteoblasts, collagen synthesis, hydroxyproline formation, and biomineralization. There are striking implications and interrelationships of this affect that relates to the evolutionary inactivation of the gene of an enzyme L-gulono-γ-lactone oxidase, which is involved in the final step of ascorbate biosynthesis, in many vertebrate species including passeriform birds, reptiles and teleost fish whose egg yolk contain phosvitin. These represent examples of how developing ex-vivo embryos of such species can achieve connective tissue and skeletal system formation in the absence of ascorbate. Copyright © 2013 Elsevier Inc. All rights reserved.

Prostaglandin E2 Adds Bone to a Cancellous Bone Site with a Closed Growth Plate and Low Bone Turnover in Ovariectomized Rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Ke, H. Z.; Jee, W. S. S.

1994-01-01

The objects of this study were to determine the responses of a cancellous bone site with a closed growth plate (the distal tibial metaphysis, DTM) to ovariectomy (OVX) and OVX plus a prostaglandin E2 (PGE2) treatment, and compare the site's response to previous findings reported for another site (the proximal tibial metaphysis, PTM). Thirty-five 3-month old female Sprague-Dawley rats were divided into five groups: basal, sham-OVX, and OVX+0, +1, or +6 mg PGE2/kg/d injected subcutaneously for 3 months and given double fluorescent labels before sacrifice. Cancellous bone histomorphometric analyses were performed on 20-micron-thick undecalcified DTM sections. Similar to the PTM, the DTM showed age-related decreases in bone formation and increases in bone resorption, but it differed in that at 3 months post-OVX; there was neither bone loss nor changes in formation endpoints. Giving 1 mg PGE2/kg/d to OVX rats prevented most age-related changes and maintained the bone formation histomorphometry near basal levels. Treating OVX rats with 6 mg PGE2/kg/d prevented age-related bone changes, added extra bone, and improved microanatomical structure by stimulating bone formation without altering bone resorption. Furthermore, after PGE2 administration, the DTM, a cancellous bone site with a closed growth plate, inereased bone formation more than did the cancellous bone in the PTM.

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

PubMed Central

Quint, Patrick; Ruan, Ming; Pederson, Larry; Kassem, Moustapha; Westendorf, Jennifer J.; Khosla, Sundeep; Oursler, Merry Jo

2013-01-01

Normal bone turnover requires tight coupling of bone resorption and bone formation to preserve bone quantity and structure. With aging and during several pathological conditions, this coupling breaks down, leading to either net bone loss or excess bone formation. To preserve or restore normal bone metabolism, it is crucial to determine the mechanisms by which osteoclasts and osteoblast precursors interact and contribute to coupling. We showed that osteoclasts produce the chemokine sphingosine 1-phosphate (S1P), which stimulates osteoblast migration. Thus, osteoclast-derived S1P may recruit osteoblasts to sites of bone resorption as an initial step in replacing lost bone. In this study we investigated the mechanisms by which S1P stimulates mesenchymal (skeletal) cell chemotaxis. S1P treatment of mesenchymal (skeletal) cells activated RhoA GTPase, but this small G protein did not contribute to migration. Rather, two S1P receptors, S1PR1 and S1PR2, coordinately promoted migration through activation of the JAK/STAT3 and FAK/PI3K/AKT signaling pathways, respectively. These data demonstrate that the chemokine S1P couples bone formation to bone resorption through activation of kinase signaling pathways. PMID:23300082

Effects of Resistive Vibration Exercise Combined with Whey Protein and KHCO3 on Bone Tturnover Markers in Head-down Tilt Bed Rest (MTBR-MNX Study)

NASA Technical Reports Server (NTRS)

Graf, Sonja; Baecker, Natalie; Buehlmeier, Judith; Fischer, Annelie; Smith, Scott M.; Heer, Martina

2014-01-01

High protein intake further increases bone resorption markers in head-down tilt bed rest (HDBR), most likely induced by low-grade metabolic acidosis. Adding an alkaline salt to a diet with high protein content prevents this additional rise of bone resorption markers in HDBR. In addition, high protein intake, specifically whey protein, increases muscle protein synthesis and improves glucose tolerance, which both are affected by HDBR. Resistive vibration exercise (RVE) training counteracts the inactivity-induced bone resorption during HDBR. To test the hypothesis that WP plus alkaline salt (KHCO3) together with RVE during HDBR will improve bone turnover markers, we conducted a randomized, three-campaign crossover design study with 12 healthy, moderately fit male subjects (age 34+/-8 y, body mass [BM] 70 +/- 8 kg). All study campaigns consisted of a 7-d ambulatory period, 21days of -6 deg. head-down tilt bed rest (HDBR), and a 6-d recovery period. Diet was standardized and identical across phases. In the control (CON) campaign, subjects received no supplement or RVE. In the intervention campaigns, subjects received either RVE alone or combined with WP and KHCO3 (NEX). WP was applied in 3 doses per day of 0.6 g WP/kg BM together with 6 doses of 15 mmol KHCO3 per day. Eleven subjects completed the RVE and CON campaign, 8 subjects completed all three campaigns. On day 21 of HDBR excretion of the bone resorption marker C-telopeptide (CTX) was 80+/-28% (p<0.001) higher than baseline, serum calcium concentrations increased by 12 +/- 29% (p<0.001) and serum osteocalcin concentrations decreased by 6+/-12% (p=0.001). Urinary CTX excretion was 11+/- 25% (p=0.02) lower on day 21 of HDBR in the RVE- and tended to decrease by 3+/- 22% (p=0.06) in the NEX campaign compared to CON. Urinary calcium excretion was higher on day 21 in HDBR in the RVE and NEX (24+/- 43% p=0.01; 25+/- 37% p=0.03) compared to the CON campaign. We conclude that combination of RVE with WP/KHCO3 was not superior to RVE alone in any of these results.

Excessive dietary intake of vitamin A reduces skull bone thickness in mice

PubMed Central

Öhman, Caroline; Calounova, Gabriela; Rasmusson, Annica; Andersson, Göran; Pejler, Gunnar; Melhus, Håkan

2017-01-01

Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces. PMID:28426756

Changes in biomarkers of bone turnover in an aripiprazole add-on or switching study.

PubMed

Lodhi, Rohit J; Masand, Salaj; Malik, Amna; Shivakumar, Kuppuswami; McAllister, Victoria D M; O'Keane, Veronica; Young, Leah C; Heald, Adrian H; Sherwood, Roy A; Aitchison, Katherine J

2016-02-01

The association between mental illness and osteoporosis and fractures is particularly pronounced in psychotic disorders. Antipsychotic use has previously been described to affect bone density. A 52-week follow-up of patients switched to aripiprazole or with aripiprazole added on, conducting a specific analysis of markers of bone turnover: urinary NTX (a biomarker of bone resorption) and serum BSAP (a biomarker of bone formation). Baseline and serial measurements of bone markers NTX, BSAP and of hormones prolactin, oestrogen and testosterone were done at weeks 0 and 1, 2, 6, 12, 26 and 52, respectively. NTX concentration reduced over time but this did not reach significance in the whole group (log-NTX: β=-0.0012, p=0.142). For BSAP the addition of or replacement with aripiprazole produced a significant reduction (log-BSAP: β=-0.00039, p=0.002). Analysis with prolactin similarly showed a significant reduction (log-prolactin: β=-0.0024, p<0.001); other hormones did not change significantly. Sensitivity analysis to compare the switchers to aripiprazole versus the "add-on" showed that the former group had a significant reduction in NTX. We found that switching to aripiprazole was associated with changes in molecular biomarkers of bone resorption, indicating a more favourable profile for bone health. Copyright © 2015 Elsevier B.V. All rights reserved.

Contribution of dietary and loading changes to the effects of suspension on mouse femora

NASA Technical Reports Server (NTRS)

Simske, S. J.; Broz, J. J.; Fleet, M. L.; Schmeister, T. A.; Gayles, E. C.; Luttges, M. W.; Spooner, B. S. (Principal Investigator)

1994-01-01

The present study assessed the contributions of feeding changes and unloading to the overall measured effects of 2-wk hindlimb (Tail) suspension on the mouse femora. Feeding changes were addressed by considering the effects of matched feeding among suspended and control mice. The effects of hind limb unloading were considered by comparing suspended mice to mice equipped identically (though not suspended) and matched-fed. The feeding and unloading aspects of suspension appear to cause distinctly differing effects on the stereotypic modeling of the femora. Matched-feeding was accompanied by increased resorption surface in comparison to suspended mice, while unloading led to reduced bone formation at the mid-diaphysis of the femora. Reduced mineral content was observed in the bones of suspended mice when compared to the other mice groups, but without increased resorption surface. Thus, the unloading aspects of the antiorthostatic suspension protocol apparently causes reduced formation and mineralization in the femur.

Quantitative Kinetics Evaluation of Blocks Versus Granules of Biphasic Calcium Phosphate Scaffolds (HA/β-TCP 30/70) by Synchrotron Radiation X-ray Microtomography: A Human Study.

PubMed

Giuliani, Alessandra; Manescu, Adrian; Mohammadi, Sara; Mazzoni, Serena; Piattelli, Adriano; Mangano, Francesco; Iezzi, Giovanna; Mangano, Carlo

2016-02-01

Successful bone regeneration using both granules and blocks of biphasic calcium phosphate materials has been reported in the recent literature, in some clinical applications for maxillary sinus elevation, but the long-term kinetics of bone regeneration has still not been fully investigated. Twenty-four bilateral sinus augmentation procedures were performed and grafted with hydroxyapatite/β-tricalcium phosphate 30/70, 12 with granules and 12 with blocks. The samples were retrieved at different time points and were evaluated for bone regeneration, graft resorption, neovascularization, and morphometric parameters by computed microtomography and histology. A large amount of newly formed bone was detected in the retrieved specimens, together with a good rate of biomaterial resorption and the formation of a homogeneous and rich net of new vessels. The morphometric values were comparable at 5/6 months from grafting but, 9 months after grafting, revealed that the block-based specimens mimicked slightly better than granule-based samples the healthy native bone of the maxillary site. The scaffold morphology was confirmed to influence the long-term kinetics of bone regeneration.

Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass.

PubMed

Hirozane, Toru; Tohmonda, Takahide; Yoda, Masaki; Shimoda, Masayuki; Kanai, Yae; Matsumoto, Morio; Morioka, Hideo; Nakamura, Masaya; Horiuchi, Keisuke

2016-09-28

Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-κB signaling and an increase in the expression of NF-κB-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

Early changes in parameters of bone and mineral metabolism during therapy for hyper- and hypothyroidism.

PubMed

Sabuncu, T; Aksoy, N; Arikan, E; Ugur, B; Tasan, E; Hatemi, H

2001-01-01

The effects of thyroid hormones on various organs and metabolic systems have been the focus of intensive research. In this study we investigated the mechanisms of the changes in some parameters of bone and mineral metabolism before and during treatment of hyper- and hypothyroidism. Our study groups were as follows; 1) Untreated hyperthyroid patients (n= 38), 2) Hyperthyroid patients treated for three months (n=21), 3) Untreated hypothyroid patients (n=27), 4) Hypothyroid patients treated for three months (n= 20), and 5) Euthyroid control subjects (age, weight, sex and menopausal status matched) (n = 47). As expected, the mean serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and urinary Ca/creatinine and deoxypyridinoline (D-Pyr)/creatinine levels were higher in group-1 than in the control group. Serum PTH level was lower in group-1 than in group-5. However, after treatment for three months (group-2) we found that the serum and urinary levels of these parameters (except ALP) were not different than in the control group. Group-3 and group-4 did not show any differences in these parameters compared with group-5. Covariance analysis showed that urinary D-Pyr excretion had a positive, independent relationship to the serum free T3 level and age (P < 0.001 and P = 0.02, respectively). These results suggest that both bone formation and resorption markers increase in hyperthyroid patients, and with the treatment, particularly, in the period of first three months the bone resorption markers decrease rapidly. If the treatment is maintained the decrease slows, becoming more gradual. However, bone formation markers like ALP remain high in hyperthyroid patients during the treatment. In the light of this data, it is possible to conclude that osteoblastic activity lasts longer in hyperthyroidism. On the other hand, we demonstrated that these bone formation and resorption markers do not seem to be different in hypothyroid patients, even during the treatment, compared to the euthyroid controls.

Effect of bisphosphonates on root resorption after tooth replantation - a systematic review.

PubMed

Najeeb, Shariq; Siddiqui, Fahad; Khurshid, Zohaib; Zohaib, Sana; Zafar, Muhammad Sohail; Ansari, Shazia Akbar

2017-04-01

Replantation of avulsed teeth may lead to root resorption. Bisphosphonates (BPs), a class of drugs of used to treat resorptive diseases of the bone such as osteoporosis and Paget's disease, have been observed to exert an antiresorptive effect on periodontal bone as well. The antiresorptive properties of BPs could prove them useful in preventing root resorption of replanted avulsed teeth. The aim of this systematic review was to analyze and summarize the currently available literature concerning the use of BPs in preventing root resorption of avulsed teeth. PubMed/MEDLINE, Google Scholar, ISI Web of Knowledge, and Embase databases were searched using keywords 'bisphosphonate', 'replantation', and 'tooth'. Quality assessment of each study was carried out. In addition, general characteristics and outcomes of each study were summarized. After exclusion of 116 irrelevant articles, 10 animal studies were included in this review. The majority of the studies suggest that surface application of zoledronate or alendronate reduces root resorption of replanted teeth in animal models. Surface treatment with etidronate had no significant effect on root resorption, and intracanal etidronate accelerated resorption. Surface application of zoledronate and alendronate reduces root resorption of replanted teeth in animal models. However, the efficacy of intracanal usage of BPs is still debatable. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events.

PubMed

Feller, Liviu; Khammissa, Razia A G; Thomadakis, George; Fourie, Jeanine; Lemmer, Johan

2016-01-01

Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption.

Denosumab in Postmenopausal Osteoporosis: What the Clinician Needs to Know

PubMed Central

Lewiecki, E. Michael

2009-01-01

Denosumab is a subcutaneously (SC) administered investigational fully human monoclonal antibody to receptor activator of nuclear factor-kB ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption. RANKL stimulates the formation, activity, and survival of osteoclasts, and is implicated in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with increased bone remodeling. Denosumab binds RANKL, preventing it from binding to RANK, thereby reducing the formation, activity, and survival of osteoclasts and slowing the rate of bone resorption. Postmenopausal women with low bone mineral density (BMD) treated with denosumab have a reduction of bone turnover markers and an increase in BMD that is rapid, sustained, and reversible. In postmenopausal women with osteoporosis, denosumab reduces the risk of vertebral, hip, and nonvertebral fractures. In postmenopausal women with low BMD randomized to receive denosumab or alendronate, denosumab is associated with a significantly greater increase in BMD and further reduction in bone turnover markers compared with alendronate. In postmenopausal women with low BMD who were previously treated with alendronate, those who switched to denosumab have a significantly greater BMD increase and further reduction in bone turnover markers compared with those continuing alendronate. Denosumab is well tolerated with a favorable safety profile. It is a promising emerging drug for the prevention and treatment of osteoporosis, offering a long dosing interval of every 6 months and convenient SC dosing, with the potential of improving long-term adherence to therapy compared with current oral treatments. PMID:22870424

Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

PubMed Central

Sato, M; Grasser, W; Endo, N; Akins, R; Simmons, H; Thompson, D D; Golub, E; Rodan, G A

1991-01-01

Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts. Images PMID:1661297

Effect of Alendronate with β - TCP Bone Substitute in Surgical Therapy of Periodontal Intra-Osseous Defects: A Randomized Controlled Clinical Trial.

PubMed

Naineni, Rohini; Ravi, Vishali; Subbaraya, Dwijendra Kocherlakota; Prasanna, Jammula Surya; Panthula, Veerendranath Reddy; Koduganti, Rekha Rani

2016-08-01

Alendronate (ALN), an aminobisphosphonate, inhibits osteoclastic bone resorption and also stimulates osteogenesis. Beta-Tricalcium Phosphate (β-TCP) is an osteoconductive graft material which provides a scaffold for bone formation and also a widely used drug delivery vehicle for growth factors and antibiotics. Drug delivery vehicles, like β-TCP, improve the potency of the drugs by specific local site delivery of the drug, optimal release characteristics and easy handling. The aim of the this study was to evaluate the bone formation potential of 400μg ALN delivered in β-TCP in the treatment of periodontal intra-osseous defects. Thirty patients with periodontal defects were randomly assigned to 400μg ALN + β-TCP + Saline (test) group and β-TCP + Saline (active-control) group. Clinical parameters like Clinical Attachment Level (CAL) gain, Probing Depth (PD) reduction, post-operative Gingival Recession (GR) were assessed from the baseline, 3 months and 6 months recordings. Radiographic parameters like Linear Bone Growth (LBG), Percentage Bone Fill (%BF), and change in alveolar crest height (ACH) were assessed from baseline and 6 months radiographs. Mean measurements in the ALN test group for CAL gain (3.4 ± 0.74 mm), PD reduction (4.33 ± 0.82 mm), LBG (2.88 ± 0.88 mm), and %BF (51.98 ± 15.84%) were significantly greater with a p-value <0.05 compared to the mean measurements of CAL gain (2.20 ± 0.86 mm), PD reduction (3.20 ± 1.15 mm), LBG (1.70 ± 0.39 mm), and %BF (30.35 ± 6.88%) of the control group. There was mild alveolar crestal apposition (0.32 ± 0.68 mm) in the ALN test group and mild alveolar crestal resorption (-0.24 ± 0.40 mm) in the control group. 400μg ALN combined with β-TCP bone graft material was effective in improving soft tissue parameters, inhibiting alveolar crestal resorption and enhancing bone formation, compared to β-TCP alone.

SLP-76 couples Syk to the osteoclast cytoskeleton.

PubMed

Reeve, Jennifer L; Zou, Wei; Liu, Yuli; Maltzman, Jonathan S; Ross, F Patrick; Teitelbaum, Steven L

2009-08-01

The capacity of the osteoclast (OC) to resorb bone is dictated by cytoskeletal organization, which in turn emanates from signals derived from the alpha(v)beta(3) integrin and c-Fms. Syk is key to these signals and, in other cells, this tyrosine kinase exerts its effects via intermediaries including the SLP adaptors, SLP-76 and BLNK (B cell linker). Thus, we asked whether these two SLP proteins regulate OC function. We find BLNK-deficient OCs are normal, whereas cytoskeletal organization of those lacking SLP-76 is delayed, thus modestly reducing bone resorption in vitro. Cytoskeletal organization and bone resorption are more profoundly arrested in cultured OCs deficient in BLNK and SLP-76 double knockout (DKO) phenotypes. In contrast, stimulated bone resorption in vivo is inhibited approximately 40% in either SLP-76(-/-) or DKO mice. This observation, taken with the fact that DKO OCs are rescued by retroviral transduction of only SLP-76, indicates that SLP-76 is the dominant SLP family member in the resorptive process. We also find SLP-76 is phosphorylated in a Syk-dependent manner. Furthermore, in the absence of the adaptor protein, integrin-mediated phosphorylation of Vav3, the OC cytoskeleton-organizing guanine nucleotide exchange factor, is abrogated. In keeping with a central role of SLP-76/Vav3 association in osteoclastic resorption, retroviral transduction of SLP-76, in which the Vav binding site is disrupted (3YF), fails to normalize the cytoskeleton of DKO OCs and the resorptive capacity of the cells. Finally, c-Fms-activated Syk also exerts its OC cytoskeleton-organizing effect in a SLP-76/Vav3-dependent manner.

[Calcitonin as an alternative treatment for root resorption].

PubMed

Pierce, A; Berg, J O; Lindskog, S

1989-01-01

Inflammatory root resorption is a common finding following trauma and will cause eventual destruction of the tooth root if left untreated. This study examined the effects of intrapulpal application of calcitonin, a hormone known to inhibit osteoclastic bone resorption, on experimental inflammatory root resorption induced in monkeys. Results were histologically evaluated using a morphometric technique and revealed that calcitonin was an effective medicament for the treatment of inflammatory root resorption. It was concluded that this hormone could be a useful therapeutic adjunct in difficult cases of external root resorption.

Association analysis of clinical aspects and vitamin D receptor gene polymorphism with external apical root resorption in orthodontic patients.

PubMed

Fontana, Maria Luiza S Simas Netta; de Souza, Cleber Machado; Bernardino, José Fabio; Hoette, Felix; Hoette, Maura Levi; Thum, Lotario; Ozawa, Terumi O; Capelozza Filho, Leopoldino; Olandoski, Marcia; Trevilatto, Paula Cristina

2012-09-01

Vitamin D is responsible for the regulation of certain genes at the transcription level, via interaction with the vitamin D receptor, and influences host immune responses and aspects of bone development, growth, and homeostasis. Our aim was to investigate the association of TaqI vitamin D receptor gene polymorphism with external apical root resorption during orthodontic treatment. Our subjects were 377 patients with Class II Division 1 malocclusion, divided into 3 groups: (1) 160 with external apical root resorption ≤1.43 mm, (2) 179 with external apical root resorption >1.43 mm), and (3) 38 untreated subjects. External apical root resorption of the maxillary incisors was evaluated on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, vitamin D receptor TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables with external apical root resorption (P <0.05). There was a higher proportion of external apical root resorption in orthodontically treated patients compared with the untreated subjects. In patients orthodontically treated, age higher than 14 years old, initial size of the maxillary incisor root superior to 30 mm, and premolar extraction were associated with increased external apical root resorption. Genotypes containing the C allele were weakly associated with protection against external apical root resorption (CC + CT × TT [odds ratio, 0.29; 95% confidence interval, 0.07-1.23; P = 0.091]) when treated orthodontic patients were compared to untreated individuals. Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Genistein supplementation increases bone turnover but does not prevent alcohol-induced bone loss in male mice.

PubMed

Yang, Carrie S; Mercer, Kelly E; Alund, Alexander W; Suva, Larry J; Badger, Thomas M; Ronis, Martin J J

2014-10-01

Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy protein-associated phytoestrogens such as genistein (GEN). In this study, male mice were pair-fed (PF), a control diet, an ethanol (EtOH) diet, or EtOH diet supplemented with 250 mg/kg of GEN for 8 weeks to test if GEN protects against bone loss associated with chronic drinking. Interestingly, alcohol consumption reduced cortical area and thickness and trabecular bone volume in both EtOH and EtOH/GEN groups when compared to the corresponding PF and PF/GEN controls, P < 0.05. However, in the trabecular bone compartment, we observed a significant increase in overall trabecular bone density in the PF/GEN group compared to the PF controls. Bone loss in the EtOH-treated mice was associated with the inhibition of osteoblastogenesis as indicated by decreased alkaline phosphatase staining in ex vivo bone marrow cultures, P < 0.05. GEN supplementation improved osteoblastogenesis in the EtOH/GEN cultures compared to the EtOH group, P < 0.05. Vertebral expression of bone-formation markers, osteocalcin, and runt-related transcription factor 2 (Runx2) was also significantly up-regulated in the PF/GEN and EtOH/GEN groups compared to the PF and EtOH-treated groups. GEN supplementation also increased the expression of receptor activator of nuclear factor κ-B ligand (RANKL) in the PF/GEN, an increase that persisted in the EtOH/GEN-treated animals (P < 0.05), and increased basal hydrogen peroxide production and RANKL mRNA expression in primary bone marrow cultures in vitro, P < 0.05. These findings suggest that GEN supplementation increases the overall bone remodeling and, in the context of chronic alcohol consumption, does not protect against the oxidative stress-associated EtOH-mediated bone resorption. © 2014 by the Society for Experimental Biology and Medicine.

Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice.

PubMed

Figeac, Florence; Andersen, Ditte C; Nipper Nielsen, Casper A; Ditzel, Nicholas; Sheikh, Søren P; Skjødt, Karsten; Kassem, Moustapha; Jensen, Charlotte H; Abdallah, Basem M

2018-05-01

Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss. Copyright © 2018 Elsevier Inc. All rights reserved.

PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

PubMed Central

Fujiwara, Toshifumi; Ye, Shiqiao; Winchell, Caylin G.; Andrews, Norma W.; Voth, Daniel E.; Varughese, Kottayil I.; Mackintosh, Samuel G.; Feng, Yunfeng; Nakamura, Takashi; Manolagas, Stavros C.

2016-01-01

Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts. Mechanistically, we indicated that DEF8 interacts with PLEKHM1 and promotes its binding to RAB7, whereas the binding of FAM98A and NDEL1 with PLEKHM1 connects lysosomes to microtubules. Importantly, suppression of these proteins results in lysosome positioning and bone resorption defects similar to those of Plekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7. PMID:27777970

Bone Metabolism on ISS Missions

NASA Technical Reports Server (NTRS)

Smith, S. M.; Heer, M. A.; Shackelford, L. C.; Zwart, S. R.

2014-01-01

Spaceflight-induced bone loss is associated with increased bone resorption (1, 2), and either unchanged or decreased rates of bone formation. Resistive exercise had been proposed as a countermeasure, and data from bed rest supported this concept (3). An interim resistive exercise device (iRED) was flown for early ISS crews. Unfortunately, the iRED provided no greater bone protection than on missions where only aerobic and muscular endurance exercises were available (4, 5). In 2008, the Advanced Resistive Exercise Device (ARED), a more robust device with much greater resistance capability, (6, 7) was launched to the ISS. Astronauts who had access to ARED, coupled with adequate energy intake and vitamin D status, returned from ISS missions with bone mineral densities virtually unchanged from preflight (7). Bone biochemical markers showed that while the resistive exercise and adequate energy consumption did not mitigate the increased bone resorption, bone formation was increased (7, 8). The typical drop in circulating parathyroid hormone did not occur in ARED crewmembers. In 2014, an updated look at the densitometry data was published. This study confirmed the initial findings with a much larger set of data. In 42 astronauts (33 male, 9 female), the bone mineral density response to flight was the same for men and women (9), and those with access to the ARED did not have the typical decrease in bone mineral density that was observed in early ISS crewmembers with access to the iRED (Figure 1) (7). Biochemical markers of bone formation and resorption responded similarly in men and women. These data are encouraging, and represent the first in-flight evidence in the history of human space flight that diet and exercise can maintain bone mineral density on long-duration missions. However, the maintenance of bone mineral density through bone remodeling, that is, increases in both resorption and formation, may yield a bone with strength characteristics different from those that existed before space flight. Studies to assess bone strength after flight are underway at NASA, to better understand the results of bone remodeling. Studies are also underway to evaluate optimized exercise protocols and nutritional countermeasures. Regardless, there is clear evidence of progress being made to protect bone during spaceflight.

Disorders of Bone Remodeling

PubMed Central

Feng, Xu; McDonald, Jay M.

2013-01-01

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

Facilitation of bone resorption activities in synovial lavage fluid patients with mandibular condyle fractures.

PubMed

Takano, H; Takahashi, T; Nakata, A; Nogami, S; Yusa, K; Kuwajima, S; Yamazaki, M; Fukuda, M

2016-05-01

The aim of this study was to investigate the bone resorption effect of the mediators delivered in joint cavity of patients with mandibular condyle fractures by detecting osteoclast markers using cellular biochemistry methods, and by analysing bone resorption activities via inducing osteoclast differentiation of the infiltrated cells from arthrocentesis. Sixteen joints in 10 patients with mandibular condyle fractures were evaluated. The control group consisted of synovial fluid (SF) samples from seven joints of four volunteers who had no clinical signs or symptoms involving the temporomandibular joint (TMJ) or disc displacement. We collected SF cells from all patients during therapeutic arthrocentesis. The infiltrating cells from TMJ SF were cultured, differentiated into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells and examined bone resorption activities. We also investigated factors related to osteoclast induction of SF, using ELISA procedures. Osteoclast-like cells were induced from the SF cells obtained from all patients with condylar fractures. These multinucleated giant cells were positive for TRAP and actin, and had the ability to absorb dentin slices. The levels of macrophage colony-stimulating factor (M-CSF), prostaglandin E2 (PGE2), soluble form of receptor activator of nuclear factor kappa-B ligand (sRANKL) and osteoprotegerin (OPG), in SF samples from the patients, were significantly higher than in the controls. These findings indicate that bone resorption activities in SF from patients with mandibular condyle fractures were upregulated and may participate in the pathogenesis and wound healing. © 2016 The Authors. Journal of Oral Rehabilitation Published by John Wiley & Sons Ltd.

Fully porous 3D printed titanium femoral stem to reduce stress-shielding following total hip arthroplasty.

PubMed

Arabnejad, Sajad; Johnston, Burnett; Tanzer, Michael; Pasini, Damiano

2017-08-01

Current hip replacement femoral implants are made of fully solid materials which all have stiffness considerably higher than that of bone. This mechanical mismatch can cause significant bone resorption secondary to stress shielding, which can lead to serious complications such as peri-prosthetic fracture during or after revision surgery. In this work, a high strength fully porous material with tunable mechanical properties is introduced for use in hip replacement design. The implant macro geometry is based off of a short stem taper-wedge implant compatible with minimally invasive hip replacement surgery. The implant micro-architecture is fine-tuned to locally mimic bone tissue properties which results in minimum bone resorption secondary to stress shielding. We present a systematic approach for the design of a 3D printed fully porous hip implant that encompasses the whole activity spectrum of implant development, from concept generation, multiscale mechanics of porous materials, material architecture tailoring, to additive manufacturing, and performance assessment via in vitro experiments in composite femurs. We show that the fully porous implant with an optimized material micro-structure can reduce the amount of bone loss secondary to stress shielding by 75% compared to a fully solid implant. This result also agrees with those of the in vitro quasi-physiological experimental model and the corresponding finite element model for both the optimized fully porous and fully solid implant. These studies demonstrate the merit and the potential of tuning material architecture to achieve a substantial reduction of bone resorption secondary to stress shielding. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1774-1783, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Three-Dimensional Dynamic Bone Histomorphometry

PubMed Central

Slyfield, C.R.; Tkachenko, E.V.; Wilson, D.L.; Hernandez, C.J.

2011-01-01

Dynamic bone histomorphometry is the standard method for measuring bone remodeling at the level of individual events. While dynamic bone histomorphometry is an invaluable tool for understanding osteoporosis and other metabolic bone diseases, the technique’s two-dimensional nature requires the use of stereology and prevents measures of individual remodeling event number and size. Here, we use a novel three-dimensional fluorescence imaging technique to achieve measures of individual resorption cavities and formation events. We perform this three-dimensional histomorphometry approach using a common model of postmenopausal osteoporosis, the ovariectomized rat. The three-dimensional images demonstrate the spatial relationship between resorption cavities and formation events consistent with the hemi-osteonal model of cancellous bone remodeling. Established ovariectomy was associated with significant increases in the number of resorption cavities per unit bone surface (2.38 ± 0.24 mm−2 SHAM v. 3.86 ± 0.35 mm−2 OVX, mean ± SD, p < 0.05) and total volume occupied by cavities per unit bone volume (0.38 ± 0.06% SHAM v. 1.12 ± 0.18% OVX, p < 0.001), but no difference in surface area per resorption cavity, maximum cavity depth, or cavity volume. Additionally, we find that established ovariectomy is associated with increased size of bone formation events due to merging of formation events (23,700 ± 6,890 μm2 SHAM v. 33,300 ± 7,950 μm2 OVX). No differences in mineral apposition rate (determined in 3D) were associated with established ovariectomy. That established estrogen depletion is associated with increased number of remodeling events with only subtle changes in remodeling event size suggests that circulating estrogens may have their primary effect on the origination of new basic multicellular units with relatively little effect on the progression and termination of active remodeling events. PMID:22028195

Immobilization-associated osteoporosis in primates

NASA Technical Reports Server (NTRS)

Young, D. R.; Niklowitz, W. J.; Brown, R. J.; Jee, W. S. S.

1986-01-01

Osteopenic changes in the tibial compact bone of fifteen adult male monkeys immobilized for up to 7 months are examined histologically. Osteonal formation in the proximal tibia is analyzed. The analysis reveals the loss of haversian bone in the proximal tibia, increased activation with excessive depth of penetration of osteoclastic activity, rapid bone loss, and resorption cavities of irregular size and orientation. Osteonal formation following reambulation is examined; the recovery of cortical is a repair and rejuvenation process characterized by refilling of resorption cavities and remodeling activities.

Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway.

PubMed

Ping, Zichuan; Hu, Xuanyang; Wang, Liangliang; Shi, Jiawei; Tao, Yunxia; Wu, Xiexing; Hou, Zhenyang; Guo, Xiaobin; Zhang, Wen; Yang, Huilin; Xu, Yaozeng; Wang, Zhirong; Geng, Dechun

2017-03-15

Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals. Melatonin alleviated titanium particle-induced depression of osteoblastic differentiation and mineralization in mMSCs. Mechanistically, melatonin was found to reduce the degradation of β-catenin, levels of which were decreased in presence of titanium particles both in vivo and in vitro. To further ensure whether the protective effect of melatonin was mediated by the Wnt/β-catenin signaling pathway, ICG-001, a selective β-catenin inhibitor, was added to the melatonin-treated groups and was found to attenuate the effect of melatonin on mMSC mineralization. We also demonstrated that melatonin modulated the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin via activation of Wnt/β-catenin signaling pathway. These findings strongly suggest that melatonin represents a promising candidate in the treatment of PPO. Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/β-catenin signaling pathway and enhancing osteogenic differentiation. Meanwhile, the ability of melatonin to modulate the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin mediated by Wnt/β-catenin signaling pathway, thereby suppressing osteoclastogenesis, may be implicated in the protective effects of melatonin on titanium-particle-induced bone resorption. These results suggested that melatonin can be considered as a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Meta-Analysis of Correlations Between Marginal Bone Resorption and High Insertion Torque of Dental Implants.

PubMed

Li, Haoyan; Liang, Yongqiang; Zheng, Qiang

2015-01-01

To evaluate correlations between marginal bone resorption and high insertion torque value (> 50 Ncm) of dental implants and to assess the significance of immediate and early/conventional loading of implants under a certain range torque value. Specific inclusion and exclusion criteria were used to retrieve eligible articles from Ovid, PubMed, and EBSCO up to December 2013. Screening of eligible studies, quality assessment, and data extraction were conducted in duplicate. The results were expressed as random/fixed-effects models using weighted mean differences for continuous outcomes with 95% confidence intervals. Initially, 154 articles were selected (11 from Ovid, 112 from PubMed, and 31 from EBSCO). After exclusion of duplicate articles and articles that did not meet the inclusion criteria, six clinical studies were selected. Assessment of P values revealed that correlations between marginal bone resorption and high insertion torque were not statistically significant and that there was no difference between immediately versus early/conventionally loaded implants under a certain range of torque. None of the meta-analyses revealed any statistically significant differences between high insertion torque and conventional insertion torque in terms of effects on marginal bone resorption.

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

PubMed Central

Gao, Yuhao; Grassi, Francesco; Ryan, Michaela Robbie; Terauchi, Masakazu; Page, Karen; Yang, Xiaoying; Weitzmann, M. Neale; Pacifici, Roberto

2006-01-01

T cell–produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-γ is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-γ has variable effects in bone is unknown. Here we show that IFN-γ blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-α. Analysis of the in vivo effects of IFN-γ in 3 mouse models of bone loss — ovariectomy, LPS injection, and inflammation via silencing of TGF-β signaling in T cells — reveals that the net effect of IFN-γ in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-γ has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-γ signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis. PMID:17173138

POTASSIUM CITRATE DECREASES BONE RESORPTION IN POSTMENOPAUSAL WOMEN WITH OSTEOPENIA: A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL.

PubMed

Gregory, Naina Sinha; Kumar, Rekha; Stein, Emily M; Alexander, Ellen; Christos, Paul; Bockman, Richard S; Rodman, John S

2015-12-01

Diets rich in animal protein, such as the typical American diet, are thought to create a high acid load. An association between acid load and bone loss has led to the idea that providing positive alkaline salt therapy could have beneficial effects on bone metabolism. The objective of this study was to investigate the effects of potassium citrate (K-citrate), 40 mEq daily, over 1 year on bone resorption and formation. A randomized, double-blind, placebo-controlled trial of 83 women with postmenopausal osteopenia. Levels of bone turnover markers, specifically urinary N-telopeptide of collagen type 1 (u-NTX), amino-terminal propeptide of type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) were compared. Changes in bone mineral density (BMD) were also examined. K-citrate decreased both u-NTX (P = .005) and serum P1NP (P<.001) starting at month 1 and continuing through month 12. No significant change was seen in BSAP or OC. No significant change was seen in lumbar or hip BMD between the 2 groups. In women with postmenopausal osteopenia, treatment with K-citrate for 1 year resulted in a significant decrease in markers of turnover. The effect on markers of bone formation was not consistent. K-citrate may serve as a potential treatment for bone loss that is well tolerated and without any significant known long-term consequences.

Direct influence of titanium and zirconia particles on the morphology and functionality of mature human osteoclasts.

PubMed

Pasold, Juliane; Markhoff, Jana; Tillmann, Jenny; Krogull, Martin; Pisowocki, Phillip; Bader, Rainer

2017-09-01

Within the last ten years of biomedical implants, the focus is increasingly on bioceramics, specifically on zirconia (ZrO 2 ). Hence, we analyzed the impact of ZrO 2 particles in comparison to titanium particles on mature human osteoclasts (OCs) as little is known about the direct effect of wear particles on mature OCs and their role in the osteolytic process during aseptic endoprosthesis loosening. Changes in cell morphology and functionality of OCs incubated with particles in different concentrations were investigated in vitro. OCs tend to be enlarged after three days of cultivation with both types of particles, especially with high concentrations of ZrO 2 , suggesting increased cell fusion. Further, we identified significantly increased expression of OC specific and bone matrix related genes: VNR, RANK, TRAP, and CTSK pointing on a direct stimulatory particle effect on the functionality of mature OCs. In completion, we quantified the bone resorption activity of particle treated mature OCs but could not detect a significant difference in bone resorption compared to OCs cultivated without particles. However, we could identify significantly higher gene expression of MMP-1 in particle treated OCs compared to untreated control OCs after three days of incubation. We also detected an impaired production of the tissue inhibitor of metalloproteinase, especially for OCs treated with high ZrO 2 concentrations. In conclusion, our in vitro data show that abrasion particles could have a direct influence on mature OCs and therefore could promote increased OC-mediated bone resorption during aseptic loosening of total joint replacements. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2608-2615, 2017. © 2017 Wiley Periodicals, Inc.

Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study.

PubMed

Tanaka, Shinya; Yoshida, Akira; Kono, Shinjiro; Ito, Manabu

2017-05-01

Evidence related to the effectiveness of combination drug therapy for the treatment of osteoporosis is currently considered insufficient. Therefore, this study was performed to clarify the effects of monotherapy, and combination therapy, with a bisphosphonate (minodronic acid hydrate), a bone resorption inhibitor, and calcitonin (elcatonin), which is effective for the alleviation of pain due to vertebral fractures in osteoporotic patients. Study participants comprised of 51 female subjects with post-menopausal osteoporosis, whose main complaint was acute lower back pain caused by vertebral fractures. Subjects were randomly allocated into three groups and then administered with either intramuscular injections of elcatonin at a dose of 20 units weekly, minodronic acid hydrate at a dose of 1 mg daily, or a combination of these two drugs. As primary endpoints, time-dependent changes in levels of pain were assessed using a visual analog scale from baseline to 6 months of duration. In addition, we examined the effects of monotherapies, and a combination therapy on bone resorption, with changes in bone mineral density at 4 sites and advanced hip assessment parameters from baseline to 6 months. A two-tailed significance level of 5% was used for hypothesis testing. Elcatonin monotherapy showed some alleviation of pain immediately after any vertebral fractures, which was more than in the minodronic acid hydrate monotherapy group. In addition, the minodronic acid hydrate monotherapy group experienced more effective inhibited bone resorption than the elcatonin monotherapy group. In the combination therapy, the efficacy for alleviating pain and inhibiting bone resorption was equivalent to the effect observed in the elcatonin and minodronic acid hydrate monotherapy groups respectively, with further improved values of bone mineral density observed in the femoral neck and lumbar vertebrae, and in parameters of advanced hip assessment compared with both monotherapy groups. Combination therapy with elcatonin and minodronic acid hydrate appears to be an effective treatment for osteoporosis patients with lower back pain, caused by fresh vertebral fractures. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The response of bone to unloading

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Halloran, B. P.

1999-01-01

Skeletal unloading leads to decreased bone formation and decreased bone mass. Bone resorption is uncoupled from bone formation, contributing to the bone loss. During spaceflight bone is lost principally from the bones most loaded in the 1-g environment, and some redistribution of bone from the lower extremities to the head appears to take place. Although changes in calcitropic hormones have been demonstrated during skeletal unloading (PTH and 1,25(OH)2D decrease), it remains unclear whether such changes account for or are in response to the changes in bone formation and resorption. Bed rest studies with human volunteers and hindlimb elevation studies with rats have provided useful data to help explain the changes in bone formation during spaceflight. These models of skeletal unloading reproduce a number of the conditions associated with microgravity, and the findings from such studies confirm many of the observations made during spaceflight. Determining the mechanism(s) by which loading of bone is sensed and translated into a signal(s) controlling bone formation remains the holy grail in this field. Such investigations couple biophysics to biochemistry to cell and molecular biology. Although studies with cell cultures have revealed biochemical responses to mechanical loads comparable to that seen in intact bone, it seems likely that matrix-cell interactions underlie much of the mechanocoupling. The role for systemic hormones such as PTH, GH, and 1,25(OH)2D compared to locally produced factors such as IGF-I, PTHrP, BMPs, and TGF-beta in modulating the cellular response to load remains unclear. As the mechanism(s) by which bone responds to mechanical load with increased bone formation are further elucidated, applications of this knowledge to other etiologies of osteoporosis are likely to develop. Skeletal unloading provides a perturbation in bone mineral homeostasis that can be used to understand the mechanisms by which bone mineral homeostasis is maintained, with the expectation that such understanding will lead to effective treatment for disuse osteoporosis.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events

PubMed Central

Thomadakis, George; Fourie, Jeanine; Lemmer, Johan

2016-01-01

Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption. PMID:27119080

Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway

PubMed Central

Duan, Xiaohong; Liu, Jin; Zheng, Xueni; Wang, Zhe; Zhang, Yanli; Hao, Ying; Yang, Tielin; Deng, Hongwen

2016-01-01

Vacuolar-type H +-ATPase (V-ATPase) is a highly conserved, ancient enzyme that couples the energy of ATP hydrolysis to proton transport across vesicular and plasma membranes of eukaryotic cells. Previously reported mutations of various V-ATPase subunits are associated with increased bone density. We now show that haploinsufficiency for the H subunit of the V1 domain (ATP6V1H) is associated with osteoporosis in humans and mice. A genome-wide SNP array analysis of 1625 Han Chinese found that 4 of 15 tag SNPs (26.7%) within ATP6V1H were significantly associated with low spine bone mineral density. Atp6v1h+/- knockout mice generated by the CRISPR/Cas9 technique had decreased bone remodeling and a net bone matrix loss. Atp6v1h+/- osteoclasts showed impaired bone formation and increased bone resorption. The increased intracellular pH of Atp6v1h+/- osteoclasts downregulated TGF-β1 activation, thereby reducing induction of osteoblast formation but the bone mineralization was not altered. However, bone formation was reduced more than bone resorption. Our data provide evidence that partial loss of ATP6V1H function results in osteoporosis/osteopenia. We propose that defective osteoclast formation triggers impaired bone formation by altering bone remodeling. In the future, ATP6V1H might, therefore, serve as a target for the therapy of osteoporosis. PMID:27924156

Evaluation of novel resorbable membranes for bone augmentation in a rat model.

PubMed

Zeng, Ni; van Leeuwen, Anne; Yuan, Huipin; Bos, Ruud R M; Grijpma, Dirk W; Kuijer, Roel

2016-02-01

Our study compared two novel, biodegradable poly(trimethylene carbonate) (PTMC) barrier membranes to clinically applied barrier membranes in maintaining volume of block autologous bone grafts in a rat mandible model. Two hundred and forty rats were included in this study. Block autologous bone grafts of 5 mm in diameter were harvested from the mandibular angles and transplanted onto the contralateral side. The bone grafts were either covered with a membrane or left uncovered. The applied membranes included pure PTMC membranes, biphasic calcium phosphate (BCP) incorporated PTMC composite membranes, expanded poly(tetrafluoroethylene) (e-PTFE) membranes (Tex) and collagen membranes (Geistlich Bio-Gide). After 2, 4 and 12 weeks, the rat mandibles were retrieved and analysed by histological evaluation and μCT quantification. The histological evaluation revealed that in time the block autologous bone graft was well integrated to the recipient bone via gradually maturing newly formed bone and did not show signs of resorption, independent of membrane coverage or types of membrane. μCT quantification showed the volume of the bone graft and recipient bone together was maintained by new bone formation and recipient bone resorption. Our study showed that the use of PTMC membranes and PTMC-BCP composite membranes resulted in similar bone remodelling to the collagen membranes and e-PTFE membranes and that the use of barrier membranes did not interfere with bone remodelling of the bone grafts and recipient bones. However, the used barrier membranes seemed not to contribute in maintaining the volume of block autologous bone grafts. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Remodeling of alveolar bone crest after molar intrusion with skeletal anchorage system in dogs.

PubMed

Kanzaki, Reiko; Daimaruya, Takayoshi; Takahashi, Ichiro; Mitani, Hideo; Sugawara, Junji

2007-03-01

The aim of this study was to clarify the influence of supra-alveolar fibers on alveolar bone crest remodeling when several teeth are intruded simultaneously. The skeletal anchorage system was used to bilaterally intrude the second and third premolars of 10 beagles; supracrestal fiberotomies were performed on 1 side only. The amount of intrusion was greater and the amount of alveolar bone resorption was smaller in the fiberotomy group compared with the nonfiberotomy group. The health status (pocket depth <3 mm) of the dentogingival unit was maintained in the nonfiberotomy group during the experimental period. In the fiberotomy group, the number of osteoclasts on the marginal alveolar crest was less than in the nonfiberotomy group. The dense fiber bundles connecting the second and third premolars and the gingival attachments were maintained in the nonfiberotomy group. Pressure from the supra-alveolar fibers generated by segmental molar intrusion with the skeletal anchorage system induced alveolar bone crest resorption and remodeling, and, as a result, it prevented deepening of the gingival pocket. Periodontal status was good during tooth intrusion.

IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction.

PubMed

AlShwaimi, Emad; Berggreen, Ellen; Furusho, Hisako; Rossall, Jonathan Caleb; Dobeck, Justine; Yoganathan, Subbiah; Stashenko, Philip; Sasaki, Hajime

2013-08-15

IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and β isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1β and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation.

The botanical molecule p-hydroxycinnamic acid as a new osteogenic agent: insight into the treatment of cancer bone metastases.

PubMed

Yamaguchi, Masayoshi

2016-10-01

Bone homeostasis is maintained through a balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss with aging is induced by decreasing in osteoblastic bone formation and increasing in osteoclastic bone resorption, thereby leading to osteoporosis. Osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public heath problem. Pharmacologic and nutritional factors may play a role in the prevention and treatment of bone loss with aging. p-Hydroxycinnamic acid (HCA), which stimulates bone mineralization in mouse bone tissues in vitro, has been found to be present in the leafstalk of wasabi (Wasabi japonica MATSUM) among various food and plants. Other phenolic acids including cinnamic acid, ferulic acid, caffeic acid and 3,4-dimethoxycinnamic acid did not have osteogenic effects. HCA was demonstrated to stimulate osteoblastic bone formation and suppresses osteoclastic bone resorption in vitro by antagonizing activation of the nuclear factor kappa B. Oral administration of HCA was found to exhibit restorative effects on bone loss induced by ovariectomy and diabetic states, supporting a role in the treatment of osteoporosis. Moreover, HCA was demonstrated to prevent the suppressed osteoblastic mineralization and the enhanced osteoclastogenesis in mouse bone marrow cells cocultured with bone metastatic MDA-MB-231 human breast cancer cells in vitro. The botanical molecule HCA, as a new osteogenic agent, is suggested to play a role in the treatment of cancer bone metastases. This review will discuss an advanced recent finding that HCA may be a useful agent to treat bone metabolic disorder.

Resorption kinetics of four hydroxyapatite-based ceramics by particle induced X-ray emission and neutron activation analysis

NASA Astrophysics Data System (ADS)

Jallot, E.; Irigaray, J. L.; Oudadesse, H.; Brun, V.; Weber, G.; Frayssinet, P.

1999-05-01

From the viewpoint of hard tissue response to implant materials, calcium phosphates are probably the most compatible materials presently known. During the last few years, much attention has been paid to hydroxyapatite and β-tricalcium phosphate as potential biomaterials for bone substitute. A good implantation of biomaterials in the skeleton is to reach full integration of non-living implant with living bone. The aim of this study is to compare the resorption kinetics of four kinds of calcium phosphate ceramics: hydroxyapatite (Ca{10}(PO4)6(OH)2), hydroxyapatite doped with manganese or zinc and a composite material of 75% hydroxyapatite and 25% β-tricalcium phosphate (Ca3(PO4)2). Cylinders (5 6 mm in diameter) of these ceramics were packed into holes made in the femur diaphysis of mature ovine. At 2, 4, 8, 12, 16, 20, 28, 36 and 48 weeks after the operation, bone/implant interface was embedded in polymethylmethacrylate. We used the PIXE method (particle induced X-ray emission) to measure the distribution of mineral elements (Ca, P, Sr, Zn, Mn and Fe) at the bone/implant interface. At 4, 8, 16, 28 and 48 weeks after implantation we studied a biopsy of the ceramics by neutron activation method. Then, we have a global measurement of mineral elements in the biomaterial. The results showed that the resorption kinetics of hydroxyapatite doped with zinc was faster than that of the three other bioceramics.

Osteocyte apoptosis and control of bone resorption following ovariectomy in mice.

PubMed

Emerton, K B; Hu, B; Woo, A A; Sinofsky, A; Hernandez, C; Majeska, R J; Jepsen, K J; Schaffler, M B

2010-03-01

Osteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli; however, precise spatial and temporal relationships between the two events have not been clearly established. The purpose of this study was to characterize the patterns of osteocyte apoptosis in relation to bone resorption following ovariectomy to test whether osteocyte apoptosis occurs preferentially in areas known to activate resorption. Moreover, we report that osteocyte apoptosis is necessary to initiate endocortical remodeling in response to estrogen withdrawal. Adult female C57BL/6J mice (17 weeks old) underwent either bilateral ovariectomy (OVX), or sham surgery (SHAM) and were euthanized on days 3, 7, 14, or 21 days after OVX. Diaphyseal cross-sections were stained by immunohistochemistry for activated caspase-3 as a marker of apoptosis. The percentages of caspase-positive stained osteocytes (Casp+Ot.) were measured along major and minor anatomical axes around the femoral diaphysis to evaluate the distribution of osteocyte apoptosis after estrogen loss; resorption surface was measured at the adjacent endocortical regions. In a second study to test whether osteocyte apoptosis plays a regulatory role in the initiation of bone resorption, a group of OVX mice received the pan-caspase inhibitor, QVDOPh, to inhibit osteocyte apoptosis. Remaining experimental and sham groups received either QVD or Vehicle. OVX increased osteocyte apoptosis in a non-uniform distribution throughout the femoral diaphyses. Increases in Casp+osteocytes were predominantly located in the posterior diaphyseal cortex. Here, the number of apoptotic osteocytes 4- to 7-fold higher than sham controls (p<0.005) by day 3 post-OVX and remained elevated. Increases in resorption post-OVX also occurred along the posterior endocortical surface overlying the region of osteocyte apoptosis, but these increases occurred only at 14 and 21 days post-OVX (p<0.002) well after the increases in osteocyte apoptosis. Treatment with QVD in OVX animals suppressed osteocyte apoptosis, with levels in QVD-treated samples equivalent to baseline. Moreover, the increases in osteoclastic resorption normally observed after estrogen loss did not occur in OVX mice treated with QVD. The results of this study demonstrate that osteocyte apoptosis following estrogen loss occur regionally, rather than uniformly throughout the cortex. We also showed that estrogen loss increased osteocyte apoptosis. Apoptotic osteocytes were overwhelmingly localized within the posterior cortical region, the location where endocortical resorption was subsequently activated in ovariectomized mice. Finally, the increases in osteoclastic resorption normally observed after estrogen withdrawal did not occur in the absence of osteocyte apoptosis indicating that this apoptosis is necessary to activate endocortical remodeling following estrogen loss.

Mineral balance and bone turnover in adolescents with anorexia nervosa.

PubMed

Abrams, S A; Silber, T J; Esteban, N V; Vieira, N E; Stuff, J E; Meyers, R; Majd, M; Yergey, A L

1993-08-01

We evaluated seven female adolescents with anorexia nervosa to determine whether calcium metabolism was affected by their disorder. We measured calcium absorption, urinary calcium excretion, and calcium kinetics, using a dual-tracer, stable-isotope technique during the first weeks of an inpatient nutritional rehabilitation program. Results were compared with those from a control group of seven healthy adolescent girls of similar ages. The percentage of absorption of calcium was lower in subjects with anorexia nervosa than in control subjects (16.2% +/- 6.3% vs 24.6% +/- 7.2%; p < 0.05). Urinary calcium excretion was greater in subjects with anorexia nervosa than in control subjects (6.4 +/- 2.5 vs 1.6 +/- 0.7 mg.kg-1 x day-1; p < 0.01) and was associated with bone resorption rather than calcium hyper-absorption. Calcium kinetic studies demonstrated a decreased rate of bone formation and an increased rate of bone resorption. These results suggest marked abnormalities in mineral metabolism in patients with anorexia nervosa. From these results, we hypothesize that improvement in bone mineralization during recovery from anorexia nervosa will require resolution of hormonal abnormalities, including hypercortisolism, in addition to increased calcium intake.

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

PubMed Central

Toro, E.J.; Zuo, J.; Guiterrez, A.; La Rosa, R.L.; Gawron, A.J.; Bradaschia-Correa, V.; Arana-Chavez, V.; Dolce, C.; Rivera, M.F.; Kesavalu, L.; Bhattacharyya, I.; Neubert, J.K.; Holliday, L.S.

2013-01-01

Enoxacin inhibits binding between the B-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments, and also between osteoclast formation and bone resorption in vitro. We hypothesized that a bisphosphonate derivative of enoxacin, bis-enoxacin (BE), which was previously studied as a bone-directed antibiotic, might have similar activities. BE shared a number of characteristics with enoxacin: It blocked binding between the recombinant B-subunit and microfilaments and inhibited osteoclastogenesis in cell culture with IC50s of about 10 µM in each case. BE did not alter the relative expression levels of various osteoclast-specific proteins. Even though tartrate-resistant acid phosphatase 5b was expressed, proteolytic activation of the latent pro-enzyme was inhibited. However, unlike enoxacin, BE stimulated caspase-3 activity. BE bound to bone slices and inhibited bone resorption by osteoclasts on BE-coated bone slices in cell culture. BE reduced the amount of orthodontic tooth movement achieved in rats after 28 days. Analysis of these data suggests that BE is a novel anti-resorptive molecule that is active both in vitro and in vivo and may have clinical uses. Abbreviations: BE, bis-enoxacin; V-ATPase, vacuolar H+-ATPase; TRAP, tartrate-resistant acid phosphatase; αMEM D10, minimal essential media, alpha modification with 10% fetal bovine serum; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; RANKL, receptor activator of nuclear factor kappa B-ligand; NFATc1, nuclear factor of activated T-cells; ADAM, a disintegrin and metalloprotease domain; OTM, orthodontic tooth movement. PMID:23958763

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

PubMed Central

Qiu, Zuo-Cheng; Dong, Xiao-Li; Dai, Yi; Xiao, Gao-Keng; Wang, Xin-Luan; Wong, Ka-Chun; Wong, Man-Sau; Yao, Xin-Sheng

2016-01-01

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk. PMID:27999266

Dynamic Simulation of Three Dimensional Architectural and Mechanical Alterations in Human Trabecular Bone during Menopause

PubMed Central

Liu, X. Sherry; Huang, Angela H.; Zhang, X. Henry; Sajda, Paul; Ji, Baohua; Guo, X. Edward

2008-01-01

A three dimensional (3D) computational simulation of dynamic process of trabecular bone remodeling was developed with all the parameters derived from physiological and clinical data. Contributions of the microstructural bone formation deficits: trabecular plate perforations, trabecular rod breakages, and isolated bone fragments, to the rapid bone loss and disruption of trabecular microarchitecture during menopause were studied. Eighteen human trabecular bone samples from femoral neck (FN) and spine were scanned using a micro computed tomography (μCT) system. Bone resorption and formation were simulated as a computational cycle corresponding to 40-day resorption/160-day formation. Resorption cavities were randomly created over the bone surface according to the activation frequency, which was strictly based on clinical data. Every resorption cavity was refilled during formation unless it caused trabecular plate perforation, trabecular rod breakage or isolated fragments. A 20-year-period starting 5 years before and ending 15 years after menopause was simulated for each specimen. Elastic moduli, standard and individual trabeculae segmentation (ITS)-based morphological parameters were evaluated for each simulated 3D image. For both spine and FN groups, the time courses of predicted bone loss pattern by microstructural bone formation deficits were fairly consistent with the clinical measurements. The percentage of bone loss due to trabecular plate perforation, trabecular rod breakage, and isolated bone fragments were 73.2%, 18.9% and 7.9% at the simulated 15 years after menopause. The ITS-based plate fraction (pBV/BV), mean plate surface area (pTb.S), plate number density (pTb.N), and mean rod thickness (rTb.Th) decreased while rod fraction (rBV/BV) and rod number density (rTb.N) increased after the simulated menopause. The dynamic bone remodeling simulation based on microstructural bone formation deficits predicted the time course of menopausal bone loss pattern of spine and FN. Microstructural plate perforation could be the primary cause of menopausal trabecular bone loss. The combined effect of trabeculae perforation, breakage, and isolated fragments resulted in fewer and smaller trabecular plates and more but thinner trabecular rods. PMID:18550463

The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures.

PubMed

Qin, Weiping; Sun, Li; Cao, Jay; Peng, Yuanzhen; Collier, Lauren; Wu, Yong; Creasey, Graham; Li, Jianhua; Qin, Yiwen; Jarvis, Jonathan; Bauman, William A; Zaidi, Mone; Cardozo, Christopher

2013-05-10

Mechanisms by which muscle regulates bone are poorly understood. Electrically stimulated muscle contraction reversed elevations in bone resorption and increased Wnt signaling in bone-derived cells after spinal cord transection. Muscle contraction reduced resorption of unloaded bone independently of the CNS, through mechanical effects and, potentially, nonmechanical signals (e.g. myokines). The study provides new insights regarding muscle-bone interactions. Muscle and bone work as a functional unit. Cellular and molecular mechanisms underlying effects of muscle activity on bone mass are largely unknown. Spinal cord injury (SCI) causes muscle paralysis and extensive sublesional bone loss and disrupts neural connections between the central nervous system (CNS) and bone. Muscle contraction elicited by electrical stimulation (ES) of nerves partially protects against SCI-related bone loss. Thus, application of ES after SCI provides an opportunity to study the effects of muscle activity on bone and roles of the CNS in this interaction, as well as the underlying mechanisms. Using a rat model of SCI, the effects on bone of ES-induced muscle contraction were characterized. The SCI-mediated increase in serum C-terminal telopeptide of type I collagen (CTX) was completely reversed by ES. In ex vivo bone marrow cell cultures, SCI increased the number of osteoclasts and their expression of mRNA for several osteoclast differentiation markers, whereas ES significantly reduced these changes; SCI decreased osteoblast numbers, but increased expression in these cells of receptor activator of NF-κB ligand (RANKL) mRNA, whereas ES increased expression of osteoprotegerin (OPG) and the OPG/RANKL ratio. A microarray analysis revealed that ES partially reversed SCI-induced alterations in expression of genes involved in signaling through Wnt, FSH, parathyroid hormone (PTH), oxytocin, and calcineurin/nuclear factor of activated T-cells (NFAT) pathways. ES mitigated SCI-mediated increases in mRNA levels for the Wnt inhibitors DKK1, sFRP2, and sclerostin in ex vivo cultured osteoblasts. Our results demonstrate an anti-bone-resorptive activity of muscle contraction by ES that develops rapidly and is independent of the CNS. The pathways involved, particularly Wnt signaling, suggest future strategies to minimize bone loss after immobilization.

Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells.

PubMed

Alasmari, Abeer; Lin, Shih-Chun; Dibart, Serge; Salih, Erdjan

2016-08-01

Anti-resorptive bisphosphonates (BPs) have been clinically used to prevent cancer-bone metastasis and cancer-induced bone pathologies despite the fact that the phenotypic response of the cancer-bone interactions to BP exposure is "uncharted territory". This study offers unique insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. We provide extraordinary cryptic details of the biological events that occur as a result of alendronate (ALN) treatment using 3D live cancer-bone model systems under specific bone remodeling stages. While cancer cells are susceptible to BP treatment in the absence of bone, they are totally unaffected in the presence of bone. Cancer cells colonize live bone irrespective of whether the bone is committed to bone resorption or formation and hence, cancer-bone metastasis/interactions are though to be "independent of bone remodeling stages". In our 3D live bone model systems, ALN inhibited bone resorption at the osteoclast differentiation level through effects of mineral-bound ALN on osteocytes and osteoblasts. The mineral-bound ALN rendered bone incapable of osteoblast differentiation, while cancer cells colonize the bone with striking morphological adaptations which led to a conclusion that a direct anti-cancer effect of BPs in a "live or in vivo" bone microenvironment is implausible. The above studies were complemented with mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminished endosteal cell population and degenerated osteocytes within the mineralized bone matrix.

Nicotine Affects Bone Resorption and Suppresses the Expression of Cathepsin K, MMP-9 and Vacuolar-Type H+-ATPase d2 and Actin Organization in Osteoclasts

PubMed Central

Tanaka, Hideki; Tanabe, Natsuko; Kawato, Takayuki; Nakai, Kumiko; Kariya, Taro; Matsumoto, Sakurako; Zhao, Ning; Motohashi, Masafumi; Maeno, Masao

2013-01-01

Tobacco smoking is an important risk factor for the development of several cancers, osteoporosis, and inflammatory diseases such as periodontitis. Nicotine is one of the major components of tobacco. In previous study, we showed that nicotine inhibits mineralized nodule formation by osteoblasts, and the culture medium from osteoblasts containing nicotine and lipopolysaccharide increases osteoclast differentiation. However, the direct effect of nicotine on the differentiation and function of osteoclasts is poorly understood. Thus, we examined the direct effects of nicotine on the expression of nicotine receptors and bone resorption-related enzymes, mineral resorption, actin organization, and bone resorption using RAW264.7 cells and bone marrow cells as osteoclast precursors. Cells were cultured with 10−5, 10−4, or 10−3 M nicotine and/or 50 µM α-bungarotoxin (btx), an 7 nicotine receptor antagonist, in differentiation medium containing the soluble RANKL for up 7 days. 1–5, 7, 9, and 10 nicotine receptors were expressed on RAW264.7 cells. The expression of 7 nicotine receptor was increased by the addition of nicotine. Nicotine suppressed the number of tartrate-resistant acid phosphatase positive multinuclear osteoclasts with large nuclei(≥10 nuclei), and decreased the planar area of each cell. Nicotine decreased expression of cathepsin K, MMP-9, and V-ATPase d2. Btx inhibited nicotine effects. Nicotine increased CA II expression although decreased the expression of V-ATPase d2 and the distribution of F-actin. Nicotine suppressed the planar area of resorption pit by osteoclasts, but did not affect mineral resorption. These results suggest that nicotine increased the number of osteoclasts with small nuclei, but suppressed the number of osteoclasts with large nuclei. Moreover, nicotine reduced the planar area of resorption pit by suppressing the number of osteoclasts with large nuclei, V-ATPase d2, cathepsin K and MMP-9 expression and actin organization. PMID:23555029

Bone remodelling of a proximal femur with the thrust plate prosthesis: an in vitro case.

PubMed

Taylor, W R; Ploeg, H; Hertig, D; Warner, M D; Clift, S E

2004-06-01

The key to the development of a successful implant is an understanding of the effect of bone remodelling on its long-term fixation. In this study, clinically observed patterns of bone remodelling have been compared with computer-based predictions for one particular design of prosthesis, the Thrust Plate Prosthesis (Centerpulse Orthopedics, Winterthur, Switzerland). Three-dimensional finite-element models were created using geometrical and bone density data obtained from CT scanning. Results from the bone remodelling simulation indicated that varying the relative rate of bone deposition/resorption and the interfacial conditions between the bone and the implant could produce the trend towards the two clinically observed patterns of remodelling.

In vitro and in vivo investigation of bisphosphonate-loaded hydroxyapatite particles for peri-implant bone augmentation.

PubMed

Kettenberger, Ulrike; Luginbuehl, Vera; Procter, Philip; Pioletti, Dominique P

2017-07-01

Locally applied bisphosphonates, such as zoledronate, have been shown in several studies to inhibit peri-implant bone resorption and recently to enhance peri-implant bone formation. Studies have also demonstrated positive effects of hydroxyapatite (HA) particles on peri-implant bone regeneration and an enhancement of the anti-resorptive effect of bisphosphonates in the presence of calcium. In the present study, both hydroxyapatite nanoparticles (nHA) and zoledronate were combined to achieve a strong reinforcing effect on peri-implant bone. The nHA-zoledronate combination was first investigated in vitro with a pre-osteoclastic cell assay (RAW 264.7) and then in vivo in a rat model of postmenopausal osteoporosis. The in vitro study confirmed that the inhibitory effect of zoledronate on murine osteoclast precursor cells was enhanced by loading the drug on nHA. For the in vivo investigation, either zoledronate-loaded or pure nHA were integrated in hyaluronic acid hydrogel. The gels were injected in screw holes that had been predrilled in rat femoral condyles before the insertion of miniature screws. Micro-CT-based dynamic histomorphometry and histology revealed an unexpected rapid mineralization of the hydrogel in vivo through formation of granules, which served as scaffold for new bone formation. The delivery of zoledronate-loaded nHA further inhibited a degradation of the mineralized hydrogel as well as a resorption of the peri-implant bone as effectively as unbound zoledronate. Hyaluronic acid with zoledronate-loaded nHA, thanks to its dual effect on inducing a rapid mineralization and preventing resorption, is a promising versatile material for bone repair and augmentation. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Parathyroid hormone and its analogues--molecular mechanisms of action and efficacy in osteoporosis therapy.

PubMed

Misiorowski, Waldemar

2011-01-01

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.

[Parathyroid hormone and its analogues - molecular mechanisms of action and efficacy of osteoporosis therapy].

PubMed

Misiorowski, Waldemar

2011-01-01

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.

BONE TURNOVER IN OSTEOPOROTIC WOMEN DURING LONG-TERM ORAL BISPHOSPHONATES TREATMENT: IMPLICATIONS FOR TREATMENT FAILURE AND "DRUG HOLIDAY" IN THE REAL WORLD.

PubMed

Liel, Yair; Plakht, Ygal; Tailakh, Muhammad Abu

2017-07-01

Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Gastrodin inhibits osteoclastogenesis via down-regulating the NFATc1 signaling pathway and stimulates osseointegration in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Feng; Shen, Yi; Liu, Bo

Bone is a rigid yet dynamic organ, and this dynamism is mediated by the delicate balance between osteoclastic bone resorption and osteoblastic bone formation. However, excessive activation of osteoclasts is responsible for many bone diseases such as osteoporosis, Paget disease, and tumor bone metastasis. Agents that could inhibit osteoclast formation or function are regarded as promising alternatives to treat osteoclast-related diseases. Recently, traditional Chinese medicine has attracted attention because of its multiple activities in bone metabolism. Among them, gastrodin has been reported as an anti-osteoporosis agent that reduces reactive oxygen species. However, the direct action of gastrodin on osteoclast differentiationmore » and bone resorption, and its underlying molecular mechanism, remain unknown. In this study, we investigated the effects of gastrodin on receptor activator NF-κB ligand (RANKL)-activated osteoclasts formation and bone resorption. Our results showed that gastrodin retarded RANKL-induced osteoclast differentiation efficiently by downregulating transcriptional and translational expression of nuclear factor of activated T cells cl (NFATc1), a major factor in RANKL-mediated osteoclastogenesis. Meanwhile, gastrodin prevented osteoclast maturation and migration by inhibiting the gene expression of dendrocyte expressed seven transmembrane protein (DC-STAMP), an osteoclastic-specific gene that controls cells fusion and movement. And gastrodin prevented RANKL-induced osteoclastic bone erosion in vitro. In addition, gastrodin also stimulated bone mesenchymal stem cell (BMSC) spreading and osseointegration in titanium plate. In summary, gastrodin could prevent osteoclasts formation and bone resorption via blockage of NFATc1 activity, and stimulate osseointegration in vitro. Gastrodin could be developed as a potent phytochemical candidate to treat osteolytic diseases. - Highlights: • Gastrodin suppresses osteoclasts formation and function in vitro. • Gastrodin impairs NFATc1 activation. • Gastrodin stimulates osseointegration in vitro. • Gastrodin may be used for treating osteoclast related diseases.« less

Short-term effects of mineral particle sizes on cellular degradation activity after implantation of injectable calcium phosphate biomaterials and the consequences for bone substitution.

PubMed

Gauthier, O; Bouler, J M; Weiss, P; Bosco, J; Aguado, E; Daculsi, G

1999-08-01

This in vivo study investigated the influence of two calcium phosphate particle sizes (40-80 microm and 200-500 microm) on the cellular degradation activity associated with the bone substitution process of two injectable bone substitutes (IBS). The tested biomaterials were obtained by associating a biphasic calcium phosphate (BCP) ceramic mineral phase and a 3% aqueous solution of a cellulosic polymer (hydroxypropylmethylcellulose). Both were injected into osseous defects at the distal end of rabbit femurs for 2- and 3-week periods. Quantitative results for tartrate-resistant acid phosphatase (TRAP) cellular activity, new bone formation, and ceramic resorption were studied for statistical purposes. Positive TRAP-stained degradation cells were significantly more numerous for IBS 40-80 than IBS 200-500, regardless of implantation time. BCP degradation was quite marked during the first 2 weeks for IBS 40-80, and bone colonization occurred more extensively for IBS 40-80 than for IBS 200-500. The resorption-bone substitution process occurred earlier and faster for IBS 40-80 than IBS 200-500. Both tested IBS displayed similar biological efficiency, with conserved in vivo bioactivity and bone-filling ability. Differences in calcium phosphate particle sizes influenced cellular degradation activity and ceramic resorption but were compatible with efficient bone substitution.

In long-term bedridden elderly patients with dietary copper deficiency, biochemical markers of bone resorption are increased with copper supplementation during 12 weeks.

PubMed

Kawada, Etsuo; Moridaira, Kazuaki; Itoh, Katsuhiko; Hoshino, Ayami; Tamura, Jun'ichi; Morita, Toyoho

2006-01-01

Although the effect of copper on bone has been tested in animals and healthy subjects, no studies concerning the effect of copper supplementation on bone metabolism in patients with copper deficiency have been reported because of the rarity of these patients. This study was conducted to investigate the effect of copper supplementation on bone metabolism in copper-deficient patients. This study included 10 patients (83.7 +/- 8.3 years) with dietary copper deficiency under long-term bed rest for more than 12 months. They had their diets supplemented with copper sulfate (3 mg/day) over 12 weeks in addition to their diet of only one kind of enteral food with a low concentration of copper. Serum copper and ceruloplasmin, urinary deoxypyridinoline (DPD) and collagen-type 1 N-telopeptide (NTX) (biomarkers of bone resorption), serum osteocalcin (OC) and bone-specific alkaline phosphatase (Bone ALP) (biomarkers of bone formation) were analyzed at baseline, 4 and 12 weeks after copper supplementation. DPD and NTX excretion were significantly increased 4 weeks after copper supplementation (p = 0.009 and p = 0.013, respectively). Serum bone ALP and OC were not significantly changed 12 weeks after copper supplementation (p = 0.051 and p = 0.594). In patients with nutritional copper deficiency, bone resorption markers are increased with copper supplementation. Copyright (c) 2006 S. Karger AG, Basel.

Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

PubMed Central

Lewiecki, E Michael

2011-01-01

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture. PMID:22279412

Salicortin inhibits osteoclast differentiation and bone resorption by down-regulating JNK and NF-κB/NFATc1 signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nie, Shaobo; Xu, Jiawei; Zhang, Chenghua

Receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation, and survival. Salicortin is a phenolic glycoside that has been isolated from many plants such as Populus and Salix species, and has been shown to have anti-amnesic and anti-adipogenic effects. In this study, we investigated the effect of salicortin on RANKL-induced osteoclasts formation, bone resorption, and activation of osteoclast-related signaling pathways. Salicortin suppressed RANKL-induced osteoclastogenesis in bone marrow macrophage cultures in a dose-dependent manner, and inhibited osteoclastic bone resorption activity without any cytotoxicity. Salicortin inhibited RANKL-induced c-Jun N-terminal kinase and NF-κB activation, concomitant with retardedmore » IκBα phosphorylation and inhibition of p65 nuclear translocation, leading to impaired transcription of nuclear factor of activated T cells c1 (NFATc1) and expression of osteoclastic-specific genes. Taken together, our findings demonstrate that salicortin inhibits NF-κB and NFATc1 activation, leading to attenuation of osteoclastogenesis and bone resorption. Thus, salicortin may be of interest in developments of treatment for osteoclast related diseases. - Highlights: • Salicortin suppresses osteoclastogenesis in vitro. • Salicortin impairs the JNK and NF-κB/NFATc1 signaling pathway. • Salicortin may be of interest in developments of osteoporosis treatment.« less

FOR WHOM THE BELL TOLLS: DISTRESS SIGNALS FROM LONG-LIVED OSTEOCYTES AND THE PATHOGENESIS OF METABOLIC BONE DISEASES

PubMed Central

Manolagas, Stavros C.; Parfitt, A. Michael

2012-01-01

Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab. PMID:23010104

Risedronate Prevents Early Radiation-Induced Osteoporosis in Mice at Multiple Skeletal Locations

PubMed Central

Willey, Jeffrey S.; Livingston, Eric W.; Robbins, Michael E.; Bourland, J. Daniel; Tirado-Lee, Leidamarie; Smith-Sielicki, Hope; Bateman, Ted A.

2009-01-01

Introduction Irradiation of normal, non-malignant bone during cancer therapy can lead to atrophy and increased risk of fracture at several skeletal sites, particularly the hip. This bone loss has been largely attributed to damaged osteoblasts. Little attention has been given to increased bone resorption as a contributor to radiation-induced osteoporosis. Our aims were to identify if radiation increases bone resorption resulting in acute bone loss, and if bone loss could be prevented by administering risedronate. Methods Twenty-week old female C57BL/6 mice were either: not irradiated and treated with placebo (NR+PL); whole-body irradiated with 2 Gy X-rays and treated with placebo (IR+PL); or irradiated and treated with risedronate (IR+RIS; 30μg/kg every other day). Calcein injections were administered 7 and 2 days before sacrifice. Bones were collected 1, 2, and 3 weeks after exposure. MicroCT analysis was performed at 3 sites: proximal tibial metaphysis; distal femoral metaphysis; and the body of the 5th lumbar vertebra (L5). Osteoclasts were identified from TRAP-stained histological sections. Dynamic histomorphometry of cortical and trabecular bone was performed. Circulating TRAP5b and osteocalcin concentrations were quantified. Results In animals receiving IR+PL, significant (P < 0.05) reduction in trabecular volume fraction relative to non-irradiated controls was observed at all three skeletal sites and time points. Likewise, radiation-induced loss of connectivity and trabecular number relative to NR+PL were observed at all skeletal sites throughout the study. Bone loss primarily occurred during the first week post-exposure. Trabecular and endocortical bone formation was not reduced until Week 2. Loss of bone volume was absent in animals receiving IR+RIS. Histology indicated greater osteoclast numbers at Week 1 within IR+PL mice. Serum TRAP5b concentration was increased in IR+PL mice only at Week 1 compared to NR+PL (P = 0.05). Risedronate treatment prevented the radiation-induced increase in osteoclast number, surface, and TRAP5b. Conclusion This study demonstrated a rapid loss of trabecular bone at several skeletal sites after whole-body irradiation. Changes were accompanied by an increase in osteoclast number and serum markers of bone loss. Risedronate entirely prevented bone loss, providing further evidence that an increase in bone resorption likely caused this radiation-induced bone loss. PMID:19747571

Noni leaf and black tea enhance bone regeneration in estrogen-deficient rats.

PubMed

Shalan, Nor Aijratul Asikin Mohd; Mustapha, Noordin M; Mohamed, Suhaila

2017-01-01

Black tea and Nonileaf are among the dietary compounds that can benefit patients with bone resorption disorders. Their bone regeneration effects and their mechanisms were studied in estrogen-deficient rats. Noni leaves (three doses) and black tea water extracts were fed to ovariectomized rats for 4 mo, and their effects (analyzed via mechanical measurements, micro-computed tomography scan, and reverse transcriptase polymerase chain reaction mRNA) were compared with Remifemin (a commercial phytoestrogen product from black cohosh). The water extracts (dose-dependently for noni leaves) increased bone regeneration biomarker (runt-related transcription factor 2, bone morphogenetic protein 2, osteoprotegerin, estrogen receptor 1 [ESR1], collagen type I alpha 1A) expressions and reduced the inflammatory biomarkers (interleukin-6, tumor necrosis factor-α, nuclear factor [NF]-κB, and receptor activator of NF-κB ligand) mRNA expressions/levels in the rats. The extracts also improved bone physical and mechanical properties. The extracts demonstrated bone regeneration through improving bone size and structure, bone mechanical properties (strength and flexibility), and bone mineralization and density. The catechin-rich extract favored bone regeneration and suppressed bone resorption. The mechanisms involved enhancing osteoblast generation and survival, inhibiting osteoclast growth and activities, suppressing inflammation, improving bone collagen synthesis and upregulating ESR1 expression to augment phytoestrogenic effects. Estrogen deficiency bone loss and all extracts studied (best effect from Morinda leaf at 300 mg/kg body weight) mitigated the loss, indicating benefits for the aged and menopausal women. Copyright © 2016 Elsevier Inc. All rights reserved.

The influence of different loads on the remodeling process of a bone and bioresorbable material mixture with voids

NASA Astrophysics Data System (ADS)

Giorgio, Ivan; Andreaus, Ugo; Madeo, Angela

2016-03-01

A model of a mixture of bone tissue and bioresorbable material with voids was used to numerically analyze the physiological balance between the processes of bone growth and resorption and artificial material resorption in a plate-like sample. The adopted model was derived from a theory for the behavior of porous solids in which the matrix material is linearly elastic and the interstices are void of material. The specimen—constituted by a region of bone living tissue and one of bioresorbable material—was acted by different in-plane loading conditions, namely pure bending and shear. Ranges of load magnitudes were identified within which physiological states become possible. Furthermore, the consequences of applying different loading conditions are examined at the end of the remodeling process. In particular, maximum value of bone and material mass densities, and extensions of the zones where bone is reconstructed were identified and compared in the two different load conditions. From the practical view point, during surgery planning and later rehabilitation, some choice of the following parameters is given: porosity of the graft, material characteristics of the graft, and adjustment of initial mixture tissue/bioresorbable material and later, during healing and remodeling, optimal loading conditions.

Function of Matrix IGF-1 in Coupling Bone Resorption and Formation

PubMed Central

Crane, Janet L.; Cao, Xu

2013-01-01

Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space and time dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of MSCs and HSCs and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis. PMID:24068256

Function of matrix IGF-1 in coupling bone resorption and formation.

PubMed

Crane, Janet L; Cao, Xu

2014-02-01

Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis.

Correlating the nanoscale mechanical and chemical properties of knockout mice bones

NASA Astrophysics Data System (ADS)

Kavukcuoglu, Nadire Beril

Bone is a mineral-organic composite where the organic matrix is mainly type I collagen plus small amounts of non-collagenous proteins including osteopontin (OPN), osteocalcin (OC) and fibrillin 2 (Fbn2). Mature bone undergoes remodeling continually so new bone is formed and old bone resorbed. Uncoupling between the bone resorption and bone formation causes an overall loss of bone mass and leads to diseases like osteoporosis and osteopenia. These are characterized by structural deterioration of the bone tissue and an increased risk of fracture. The non-collagenous bone proteins are known to have a role in regulating bone turnover and to affect the structural integrity of bone. OPN and OC play a key role in bone resorption and formation, while absence of Fbn-2 causes a connective tissue disorder (congenital contractural arachnodactyly) and has been associated with decreased bone mass. In this thesis nanoindentation and Raman-microspectroscopy techniques were used to investigate and correlate the mechanical and chemical properties of cortical femoral bones from OPN deficient (OPN-/-), OC deficient (OC-/-) and Fbn-2 deficient (Fbn2-/-) mice and their age, sex and background matched wild-type controls (OPN+/+, OC+/+ and Fbn2+/+). For OPN the hardness (H) and elastic modulus (E) of under 12 week OPN-/- bones were significantly lower than for OPN+/+ bones, but Raman showed no significant difference. Mechanical properties of bones from mice older than 12 weeks were not significantly different with genotype. However, mineralization and crystallinity from >50 week OPN-/- bones were significantly higher than for OPN+/+ bones. Mechanical properties of OPN-/- bones showed no variation with age, but mineralization, crystallinity and type-B carbonate substitution increased for both genotypes. For OC-/- intra-bone analyses showed that the hardness and crystallinity of the bones were significantly higher, especially in the mid-cortical sections, compared to OC+/+ bones. Fbn2-/- bones had significantly lower hardness and elastic modulus compared to Fbn2+/+ bones, but the crystallinity was higher. Type-B carbonate substitution decreased significantly in OC-/- and Fbn2-/- bones compared to their wild-type controls. The thesis has provided new insight into how non-collagenous proteins affect the nanomechanics and chemistry of bone tissue. This information will assist in the development of new treatments for osteopenia/osteoporosis.

FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation

PubMed Central

Bartell, Shoshana M.; Kim, Ha-Neui; Ambrogini, Elena; Han, Li; Iyer, Srividhya; Serra Ucer, S.; Rabinovitch, Peter; Jilka, Robert L.; Weinstein, Robert S.; Zhao, Haibo; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

2014-01-01

Besides their cell-damaging effects in the setting of oxidative stress, reactive oxygen species (ROS) play an important role in physiological intracellular signalling by triggering proliferation and survival. FoxO transcription factors counteract ROS generation by upregulating antioxidant enzymes. Here we show that intracellular H2O2 accumulation is a critical and purposeful adaptation for the differentiation and survival of osteoclasts, the bone cells responsible for the resorption of mineralized bone matrix. Using mice with conditional loss or gain of FoxO transcription factor function, or mitochondria-targeted catalase in osteoclasts, we demonstrate this is achieved, at least in part, by downregulating the H2O2-inactivating enzyme catalase. Catalase downregulation results from the repression of the transcriptional activity of FoxO1, 3 and 4 by RANKL, the indispensable signal for the generation of osteoclasts, via an Akt-mediated mechanism. Notably, mitochondria-targeted catalase prevented the loss of bone caused by loss of oestrogens, suggesting that decreasing H2O2 production in mitochondria may represent a rational pharmacotherapeutic approach to diseases with increased bone resorption. PMID:24781012

[Effects of calcitonin on osteoclast].

PubMed

Suzuki, H; Takahashi, N

2001-09-01

Osteoclasts are cells that resorb bone, and calcitonin potently inhibits this bone resorptive activity. While calcitonin does not affect primary osteoclastic differentiation, it does manifest an inhibitory effect on the bone resorptive activity of osteoclasts. It is believed that calcitonin, acting upon calcitonin receptors and through PKA and PKC signal transduction pathways, destroys cytoskeleton components such as podosomes. The "escape phenomenon" seen with osteoclasts is a known issue occurring with the use of calcitonin, and is also believed to arise due to calcitonin receptors and the PKA and PKC signal transduction pathways.

Melorheostosis and its treatment with intravenous zoledronic acid

PubMed Central

Hollick, Rosemary Jane; Black, Alison; Reid, David

2010-01-01

We report a case of melorheostosis, a rare bone disorder characterised by mesodermal dysplasia, and its successful and prolonged treatment with the intravenous bisphosphonate zoledronic acid. The middle-aged man presented with pain and swelling of his tibia, which was diagnosed by imaging and bone biopsy as being due to melorheostosis. There was early symptom control after a single infusion of intravenous zoledronic acid. Prolonged symptom relief was accompanied by long-term suppression of the bone resorption marker β cross-laps. We suggest that melorheostosis can be treated with intravenous zoledronic acid and that treatment can be monitored by the use of a specific bone resorption marker. PMID:22479293

Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency.

PubMed

Coakley, Kathryn E; Felner, Eric I; Tangpricha, Vin; Wilson, Peter W F; Singh, Rani H

2017-01-01

Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Z-scores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >-2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r 2 = 0.39; p-value = 0.017), energy (r 2 = 0.41; p-value = 0.011) and zinc (r 2 = 0.41; p-value = 0.014). CTx/P1NP was negatively associated with MF fat (r 2 = -0.44; p-value = 0.008), MF compliance (r 2 = -0.34; p-value = 0.056), and positively with food sodium (r 2 = 0.43; p-value = 0.014). CTx/P1NP decreased significantly with age (p-value = 0.002) and higher PTH (p-value = 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in patients with PAH deficiency. Bone mineral density was normal in 44 females with PAH deficiency; however, bone turnover markers suggested uncoupling of bone resorption and formation, particularly in younger patients. Adequate nutrient intake from medical food and overall medical food compliance may positively impact bone turnover.

Role of Fas and Treg Cells in Fracture Healing as Characterized in the Fas-Deficient (lpr) Mouse Model of Lupus†

PubMed Central

Al-Sebaei, Maisa O; Daukss, Dana M; Belkina, Anna C; Kakar, Sanjeev; Wigner, Nathan A; Cusher, Daniel; Graves, Dana; Einhorn, Thomas; Morgan, Elise; Gerstenfeld, Louis C

2014-01-01

Previous studies showed that loss of tumor necrosis factor α (TNFα) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNFα induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Faslpr/J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Faslpr/J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Faslpr/J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Faslpr/J mice had elevated Treg cells in both spleens and bones of B6.MRL/Faslpr/J but decreased percentage of activated T cells in bone tissues. Fracture led to ∼30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Faslpr/J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Faslpr/J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNFα signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. PMID:24677136

An enhanced version of a bone-remodelling model based on the continuum damage mechanics theory.

PubMed

Mengoni, M; Ponthot, J P

2015-01-01

The purpose of this work was to propose an enhancement of Doblaré and García's internal bone remodelling model based on the continuum damage mechanics (CDM) theory. In their paper, they stated that the evolution of the internal variables of the bone microstructure, and its incidence on the modification of the elastic constitutive parameters, may be formulated following the principles of CDM, although no actual damage was considered. The resorption and apposition criteria (similar to the damage criterion) were expressed in terms of a mechanical stimulus. However, the resorption criterion is lacking a dimensional consistency with the remodelling rate. We propose here an enhancement to this resorption criterion, insuring the dimensional consistency while retaining the physical properties of the original remodelling model. We then analyse the change in the resorption criterion hypersurface in the stress space for a two-dimensional (2D) analysis. We finally apply the new formulation to analyse the structural evolution of a 2D femur. This analysis gives results consistent with the original model but with a faster and more stable convergence rate.

Formulation and evaluation of Alendronate Sodium gel for the treatment of bone resorptive lesions in Periodontitis.

PubMed

Reddy, G Thirumal; Kumar, T M Pramod; Veena

2005-01-01

Alendronate sodium is formulated into gels and evaluated for the treatment of bone resorptive lesions in periodontitis. Carbopol 934P was used for the preparation of gels in three different concentrations. The prepared gel was evaluated for various properties such as preformulation, content uniformity, viscosity, compatibility, sterility, in vitro diffusion, and in vivo studies. The drug and the polymer were found to be compatible and confirmed by Fourier transform infrared spectroscopy. Viscosity of the gels increased with the increase in the polymer concentration. The formulations were found to be sterile. In vitro release study revealed that drug released from the gel follows non-Fickian diffusion followed by first-order release. In vivo studies were carried out for 6 months in patients. The results revealed a significant improvement in the clinical parameters such as gingival index, probing pocket depth, clinical attachment level, and potent inhibitory effect on bone resorption by inhibition of osteoclasts. In addition, there was increase in the new bone formation.

Poria cocos polysaccharide attenuates RANKL-induced osteoclastogenesis by suppressing NFATc1 activity and phosphorylation of ERK and STAT3.

PubMed

Song, Dezhi; Cao, Zhen; Tickner, Jennifer; Qiu, Heng; Wang, Chao; Chen, Kai; Wang, Ziyi; Guo, Chunyu; Dong, Shiwu; Xu, Jiake

2018-06-01

Pathological fractures caused by osteolytic lesions seriously threaten the health of patients. Osteoclasts play important roles in bone resorption whose hyperfunction are closely related to osteolytic lesions. Studies on osteoclast differentiation and function assist in the prevention of excessive bone loss associated diseases. We screened a variety of natural compounds with anti-inflammatory effect and found that poria cocos polysaccharide (PCP) inhibited RANKL-induced osteoclast formation and bone resorption via TRAcP staining, immunofluorescence, RT-PCR and western blot. PCP down-regulated phosphorylation of STAT3, P38, ERK and JNK, and thus repressed the expression of NFAcT1 and c-Fos during RANKL-induced osteoclastogenesis. Besides, the expression of bone resorption related genes such as TRAcP and CTSK was suppressed by PCP. The results suggest that PCP can be invoked as a candidate for the treatment of osteolytic diseases by inhibiting osteoclastogenesis. Copyright © 2018 Elsevier Inc. All rights reserved.

Periodontal healing in one-wall intra-bony defects in dogs following implantation of autogenous bone or a coral-derived biomaterial.

PubMed

Kim, Chang-Sung; Choi, Seong-Ho; Cho, Kyoo-Sung; Chai, Jung-Kiu; Wikesjö, Ulf M E; Kim, Chong-Kwan

2005-06-01

Autogenous bone grafts and bone biomaterials are being used as part of protocols aiming at reconstruction of periodontal defects. There is a limited biologic information on the effect of such materials on periodontal healing, in particular aberrant healing events that may prevent their general use. The objective of this study was, using histological techniques, to evaluate periodontal healing with focus on root resorption and ankylosis following implantation of autogenous bone and a coral-derived biomaterial into intra-bony defects in dogs. One-wall intra-bony periodontal defects were surgically created at the distal aspect of the second and the mesial aspect of the fourth mandibular premolars in either right or left jaw quadrants in four Beagle dogs. Each animal received particulated autogenous bone and the resorbable calcium carbonate biomaterial into discrete one-wall intra-bony defects. The mucoperiosteal flaps were positioned and sutured to their pre-surgery position. The animals were euthanized 8 weeks post-surgery when block sections of the defect sites were collected and prepared for qualitative histological analysis. There were no significant differences in periodontal healing between sites receiving autograft bone and the coral-derived biomaterial. A well-organized periodontal ligament bridging new bone and cementum regeneration was observed extending coronal to a notch prepared to delineate the apical extent of the defect. Osteoid and bone with enclosed osteocytes were formed onto the surface of both autograft and coral particles. Although small resorption pits were evident in most teeth, importantly none of the biomaterials provoked marked root resorption. Ankylosis was not observed. Particulated autogenous bone and the coral-derived biomaterial may be implanted into periodontal defects without significant healing aberrations such as root resorption and ankylosis. The histopathological evaluation suggests that the autogenous bone graft has a limited osteogenic potential as demonstrated in this study model.

Calcium-41 as a long-term biological tracer for bone resorption

NASA Astrophysics Data System (ADS)

Elmore, David; Bhattacharyya, Maryka H.; Sacco-Gibson, Nancy; Peterson, David P.

1990-12-01

The use of 41Ca (half-life 1 × 10 5 yr) as a tracer for studying calcium metabolism in living systems is compared to the shorter-lived radionuclides 45Ca (165 d) and 47Ca (45 d) and the stable isotopes 42Ca and 44Ca. The feasibility of using accelerator mass spectrometry (AMS) measurements of 41Ca for studying multi-year calcium resorption in humans was tested as part of a companion study that used 45Ca to measure the effects of dietary cadmium on calcium metabolism in dogs. It was shown that Ca resorbed from prelabeled bones correlates well with 45Ca for a period of 28 weeks. The advantage of 41Ca is that, even with a negligible radiation dose, it can be measured by AMS long after the 45Ca becomes unmeasurable.

Bone resorption analysis of platelet-derived growth factor type BB application on collagen for bone grafts secured by titanium mesh over a pig jaw defect model

PubMed Central

Herford, Alan Scott; Cicciù, Marco

2012-01-01

Purpose: The aim of this investigation was to evaluate whether the addition of the platelet derived growth factor type BB (PDGF-BB) to a collagen matrix applied on a titanium mesh would favor healing and resorption onto the grafted bone. A histologic and radiographic study of two different groups (test and control) was performed. Designs: A surgical procedure was performed on 8 pigs to obtain 16 bilateral mandibular alveolar defects. All the defects were then reconstructed with a mixture of autogenous bovine bone using titanium mesh positioning. Two groups, with a total of 16 defects were created: The first to study collagen sponge and PDGF-BB and the second to control collagen only. The collagen matrix was positioned directly over the mesh and soft tissue was closed without tensions onto both groups without attempting to obtain primary closure. Possible exposure of the titanium mesh as well as the height and volume of the new bone was recorded. Results: New bone formation averaged about 6.68 mm in the test group studied; the control group had less regenerated bone at 4.62 mm. Conclusion: PDGF-BB addition to the collagen matrix induced a strong increase in hard and soft tissue healing and favored bone formation, reducing bone resorption even if the mesh was exposed. PMID:23833493

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

PubMed Central

Cong, Qian; Jia, Hao; Li, Ping; Qiu, Shoutao; Yeh, James; Wang, Yibin; Zhang, Zhen-Lin; Ao, Junping; Li, Baojie; Liu, Huijuan

2017-01-01

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis. PMID:28382965

Morse taper dental implants and platform switching: The new paradigm in oral implantology

PubMed Central

Macedo, José Paulo; Pereira, Jorge; Vahey, Brendan R.; Henriques, Bruno; Benfatti, Cesar A. M.; Magini, Ricardo S.; López-López, José; Souza, Júlio C. M.

2016-01-01

The aim of this study was to conduct a literature review on the potential benefits with the use of Morse taper dental implant connections associated with small diameter platform switching abutments. A Medline bibliographical search (from 1961 to 2014) was carried out. The following search items were explored: “Bone loss and platform switching,” “bone loss and implant-abutment joint,” “bone resorption and platform switching,” “bone resorption and implant-abutment joint,” “Morse taper and platform switching.” “Morse taper and implant-abutment joint,” Morse taper and bone resorption,” “crestal bone remodeling and implant-abutment joint,” “crestal bone remodeling and platform switching.” The selection criteria used for the article were: meta-analysis; randomized controlled trials; prospective cohort studies; as well as reviews written in English, Portuguese, or Spanish languages. Within the 287 studies identified, 81 relevant and recent studies were selected. Results indicated a reduced occurrence of peri-implantitis and bone loss at the abutment/implant level associated with Morse taper implants and a reduced-diameter platform switching abutment. Extrapolation of data from previous studies indicates that Morse taper connections associated with platform switching have shown less inflammation and possible bone loss with the peri-implant soft tissues. However, more long-term studies are needed to confirm these trends. PMID:27011755

Long-term parenteral administration of 2-hydroxypropyl-β-cyclodextrin causes bone loss.

PubMed

Kantner, Ingrid; Erben, Reinhold G

2012-07-01

Cyclodextrins are oligosaccharides which are used in the pharmaceutical industry and research as vehicles for application of apolar substances such as steroids. The aim of this study was to examine the long-term effects of parenteral administration of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) on bone. Sham-operated (SHAM) or ovariectomized (OVX) adult rats were subcutaneously injected with physiological saline, 50, or 200 mg/kg HP-β-CD daily. After 4 months, body weight in OVX rats and uterine weight in SHAM rats were significantly lower after administration of 200 mg/kg HP-β-CD, relative to vehicle controls. At 200 mg/kg, HP-β-CD was hepatotoxic as measured by increased serum transaminases, and reduced serum albumin. Moreover, 200 mg/kg HP-β-CD led to decreased vertebral and tibial bone mineral density (BMD), and to cortical thinning at the tibial shaft. Bone loss in HP-β-CD-treated rats was associated with increased bone resorption as measured by increased renal deoxypyridinoline excretion. Although 50 mg/kg HP-β-CD was devoid of overt signs of organ toxicity and did not impair BMD, bone resorption was already increased. In summary, subcutaneous long-term administration of HP-β-CD at a daily dose of 200 mg/kg led to increased bone resorption and subsequent bone loss. Minor alterations in bone metabolism were also seen at 50 mg/kg.

Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K

DTIC Science & Technology

2009-05-01

micro synthetic calcium phosphate thin films coated onto the culture vessels. As a parallel study, a 96-well plate which contained dentin slice...bone resorption in vitro. (A) Representative images of resorption pits on dentin slices or synthetic calcium phosphate thin films are shown. Left...Osteologic Bone cell culture system (BD Bioscience) that consist of sub-micro synthetic calcium phosphate thin films coated on to the culture vessels and

Eubacterium brachy - Reactivity in In Vitro Bone Resorptive Bioassay,

DTIC Science & Technology

1983-02-10

Center Washington, D. C . 20307 If Eubacterium brachy - Reactivity in In Vitro Bone Resorptive Bioassay 1. ABSTRACT Recent studies have demonstrated an...Relative distribution of bacteria at clinically healthy and periodontally diseased sites in humans. J Clin Periodontal 5:115, 1978. 3. Evian, C ...applied foreign protein into rat gingiva. J Periodont Res 6:89, 1971. 21. Gaffer, A., Coleman, E.J., and Marcussen, H.W.: Penetration of dental plaque

Vitamin K, bone turnover, and bone mass in girls.

PubMed

Kalkwarf, Heidi J; Khoury, Jane C; Bean, Judy; Elliot, James G

2004-10-01

Vitamin K has been suggested to have a role in bone metabolism, and low vitamin K intake has been related to low bone density and increased risk of osteoporotic fracture. The objective of this study was to determine whether phylloquinone (vitamin K(1)) intake and biochemical indicators of vitamin K status are related to bone mineral content (BMC) and markers of bone formation and bone resorption in girls. Vitamin K status [plasma phylloquinone concentration and percentage of undercarboxylated osteocalcin (%ucOC)] was measured at baseline in a study of 245 healthy girls aged 3-16 y. Cross-linked N-telopeptide of type 1 collagen (NTx) breakdown, osteocalcin, and bone-specific alkaline phosphatase were measured to reflect bone resorption and formation. BMC of the total body, lumbar spine, and hip and dietary phylloquinone intake were measured annually for 4 y. Phylloquinone intake (median: 45 microg/d) was not consistently associated with bone turnover markers or BMC. Better vitamin K status (high plasma phylloquinone and low %ucOC) was associated with lower bone resorption and formation. Plasma phylloquinone was inversely associated with NTx and osteocalcin concentrations (P < 0.05), and %ucOC was positively associated with NTx and bone-specific alkaline phosphatase concentrations (P < 0.05). Indicators of vitamin K status were not consistently associated with current BMC or gain in BMC over the 4-y study period. Better vitamin K status was associated with decreased bone turnover in healthy girls consuming a typical US diet. Randomized phylloquinone supplementation trials are needed to further understand the potential benefits of phylloquinone on bone acquisition in growing children.

Facial Morphogenesis of the Earliest Europeans

PubMed Central

Lacruz, Rodrigo S.; de Castro, José María Bermúdez; Martinón-Torres, María; O’Higgins, Paul; Paine, Michael L.; Carbonell, Eudald; Arsuaga, Juan Luis; Bromage, Timothy G.

2013-01-01

The modern human face differs from that of our early ancestors in that the facial profile is relatively retracted (orthognathic). This change in facial profile is associated with a characteristic spatial distribution of bone deposition and resorption: growth remodeling. For humans, surface resorption commonly dominates on anteriorly-facing areas of the subnasal region of the maxilla and mandible during development. We mapped the distribution of facial growth remodeling activities on the 900–800 ky maxilla ATD6-69 assigned to H. antecessor, and on the 1.5 My cranium KNM-WT 15000, part of an associated skeleton assigned to African H. erectus. We show that, as in H. sapiens, H. antecessor shows bone resorption over most of the subnasal region. This pattern contrasts with that seen in KNM-WT 15000 where evidence of bone deposition, not resorption, was identified. KNM-WT 15000 is similar to Australopithecus and the extant African apes in this localized area of bone deposition. These new data point to diversity of patterns of facial growth in fossil Homo. The similarities in facial growth in H. antecessor and H. sapiens suggest that one key developmental change responsible for the characteristic facial morphology of modern humans can be traced back at least to H. antecessor. PMID:23762314

Loss of trabeculae by mechano-biological means may explain rapid bone loss in osteoporosis.

PubMed

Mulvihill, Brianne M; McNamara, Laoise M; Prendergast, Patrick J

2008-10-06

Osteoporosis is characterized by rapid and irreversible loss of trabecular bone tissue leading to increased bone fragility. In this study, we hypothesize two causes for rapid loss of bone trabeculae; firstly, the perforation of trabeculae is caused by osteoclasts resorbing a cavity so deep that it cannot be refilled and, secondly, the increases in bone tissue elastic modulus lead to increased propensity for trabecular perforation. These hypotheses were tested using an algorithm that was based on two premises: (i) bone remodelling is a turnover process that repairs damaged bone tissue by resorbing and returning it to a homeostatic strain level and (ii) osteoblast attachment is under biochemical control. It was found that a mechano-biological algorithm based on these premises can simulate the remodelling cycle in a trabecular strut where damaged bone is resorbed to form a pit that is subsequently refilled with new bone. Furthermore, the simulation predicts that there is a depth of resorption cavity deeper than which refilling of the resorption pits is impossible and perforation inevitably occurs. However, perforation does not occur by a single fracture event but by continual removal of microdamage after it forms beneath the resorption pit. The simulation also predicts that perforations would occur more easily in trabeculae that are more highly mineralized (stiffer). Since both increased osteoclast activation rates and increased mineralization have been measured in osteoporotic bone, either or both may contribute to the rapid loss of trabecular bone mass observed in osteoporotic patients.

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

PubMed Central

Spirlandeli, Adriano L.; Dick-de-Paula, Ingrid; Zamarioli, Ariane; Jorgetti, Vanda; Ramalho, Leandra N.Z.; Nogueira-Barbosa, Marcello H.; Volpon, Jose B.; Jordão, Alceu A.; Cunha, Fernando Q.; Fukada, Sandra Y.; de Paula, Francisco J.A.

2017-01-01

OBJECTIVES: The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated. METHODS: The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression. RESULTS: CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice. CONCLUSION: Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice. PMID:28492723

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment.

PubMed

Spirlandeli, Adriano L; Dick-de-Paula, Ingrid; Zamarioli, Ariane; Jorgetti, Vanda; Ramalho, Leandra N Z; Nogueira-Barbosa, Marcello H; Volpon, Jose B; Jordão, Alceu A; Cunha, Fernando Q; Fukada, Sandra Y; de Paula, Francisco J A

2017-04-01

The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated. The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression. CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice. Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.

DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component.

PubMed

Han, Xiaozhe; LaRosa, Karen B; Kawai, Toshihisa; Taubman, Martin A

2014-01-03

Porphyromonas gingivalis (Pg) is one of a constellation of oral organisms associated with human chronic periodontitis. While adaptive immunity to periodontal pathogen proteins has been investigated and is an important component of periodontal bone resorption, the effect of periodontal pathogen DNA in eliciting systemic and mucosal antibody and modulating immune responses has not been investigated. Rowett rats were locally injected with whole genomic Pg DNA in alum. Escherichia coli (Ec) genomic DNA, Fusobacterium nucleatum (Fn) genomic DNA, and saline/alum injected rats served as controls. After various time points, serum IgG and salivary IgA antibody to Ec, Fn or Pg were detected by ELISA. Serum and salivary antibody reactions with Pg surface antigens were determined by Western blot analyses and the specific antigen was identified by mass spectrometry. Effects of genomic DNA immunization on Pg bacterial colonization and experimental periodontal bone resorption were also evaluated. Sera from Pg DNA, Ec DNA and Fn DNA-injected rats did not react with Ec or Fn bacteria. Serum IgG antibody levels to Pg and Pg surface extracts were significantly higher in animals immunized with Pg DNA as compared to the control groups. Rats injected with Pg DNA demonstrated a strong serum IgG and salivary IgA antibody reaction solely to Pg fimbrillin (41kDa), the major protein component of Pg fimbriae. In the Pg DNA-immunized group, the numbers of Pg bacteria in oral cavity and the extent of periodontal bone resorption were significantly reduced after Pg infection. This study suggests that infected hosts may select specific genes from whole genomic DNA of the periodontal pathogen for transcription and presentation. The results indicate that the unique gene selected can initiate a host protective immune response to the parent bacterium. Copyright © 2013 Elsevier Ltd. All rights reserved.

Osteoclastic differentiation and resorption is modulated by bioactive metal ions Co2+, Cu2+ and Cr3+ incorporated into calcium phosphate bone cements

PubMed Central

Bernhardt, Anne; Schamel, Martha; Gbureck, Uwe; Gelinsky, Michael

2017-01-01

Biologically active metal ions in low doses have the potential to accelerate bone defect healing. For successful remodelling the interaction of bone graft materials with both bone-forming osteoblasts and bone resorbing osteoclasts is crucial. In the present study brushite forming calcium phosphate cements (CPC) were doped with Co2+, Cu2+ and Cr3+ and the influence of these materials on osteoclast differentiation and activity was examined. Human osteoclasts were differentiated from human peripheral blood mononuclear cells (PBMC) both on the surface and in indirect contact to the materials on dentin discs. Release of calcium, phosphate and bioactive metal ions was determined using ICP-MS both in the presence and absence of the cells. While Co2+ and Cu2+ showed a burst release, Cr3+ was released steadily at very low concentrations (below 1 μM) and both calcium and phosphate release of the cements was considerably changed in the Cr3+ modified samples. Direct cultivation of PBMC/osteoclasts on Co2+ cements showed lower attached cell number compared to the reference but high activity of osteoclast specific enzymes tartrate resistant acid phosphatase (TRAP), carbonic anhydrase II (CAII) and cathepsin K (CTSK) and significantly increased gene expression of vitronectin receptor. Indirect cultivation with diluted Co2+ cement extracts revealed highest resorbed area compared to all other modifications and the reference. Cu2+ cements had cytotoxic effect on PBMC/osteoclasts during direct cultivation, while indirect cultivation with diluted extracts from Cu2+ cements did not provoke cytotoxic effects but a strictly inhibited resorption. Cr3+ doped cements did not show cytotoxic effects at all. Gene expression and enzyme activity of CTSK was significantly increased in direct culture. Indirect cultivation with Cr3+ doped cements revealed significantly higher resorbed area compared to the reference. In conclusion Cr3+ doped calcium phosphate cements are an innovative cement modification because of their high cytocompatibility and support of active resorption by osteoclasts. PMID:28763481

Biocompatibility and Biocorrosion of Hydroxyapatite-Coated Magnesium Plate: Animal Experiment.

PubMed

Lim, Ho-Kyung; Byun, Soo-Hwan; Woo, Jae-Man; Kim, Sae-Mi; Lee, Sung-Mi; Kim, Bong-Ju; Kim, Hyoun-Ee; Lee, Jung-Woo; Kim, Soung-Min; Lee, Jong-Ho

2017-09-30

Magnesium (Mg) has the advantage of being resorbed in vivo, but its resorption rate is difficult to control. With uncontrolled resorption, Magnesium as a bone fixation material has minimal clinical value. During resorption not only is the strength rapidly weakened, but rapid formation of metabolite also occurs. In order to overcome these disadvantages, hydroxyapatite (HA) surface coating of pure magnesium plate was attempted in this study. Magnesium plates were inserted above the frontal bone of Sprague-Dawley rats in both the control group (Bare-Mg group) and the experimental group (HA-Mg group). The presence of inflammation, infection, hydrogen gas formation, wound dehiscence, and/or plate exposure was observed, blood tests were performed, and the resorption rate and tensile strength of the retrieved metal plates were measured. The HA-Mg group showed no gas formation or plate exposure until week 12. However, the Bare-Mg group showed consistent gas formation and plate exposure beginning in week 2. WBC (White Blood Cell), BUN (Blood Urea Nitrogen), Creatinine, and serum magnesium concentration levels were within normal range in both groups. AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) values, however, were above normal range in some animals of both groups. The HA-Mg group showed statistically significant advantage in resistance to degradation compared to the Bare-Mg group in weeks 2, 4, 6, 8, and 12. Degradation of HA-Mg plates proceeded after week 12. Coating magnesium plates with hydroxyapatite may be a viable method to maintain their strength long enough to allow bony healing and to control the resorption rate during the initial period.

Biocompatibility and Biocorrosion of Hydroxyapatite-Coated Magnesium Plate: Animal Experiment

PubMed Central

Woo, Jae-Man; Kim, Sae-Mi; Lee, Sung-Mi; Kim, Hyoun-Ee; Lee, Jung-Woo; Lee, Jong-Ho

2017-01-01

Magnesium (Mg) has the advantage of being resorbed in vivo, but its resorption rate is difficult to control. With uncontrolled resorption, Magnesium as a bone fixation material has minimal clinical value. During resorption not only is the strength rapidly weakened, but rapid formation of metabolite also occurs. In order to overcome these disadvantages, hydroxyapatite (HA) surface coating of pure magnesium plate was attempted in this study. Magnesium plates were inserted above the frontal bone of Sprague-Dawley rats in both the control group (Bare-Mg group) and the experimental group (HA-Mg group). The presence of inflammation, infection, hydrogen gas formation, wound dehiscence, and/or plate exposure was observed, blood tests were performed, and the resorption rate and tensile strength of the retrieved metal plates were measured. The HA-Mg group showed no gas formation or plate exposure until week 12. However, the Bare-Mg group showed consistent gas formation and plate exposure beginning in week 2. WBC (White Blood Cell), BUN (Blood Urea Nitrogen), Creatinine, and serum magnesium concentration levels were within normal range in both groups. AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) values, however, were above normal range in some animals of both groups. The HA-Mg group showed statistically significant advantage in resistance to degradation compared to the Bare-Mg group in weeks 2, 4, 6, 8, and 12. Degradation of HA-Mg plates proceeded after week 12. Coating magnesium plates with hydroxyapatite may be a viable method to maintain their strength long enough to allow bony healing and to control the resorption rate during the initial period. PMID:28973984

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

PubMed

Blaslov, Kristina; Katalinic, Lea; Kes, Petar; Spasovski, Goce; Smalcelj, Ruzica; Basic-Jukic, Nikolina

2014-05-01

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal transplant recipients or comparing sirolimus versus everolimus impact on bone, so only general conclusions could be drawn. Hence, the use of mTORi might be useful in patients with PRO due to their possible potential to inhibit osteoclast activity which might lead to a decreased rate of bone resorption. In addition, it should be also emphasized that they might inhibit osteoblast activity which may lead to a decreased bone formation and adynamic bone disease. Further studies are urgently needed to solve these important clinical dilemmas.

High Protein Intake Improves Insulin Sensitivity but Exacerbates Bone Resorption in Immobility (WISE Study)

NASA Technical Reports Server (NTRS)

Heer, Martina; Smith, Scott M.; Frings-Meuthen, Petra; Zwart, Sara R.; Baecker, Natalie

2012-01-01

Inactivity, like bed rest (BR), causes insulin resistance (IR) and bone loss even in healthy subjects. High protein intake seems to mitigate this IR but might exacerbate bone loss. We hypothesized that high protein intake (animal:vegetable protein ratio: 60:40), isocaloric, compared to the control group plus high potassium intake would prevent IR without affecting bone turnover. After a 20-day ambulatory adaptation to controlled confinement and diet, 16 women participated in a 60-day, 6 deg head-down-tilt BR and were assigned randomly to one of the two groups. Control subjects (CON, n=8) received 1g/kg body mass/d dietary protein. Nutrition subjects (NUT, n=8) received 1.45g/kg body mass/d dietary protein plus 7.2g branched chain amino acids per day during BR. All subjects received 1670 kcal/d. Bed rest decreased glucose disposal by 35% (p<0.05) in CON. Isocaloric high protein intake prevented insulin resistance, but exacerbated bed rest induced increase in bone resorption markers C-telopeptide (> 30%) and Ntelopeptide (>20%) (both: p<0.001). Bone formation markers were unaffected by high protein intake. We conclude from these results that high protein intake might positively affect glucose tolerance, but might also foster bone loss. Further long-duration studies are mandatory before high protein intake for diabetic patients, who have an increased fracture risk, might be recommended.

Does the Laser-Microtextured Short Implant Collar Design Reduce Marginal Bone Loss in Comparison with a Machined Collar?

PubMed Central

Sirali, Ali; Gultekin, Pinar; Yalcin, Serdar; Mijiritsky, Eitan

2016-01-01

Purpose. To compare marginal bone loss between subgingivally placed short-collar implants with machined collars and those with machined and laser-microtextured collars. Materials and Methods. The investigators used a retrospective study design and included patients who needed missing posterior teeth replaced with implants. Short-collar implants with identical geometries were divided into two groups: an M group, machined collar; and an L group, machined and laser-microtextured collar. Implants were evaluated according to marginal bone loss, implant success, and probing depth (PD) at 3 years of follow-up. Results. Sixty-two patients received 103 implants (56 in the M group and 47 in the L group). The cumulative survival rate was 100%. All implants showed clinically acceptable marginal bone loss, although bone resorption was lower in the L group (0.49 mm) than in the M group (1.38 mm) at 3 years (p < 0.01). A significantly shallower PD was found for the implants in the L group during follow-up (p < 0.01). Conclusions. Our results suggest predictable outcomes with regard to bone loss for both groups; however, bone resorption was less in the L group than in the M group before and after loading. The laser-microtextured collar implant may provide a shallower PD than the machined collar implant. PMID:27660765

Calcium and Bone Homeostasis During 4-6 Months Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.; OBrien, K.; Wastney, M.; Morukov, B.; Larina, I.; Abrams, S.; Lane, H.; Nillen, J.; Davis-Street, J.; Paloski, W. H. (Technical Monitor)

2000-01-01

Bone and calcium homeostasis are altered by weightlessness. We previously reported calcium studies on three subjects from the first joint US/Russian mission to Mir. We report here data on an additional three male subjects, whose stays on Mir were 4 (n= 1) and 6 (n=2) mos. Data were collected before, during, and after the missions. Inflight studies were conducted at 2-3 mos. Endocrine and biochemical indices were measured, along with 3-wk calcium tracer studies. Percent differences are reported compared to preflight. Ionized calcium was unchanged (2.8 +/-2.1 %) during flight. Calcium absorption was variable inflight, but was decreased after landing. Vitamin D stores were decreased 35 +/-24% inflight, similar to previous reports. Serum PTH was decreased 59 +/-9% during flight (greater than we previously reported), while 1,25(OH)(sub 2)-Vitamin D was decreased in 2 of 3 subjects. Markers of bone resorption (e.g., crosslinks) were increased in all subjects. Bone-specific alkaline phosphatase was decreased (n=1) or unchanged (n=2), while osteocalcin was decreased 34 +/-23%. Previously presented data showed that inflight bone loss is associated with increased resorption and unchanged/decreased formation. The data reported here support these earlier findings. These studies will help to extend our understanding of space flight-induced bone loss, and of bone loss associated with diseases such as osteoporosis or paralysis.

Prevalence of third molars and pathological changes related to them in dental medicine.

PubMed

Mikić, Ivana Medvedec; Zore, Irina Filipović; Crcić, Vlatka Fuchs; Matijević, Jurica; Plancak, Dario; Katunarić, Marina; Buković, Dino

2013-09-01

The purpose of this study was to determine the prevalence of third molars in terms of respondents' age. Furthermore it was desired to determine the extent of the manifestation of pathological changes, such as caries, apical lesions, and alveolar bone resorption. This study was based on 500 OPGs of patients from the Faculty of Dentistry, University of Zagreb. Patients were divided into seven age groups. The total number of molars, the number of cavities on remaining molars, the quality of endodontic treatment and the evaluation of their performance and presence of periapical lesions was analyzed. As apart of the periodontal status, the number of inadequate fillings, the number of damaged furcations and bone resorption was analyzed. The statistical analysis was performed by means of STATISTICA 7 statistical package (StatSoft, Tulsa, USA). The correlation between the total number of molars and the age of patients was analyzed by means of Spearman's correlation to the level of significance of 0.05. The number of first, second and third molars significantly decreased in higher age groups. The prevalence of caries in third molars as compared to first and second molars was generally lower, third molars were endodontic treated at least. Assessment of involved furcations showed that the lowest percentage of 8% was found in third molars. The majority of all remaining molars had bone resorption of 1-3 mm.

For whom the bell tolls: distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases.

PubMed

Manolagas, Stavros C; Parfitt, A Michael

2013-06-01

Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab. Published by Elsevier Inc.

Handling of induced hypercalcaemia in hyperthyroidism

PubMed Central

Lim, P.; Jacob, E.; Khoo, O. T.

1969-01-01

The mean serum calcium of 13 hyperthyroid patients was found to be significantly higher than that of controls matched for sex and age, though none of the patients' values were outside the normal range. Nevertheless, these patients responded very promptly to hypercalcaemia (induced by an intravenous calcium load), and their serum calcium returned to normal much more rapidly compared with the matched controls. There was also increased retention of intravenous calcium load, possibly owing to increased calcitonin production. Calcium infusion may be useful in treating bone diseases in which increased bone resorption exceeds bone accretion. PMID:5354875

The gut microbiota regulates bone mass in mice

PubMed Central

Sjögren, Klara; Engdahl, Cecilia; Henning, Petra; Lerner, Ulf H; Tremaroli, Valentina; Lagerquist, Marie K; Bäckhed, Fredrik; Ohlsson, Claes

2012-01-01

The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4+ T cells and CD11b+/GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis. © 2012 American Society for Bone and Mineral Research. PMID:22407806

Denosumab for bone diseases: translating bone biology into targeted therapy.

PubMed

Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

2011-12-01

Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

Bone Density and Dental External Apical Root Resorption

PubMed Central

Iglesias-Linares, Alejandro; Morford, Lorri Ann

2016-01-01

When orthodontic patients desire shorter treatment times with aesthetic results and long-term stability, it is important for the orthodontist to understand the potential limitations and problems that may arise during standard and/or technology-assisted accelerated treatment. Bone density plays an important role in facilitating orthodontic tooth movement (OTM), such that reductions in bone density can significantly increase movement velocity. Lifestyle, genetic background, environmental factors and disease status all can influence a patients’ overall health and bone density. In some individuals, these factors may create specific conditions that influence systemic-wide bone metabolism. Both genetic variation and the onset of a bone-related disease can influence systemic bone density and local bone density, such as is observed in the mandible and maxilla. These types of localized density changes can affect the rate of OTM and may also influence the risk of unwanted outcomes, i.e., the occurrence of dental external apical root resorption (EARR). PMID:27766484

Gestational age, sex and maternal parity correlate with bone turnover in premature infants.

PubMed

Aly, Hany; Moustafa, Mohamed F; Amer, Hanna A; Hassanein, Sahar; Keeves, Christine; Patel, Kantilal

2005-05-01

Factors affecting bone turnover in premature infants are not entirely clear but certainly are different from those influencing bones of adults and children. To identify fetal and maternal factors that might influence bone turnover, we prospectively studied 50 infants (30 preterm and 20 full-term) born at Ain Shams University Obstetric Hospital in Cairo, Egypt. Maternal parity and medical history and infant's weight, gestational age, gender and anthropometrical measurements were recorded. Cord blood samples were collected and serum type I collagen C-terminal propeptide (PICP) was assessed as a marker for fetal bone formation. First morning urine samples were collected and pyridinoline cross-links of collagen (Pyd) were measured as an index for bone resorption. Serum PICP was higher in premature infants when compared with full-term infants (73.30 +/- 15.1 versus 64.3 +/- 14.7, p = 0.022) and was higher in male premature infants when compared with females (81.64 +/- 9.06 versus 66.0 +/- 15.7, p = 0.018). In a multiple regression model using PICP as the dependent variable and controlling for different infant and maternal conditions, PICP significantly correlated with infant gender (r = 8.26 +/- 4.1, p = 0.05) maternal parity (r = -2.106 +/- 0.99, p = 0.041) and diabetes (r = 22.488 +/- 8.73, p = 0.041). Urine Pyd tended to increase in premature infants (612 +/- 308 versus 434 +/- 146, p = 0.057) and correlated significantly with gestational age (r = -63.93 +/- 19.55, p = 0.002). Therefore, bone formation (PICP) is influenced by fetal age and gender, as well as maternal parity and diabetes. Bone resorption (Pyd) is mostly dependent on gestational age only. Further in-depth studies are needed to enrich management of this vulnerable population.

Macrophage migration inhibitory factor (MIF) supports homing of osteoclast precursors to peripheral osteolytic lesions

PubMed Central

Movila, Alexandru; Ishii, Takenobu; Albassam, Abdullah; Wisitrasameewong, Wichaya; Howait, Mohammed; Yamaguchi, Tsuguno; Ruiz-Torruella, Montserrat; Bahammam, Laila; Nishimura, Kazuaki; Van Dyke, Thomas; Kawai, Toshihisa

2016-01-01

By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that SDF-1 promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of MIF, another ligand for CXCR4, in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-KI mice to establish an animal model of Polymethyl methacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFP+ cells of healthy Csf1r-eGFP-KI mice, Csf1r+/CD11b+ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1r+/RANK+ cells in vitro. Therefore, Csf1r-eGFP+/CD11b+ cells were targeted as functionally relevant OCPs in the present study. While expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1r+/CD11b+ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type mice compared to that detected in MIF-KO mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of wild-type mice in conjunction with an increased number of infiltrating CXCR4+ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can down-modulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing mAb inhibited the homing of CXCR4+ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4+ OCPs. PMID:27082509

Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

PubMed Central

Walker, Emma C.; McGregor, Narelle E.; Poulton, Ingrid J.; Solano, Melissa; Pompolo, Sueli; Fernandes, Tania J.; Constable, Matthew J.; Nicholson, Geoff C.; Zhang, Jian-Guo; Nicola, Nicos A.; Gillespie, Matthew T.; Martin, T. John; Sims, Natalie A.

2010-01-01

Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr–/– osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer. PMID:20051625

Trabecular bone adaptation to low-magnitude high-frequency loading in microgravity.

PubMed

Torcasio, Antonia; Jähn, Katharina; Van Guyse, Maarten; Spaepen, Pieter; Tami, Andrea E; Vander Sloten, Jos; Stoddart, Martin J; van Lenthe, G Harry

2014-01-01

Exposure to microgravity causes loss of lower body bone mass in some astronauts. Low-magnitude high-frequency loading can stimulate bone formation on earth. Here we hypothesized that low-magnitude high-frequency loading will also stimulate bone formation under microgravity conditions. Two groups of six bovine cancellous bone explants were cultured at microgravity on a Russian Foton-M3 spacecraft and were either loaded dynamically using a sinusoidal curve or experienced only a static load. Comparable reference groups were investigated at normal gravity. Bone structure was assessed by histology, and mechanical competence was quantified using μCT and FE modelling; bone remodelling was assessed by fluorescent labelling and secreted bone turnover markers. Statistical analyses on morphometric parameters and apparent stiffness did not reveal significant differences between the treatment groups. The release of bone formation marker from the groups cultured at normal gravity increased significantly from the first to the second week of the experiment by 90.4% and 82.5% in response to static and dynamic loading, respectively. Bone resorption markers decreased significantly for the groups cultured at microgravity by 7.5% and 8.0% in response to static and dynamic loading, respectively. We found low strain magnitudes to drive bone turnover when applied at high frequency, and this to be valid at normal as well as at microgravity. In conclusion, we found the effect of mechanical loading on trabecular bone to be regulated mainly by an increase of bone formation at normal gravity and by a decrease in bone resorption at microgravity. Additional studies with extended experimental time and increased samples number appear necessary for a further understanding of the anabolic potential of dynamic loading on bone quality and mechanical competence.

Galectin-3 is essential for proper bone cell differentiation and activity, bone remodeling and biomechanical competence in mice.

PubMed

Iacobini, Carla; Fantauzzi, Claudia Blasetti; Bedini, Rossella; Pecci, Raffaella; Bartolazzi, Armando; Amadio, Bruno; Pesce, Carlo; Pugliese, Giuseppe; Menini, Stefano

2018-02-09

Galectin-3 is constitutively expressed in bone cells and was recently shown to modulate osteogenic transdifferentiation of vascular smooth muscle cells and atherosclerotic calcification. However, the role of galectin-3 in bone physiology is largely undefined. To address this issue, we analyzed (1) the skeletal features of 1-, 3- and 6-month-old galectin-3 null (Lgals3 -/- ) and wild type (WT) mice and (2) the differentiation and function of osteoblasts and osteoclasts derived from these animals. Long bone phenotype, gene expression profile, and remodeling were investigated by micro-computed tomography, real time-PCR, static and dynamic histomorphometry, and assessment of biochemical markers of bone resorption and formation. Bone competence was also evaluated by biomechanical testing at 3 months. In vitro, the effects of galectin-3 deficiency on bone cell differentiation and function were investigated by assessing (a) gene expression of osteoblast markers, alkaline phosphatase activity, mineralization assay, and WNT/β-catenin signaling (of which galectin-3 is a known regulator) in osteoblasts; and (b) tartrate-resistant acid phosphatase activity and bone resorption activity in osteoclasts. Lgals3 -/- mice revealed a wide range of age-dependent alterations including lower bone formation and higher bone resorption, accelerated age-dependent trabecular bone loss (p < 0.01 vs. WT at 3 months) and reduced bone strength (p < 0.01 vs. WT at 3 months). These abnormalities were accompanied by a steady inflammatory state, as revealed by higher bone expression of the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 (p < 0.001 vs. WT at 3 months), increased content of osteal macrophages (p < 0.01 vs. WT at 3 months), and reduced expression of markers of alternative (M2) macrophage activation. Lgals3 -/- osteoblasts and osteoclasts showed impaired terminal differentiation, reduced mineralization capacity (p < 0.01 vs. WT cells) and resorption activity (p < 0.01 vs. WT cells). Mechanistically, impaired differentiation and function of Lgals3 -/- osteoblasts was associated with altered WNT/β-catenin signaling (p < 0.01 vs. WT cells). These data provide evidence for a contribution of galectin-3 to bone cell maturation and function, bone remodeling, and biomechanical competence, thus identifying galectin-3 as a promising therapeutic target for age-related disorders of bone remodeling. Copyright © 2018. Published by Elsevier Inc.

[Mechanism of "crescent sign" formation in avascular necrosis of femoral head].

PubMed

Zhang, Nianfei; Qi, Shengwen; Chai, Jianfeng

2008-03-01

To investigate corresponding relation between structure change of the femoral head with "crescent sign" and stress exerted on the avascular necrosis of femoral head, to explore the mechanism of the "crescent sign" formation. From March 1998 to April 2003, the femoral heads of 18 hips in 16 cases having osteonecrosis and "crescent sign" in X-ray film before total hip arthroplasty, were collected. General and coronal section plane morphology of the femoral heads were observed. The principle of effective stress and stress concentration theory were used to explain the phenomena and structure changes in osteonecrosis of the femoral head. Cancellous bone existed as a three-dimensional, interconnected network of trabeculae rods and plates, with 50%-90% of porosity and 20-30 mmHg bone marrow pressure. According to the definition of porous media, bones especially cancellous bone was a kind of solid and liquid two phases porous media. Cross-sectional structure changes in the junction between subchondral plate and cancellous were the place where stress concentrated. The principle of effective stress and stress concentration theory could explain the phenomena and their relationship that occurred in avascular necrosis of the femoral head. The "crescent sign" starts in an area of very focal resorption in the subchondral plate laterally and peripherally. The focal resorption in the subchondral plate breaks the continuity of subchondral plate and causes stress concentration in the resorption region. The concentrated stress accumulates in the junction between subchondral plate and unrepaired necrotic cancellous bone brings on the fracture right below the subchondral plate. The focal resorption of the subchondral plate also provides a pathway for the pore water in the unrepaired necrotic bone skeleton to outflow, therefore cause effective stress increase and unrepaired necrotic bone skeleton be compacted by increased effective stress applied on unrepaired necrotic cancellous bone skeleton, and results in the volume decrease of unrepaired necrotic cancellous bone and the formation of cavum below the subchondral plate. The cavum shows "crescent sign" in the X-ray film.

Bone resorption and remodeling in murine collagenase-induced osteoarthritis after administration of glucosamine

PubMed Central

2011-01-01

Introduction Glucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage. Glucosamine has been clinically introduced for the treatment of osteoarthritis but the data about its protective role in disease are insufficient. The goal of this study was to investigate the effect of long term administration of glucosamine on bone resorption and remodeling. Methods The effect of glucosamine on bone resorption and remodeling was studied in a model of collagenase-induced osteoarthritis (CIOA). The levels of macrophage-inflammatory protein (MIP)-1α, protein regulated upon activation, normal T-cell expressed, and secreted (RANTES), soluble receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, 4 and 10 in synovial fluid were measured by enzyme-linked immunosorbent assay (ELISA). Cell populations in synovial extracts and the expression of RANKL, of receptors for TNF-α (TNF-αR) and interferon γ (IFN-γR) on clusters of differentiation (CD) three positive T cells were analyzed by flow cytometry. Transforming growth factor (TGF)-β3, bone morphogenetic protein (BMP)-2, phosphorylated protein mothers against decapentaplegic homolog 2 (pSMAD-2), RANKL and Dickkopf-1 protein (DKK-1) positive staining in CIOA joints were determined by immunohistochemistry. Results The administration of glucosamine hydrochloride in CIOA mice inhibited loss of glycosaminoglycans (GAGs) and proteoglycans (PGs) in cartilage, bone erosion and osteophyte formation. It decreased the levels of soluble RANKL and IL-6 and induced IL-10 increase in the CIOA joint fluids. Glucosamine limited the number of CD11b positive Ly6G neutrophils and RANKL positive CD3 T cells in the joint extracts. It suppressed bone resorption via down-regulation of RANKL expression and affected bone remodeling in CIOA by decreasing BMP-2, TGF-β3 and pSMAD-2 expression and up-regulating DKK-1 joint levels. Conclusions Our data suggest that glucosamine hydrochloride inhibits bone resorption through down-regulation of RANKL expression in the joints, via reduction of the number of RANKL positive CD3 T cells and the level of sRANKL in the joints extracts. These effects of glucosamine appear to be critical for the progression of CIOA and result in limited bone remodeling of the joints. PMID:21410959

Chondroitin and glucosamine sulfate in combination decrease the pro-resorptive properties of human osteoarthritis subchondral bone osteoblasts: a basic science study

PubMed Central

Tat, Steeve Kwan; Pelletier, Jean-Pierre; Vergés, Josep; Lajeunesse, Daniel; Montell, Eulàlia; Fahmi, Hassan; Lavigne, Martin; Martel-Pelletier, Johanne

2007-01-01

Early in the pathological process of osteoarthritis (OA), subchondral bone remodelling, which is related to altered osteoblast metabolism, takes place. In the present study, we explored in human OA subchondral bone whether chondroitin sulfate (CS), glucosamine sulfate (GS), or both together affect the major bone biomarkers, osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B ligand (RANKL), and the pro-resorptive activity of OA osteoblasts. The effect of CS (200 μg/mL), GS (50 and 200 μg/mL), or both together on human OA subchondral bone osteoblasts, in the presence or absence of 1,25(OH)2D3 (vitamin D3) (50 nM), was determined on the bone biomarkers alkaline phosphatase and osteocalcin, on the expression (mRNA) and production (enzyme-linked immunosorbent assay) of bone remodelling factors OPG and RANKL, and on the pro-resorptive activity of these cells. For the latter experiments, human OA osteoblasts were incubated with differentiated peripheral blood mononuclear cells on a sub-micron synthetic calcium phosphate thin film. Data showed that CS and GS affected neither basal nor vitamin D3-induced alkaline phosphatase or osteocalcin release. Interestingly, OPG expression and production under basal conditions or vitamin D3 treatment were upregulated by CS and by both CS and GS incubated together. Under basal conditions, RANKL expression was significantly reduced by CS and by both drugs incubated together. Under vitamin D3, these drugs also showed a decrease in RANKL level, which, however, did not reach statistical significance. Importantly, under basal conditions, CS and both compounds combined significantly upregulated the expression ratio of OPG/RANKL. Vitamin D3 decreased this ratio, and GS further decreased it. Both drugs reduced the resorption activity, and statistical significance was reached for GS and when CS and GS were incubated together. Our data indicate that CS and GS do not overly affect cell integrity or bone biomarkers. Yet CS and both compounds together increase the expression ratio of OPG/RANKL, suggesting a positive effect on OA subchondral bone structural changes. This was confirmed by the decreased resorptive activity for the combination of CS and GS. These data are of major significance and may help to explain how these two drugs exert a positive effect on OA pathophysiology. PMID:17996099

One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons.

PubMed

Gerbaix, Maude; Gnyubkin, Vasily; Farlay, Delphine; Olivier, Cécile; Ammann, Patrick; Courbon, Guillaume; Laroche, Norbert; Genthial, Rachel; Follet, Hélène; Peyrin, Françoise; Shenkman, Boris; Gauquelin-Koch, Guillemette; Vico, Laurence

2017-06-01

The weightless environment during spaceflight induces site-specific bone loss. The 30-day Bion-M1 mission offered a unique opportunity to characterize the skeletal changes after spaceflight and an 8-day recovery period in mature male C57/BL6 mice. In the femur metaphysis, spaceflight decreased the trabecular bone volume (-64% vs. Habitat Control), dramatically increased the bone resorption (+140% vs. Habitat Control) and induced marrow adiposity invasion. At the diaphysis, cortical thinning associated with periosteal resorption was observed. In the Flight animal group, the osteocyte lacunae displayed a reduced volume and a more spherical shape (synchrotron radiation analyses), and empty lacunae were highly increased (+344% vs. Habitat Control). Tissue-level mechanical cortical properties (i.e., hardness and modulus) were locally decreased by spaceflight, whereas the mineral characteristics and collagen maturity were unaffected. In the vertebrae, spaceflight decreased the overall bone volume and altered the modulus in the periphery of the trabecular struts. Despite normalized osteoclastic activity and an increased osteoblast number, bone recovery was not observed 8 days after landing. In conclusion, spaceflight induces osteocyte death, which may trigger bone resorption and result in bone mass and microstructural deterioration. Moreover, osteocyte cell death, lacunae mineralization and fatty marrow, which are hallmarks of ageing, may impede tissue maintenance and repair.

Effects of atorvastatin on bone mineral density (BMD) and bone metabolism in elderly males with osteopenia and mild dyslipidemia: a 1-year randomized trial.

PubMed

Chen, Zhi-guo; Cai, Hua-jie; Jin, Xian; Lu, Jin-hua; Wang, Jing; Fang, Ning-yuan

2014-01-01

We explored the effects of atorvastatin on BMD and biochemical markers of bone metabolism in a 1-year, prospective, randomized controlled study. 64 male patients with osteopenia and mild dyslipidemia (mean age 80.1±6.6 years) were randomized to a 1-year atorvastatin treatment or control. BMD of hip and lumbar spine was measured with dual-energy X-ray absorptionmetry (DXA). Bone metabolic markers including resorption markers β-c-terminal telopeptide of type I collagen (CTx), formative markers osteocalcin (OC), 25-hydroxyvitamin D (25(OH)D) were measured with electrochemiluminescence immunoassay (ECLIA). Other bone metabolism markers including intact parathyroid hormone (iPTH) and testosterone were measured with chemiluminescence enzyme immunoassay (CLEIA). Levels of serum lipid and biochemical parameters were measured with automatic biochemical analyzer. All the parameters were recorded at baseline, and at 6 and 12 months, respectively. Compared with the control group, the atorvastatin treatment group showed significant reduction of triglyceride (TG, P<0.01) and low-density lipoprotein cholesterol (LDL-C, P<0.01). At 12 month, total hip BMD in atorvastatin group was significantly higher (P<0.01) compared with the control group, while there were no similar effect on femoral neck or lumbar spine between the two groups (P=0.48 and 0.53 respectively). Meanwhile, CTx significantly reduced in atorvastatin treatment group (P<0.001) compared with baseline. Our findings suggest that in elderly male patients with osteopenia and mild dyslipidemia, therapeutic doses of atorvastatin were associated with positive effects on BMD, probably mediated by suppressed bone resorption. Copyright © 2014. Published by Elsevier Ireland Ltd.

Computational Evaluation of the Effects of Bone Ingrowth on Bone Resorptive Remodeling after a Cementless Total Hip Arthroplasty

NASA Astrophysics Data System (ADS)

Jung, Duk-Young; Kang, Yu-Bong; Tsutsumi, Sadami; Nakai, Ryusuke; Ikeuchi, Ken; Sekel, Ron

In this study, we simulated a wide cortex separation from a cementless hip prosthesis using the bone resorption remodeling method that is based on the generation of high compressive stress around the distal cortical bone. Thereafter, we estimated the effect on late migration quantities of the hip prosthesis produced by the interface state arising from bone ingrowth. This was accomplished using cortical bone remodeling over a long period of time. Two-dimensional natural hip and implanted hip FEM models were constructed with each of the following interface statements between the bone and prosthesis: (1) non-fixation, (2) proximal 1/3, (3) proximal 2/3 and (4) full-fixation. The fixation interfaces in the fully and partially porous coated regions were rigidly fixed by bony ingrowth. The non-fixation model was constructed as a critical situation, with the fibrous or bony tissue not integrated at all into the implant surface. The daily load history was generated using the three loading cases of a one-legged stance as well as abduction and adduction motions. With the natural hip and one-legged stance, the peak compressive principal stresses were found to be under the criteria value for causing bone resorption, while no implant movement occurred. The migration magnitude of the stem of the proximal 1/3 fixation model with adduction motion was much higher, reaching 6%, 11%and 21%greater than those of the non-fixation, proximal 2/3 fixation and all-fixation models, respectively. The full-fixation model showed the lowest compressive principal stress and implant movement. Thus, we concluded that the late loosening and subsequent movement of the stem in the long term could be estimated with the cortical bone remodeling method based on a high compressive stress at the bone-implant interface. The change caused at the bone-prosthesis interface by bony or fibrous tissue ingrowth constituted the major factor in determining the extent of cortical bone resorption occurring with clinical loosening and subsequent implant movement.

Advances in the discovery of cathepsin K inhibitors on bone resorption.

PubMed

Lu, Jun; Wang, Maolin; Wang, Ziyue; Fu, Zhongqi; Lu, Aiping; Zhang, Ge

2018-12-01

Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors. These inhibitors are derived from synthetic compounds or natural products, some of which have passed preclinical studies and are presently in clinical trials at different stages of advancement. In this review, we briefly summarised the historic development of Cat K inhibitors and discussed the relationship between structures of inhibitors and active sites in Cat K for the purpose of guiding future development of inhibitors.

Additive effect of PTH (1-34) and zoledronate in the prevention of disuse osteopenia in rats.

PubMed

Vegger, Jens Bay; Nielsen, Esben Sommer; Brüel, Annemarie; Thomsen, Jesper Skovhus

2014-09-01

Immobilization is known to cause a rapid bone loss due to increased osteoclastic bone resorption and decreased osteoblastic bone formation. Zoledronate (Zln) is a potent anti-resorptive pharmaceutical, while intermittent PTH is a potent bone anabolic agent. The aim of the present study was to investigate whether PTH or Zln alone or in combination could prevent immobilization-induced osteopenia. Immobilization was achieved by injecting 4IU Botox (BTX) into the right hind limb musculature. Seventy-two 16-week-old female Wistar rats were randomized into 6 groups; baseline (Base), control (Ctrl), BTX, BTX+PTH, BTX+Zln, and BTX+PTH+Zln. PTH (1-34) (80μg/kg) was given 5days/week and Zln (100μg/kg) was given once at study start. The animals were killed after 4weeks of treatment. The bone properties were evaluated using DEXA, μCT, dynamic bone histomorphometry, and mechanical testing. BTX resulted in lower femoral trabecular bone volume fraction (BV/TV) (-25%, p<0.05), lower tibial trabecular bone formation rate (BFR/BS) (-29%, p<0.05), and lower bone strength (Fmax) at the distal femur (-19%, p<0.001) compared with Ctrl. BTX+PTH resulted in higher femoral BV/TV (+31%, p<0.05), higher tibial trabecular BFR/BS (+297%, p<0.05), and higher Fmax at the distal femur (+11%, p<0.05) compared with BTX. BTX+Zln resulted in higher femoral BV/TV (+36%, p<0.05), lower tibial trabecular BFR/BS (-93%, p<0.05), and higher Fmax at the distal femur (+10%, p<0.05) compared with BTX. BTX+PTH+Zln resulted in higher femoral BV/TV (+70%, p<0.001), higher tibial trabecular BFR/BS (+59%, p<0.05), and higher Fmax at the distal femur (+32%, p<0.001) compared with BTX. In conclusion, BTX-induced immobilization led to lower BV/TV, BFR/BS, and Fmax. In general, PTH or Zln alone prevented the BTX-induced osteopenia, whereas PTH and Zln given in combination not only prevented, but also increased BV/TV and BFR/BS, and maintained Fmax at the distal femoral metaphysis compared with Ctrl. Copyright © 2014 Elsevier Inc. All rights reserved.

Optimising antiresorptive therapies in postmenopausal women: why do we need to give due consideration to the degree of suppression?

PubMed

Karsdal, Morten A; Qvist, Per; Christiansen, Claus; Tankó, László B

2006-01-01

Accelerated bone turnover with bone resorption exceeding bone formation is a major mechanism underlying postmenopausal bone loss and hence the development of osteoporosis. Accordingly, inhibition of bone resorption is a rational approach for the prevention of osteoporosis. In this context, the most logical option, hormone replacement therapy, reverses the rate of bone turnover to premenopausal levels, whereas the magnitude of inhibition by amino-bisphosphonates and the recently introduced anti-receptor activator of NFkappaB ligand (RANKL) antibody often exceeds this. As bone turnover has crucial implications for the continuous renewal of bone tissue, the over-suppression of bone turnover has potential consequences for bone quality and strength. Long-term treatment with potent bisphosphonates has recently been associated with osteonecrosis of the jaw and dose-dependent increases in micro-crack accumulation in animals. Although these observations are the subject of ongoing discussions, it is timely to discuss whether the over-suppression of bone turnover below premenopausal levels is really our ultimate goal when defining the success criteria for antiresorptive agents. In this review, the implications of high and excessively low bone turnover of endogenous origin for bone quality, fracture risk and integrity of the jaw are discussed. In addition, animal and clinical research revealing initial findings regarding the potential adverse effects of drug-induced suppression of bone remodeling are summarised. The inhibition of bone resorption, which is either transient between doses (e.g. with calcitonin) or does not exceed premenopausal levels (with hormone replacement therapy or selective estrogen receptor modulators), is preferable because it not only provides similar antifracture efficacy but can also assist in the maintenance of the dynamic repair of micro-cracks/micro-fractures.

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

PubMed Central

Tu, Xiaolin; Delgado-Calle, Jesus; Condon, Keith W.; Maycas, Marta; Zhang, Huajia; Carlesso, Nadia; Taketo, Makoto M.; Burr, David B.; Plotkin, Lilian I.; Bellido, Teresita

2015-01-01

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcatOt mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcatOt mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcatOt mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcatOt mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone. PMID:25605937

Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice.

PubMed

Thongchote, Kanogwun; Svasti, Saovaros; Teerapornpuntakit, Jarinthorn; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2014-06-15

A marked decrease in β-globin production led to β-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous β-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1-2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1α and -1β. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in β-thalassemia. Copyright © 2014 the American Physiological Society.

Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta.

PubMed

Shi, Changgui; Hu, Bo; Guo, Lei; Cao, Peng; Tian, Ye; Ma, Jun; Chen, Yuanyuan; Wu, Huiqiao; Hu, Jinquan; Deng, Lianfu; Zhang, Ying; Yuan, Wen

2016-05-01

Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (μCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis

PubMed Central

Su, Nan; Sun, Qidi; Li, Can; Lu, Xiumin; Qi, Huabing; Chen, Siyu; Yang, Jing; Du, Xiaolan; Zhao, Ling; He, Qifen; Jin, Min; Shen, Yue; Chen, Di; Chen, Lin

2010-01-01

Achondroplasia (ACH) is a short-limbed dwarfism resulting from gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Previous studies have shown that ACH patients have impaired chondrogenesis, but the effects of FGFR3 on bone formation and bone remodeling at adult stages of ACH have not been fully investigated. Using micro-computed tomography and histomorphometric analyses, we found that 2-month-old Fgfr3G369C/+ mice (mouse model mimicking human ACH) showed decreased bone mass due to reduced trabecular bone volume and bone mineral density, defect in bone mineralization and increased osteoclast numbers and activity. Compared with primary cultures of bone marrow stromal cells (BMSCs) from wild-type mice, Fgfr3G369C/+ cultures showed decreased cell proliferation, increased osteogenic differentiation including up-regulation of alkaline phosphatase activity and expressions of osteoblast marker genes, and reduced bone matrix mineralization. Furthermore, our studies also suggest that decreased cell proliferation and enhanced osteogenic differentiation observed in Fgfr3G369C/+ BMSCs are caused by up-regulation of p38 phosphorylation and that enhanced Erk1/2 activity is responsible for the impaired bone matrix mineralization. In addition, in vitro osteoclast formation and bone resorption assays demonstrated that osteoclast numbers and bone resorption area were increased in cultured bone marrow cells derived from Fgfr3G369C/+ mice. These findings demonstrate that gain-of-function mutation in FGFR3 leads to decreased bone mass by regulating both osteoblast and osteoclast activities. Our studies provide new insight into the mechanism underlying the development of ACH. PMID:20053668

Socket preservation using bovine bone mineral and collagen membrane: a randomized controlled clinical trial with histologic analysis.

PubMed

Cardaropoli, Daniele; Tamagnone, Lorenzo; Roffredo, Alessandro; Gaveglio, Lorena; Cardaropoli, Giuseppe

2012-08-01

After tooth extraction, varying amounts of bone resorption occur because of qualitative and quantitative changes at the edentulous site of the alveolar process. The aims of this randomized controlled clinical trial were (1) to compare the postextraction changes in residual ridge dimensions during spontaneous healing with those during socket preservation, (2) to analyze the histologic and histomorphometric aspects of the grafted sockets, and (3) to compare probing procket depth (PPD) and clinical attachment level (CAL) changes at teeth adjacent to extraction sites. Forty-eight teeth were extracted from 41 patients referred for extraction of 1 or more maxillary or mandibular premolars or molars. The edentulous sites were randomly assigned to the control (EXT, extraction alone) or experimental groups (SP, extraction and socket preservation). In the SP group, the sockets were filled with bovine bone mineral and covered with porcine collagen membrane. At baseline and after 4 months, PPD, gingival recession (REC), and CAL were measured at teeth adjacent to the edentulous sites. The changes in ridge dimensions from baseline to 4 months were assessed on dental casts. At 4 months, bone was harvested from the grafted areas in the SP group and the edentulous areas in the EXT group. PPD, REC, and CAL were comparable between groups. However, from baseline to 4 months, the SP group showed significantly less reduction in ridge width (1.04 ± 1.08 mm vs 4.48 ± 0.65 mm, P < .001) and height (0.46 ± 0.46 mm vs 1.54 ± 0.33 mm, P < .001). Histologically, the grafted sockets exhibited various stages of bone maturation and formation without inflammatory responses. No significant difference in the mineralized and nonmineralized fractions was noted between the groups. Socket preservation using bovine bone mineral and porcine collagen membrane considerably limits the amount of horizontal and vertical bone resorption when compared with extraction alone.

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate*

PubMed Central

Thaler, Roman; Maurizi, Antonio; Roschger, Paul; Sturmlechner, Ines; Khani, Farzaneh; Spitzer, Silvia; Rumpler, Monika; Zwerina, Jochen; Karlic, Heidrun; Dudakovic, Amel; Klaushofer, Klaus; Teti, Anna; Rucci, Nadia; Varga, Franz; van Wijnen, Andre J.

2016-01-01

Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-κB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (∼20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis. PMID:26757819

Reduced bone resorption by intake of dietary vitamin D and K from tailor-made Atlantic salmon: A randomized intervention trial.

PubMed

Graff, Ingvild Eide; Øyen, Jannike; Kjellevold, Marian; Frøyland, Livar; Gjesdal, Clara Gram; Almås, Bjørg; Rosenlund, Grethe; Lie, Øyvind

2016-10-25

Suboptimal vitamin D status is common among humans, and might increase bone resorption with subsequent negative effects on bone health. Fatty fish, including Atlantic salmon, is an important dietary vitamin D source. However, due to a considerable change in fish feed composition, the contribution of vitamin D from salmon fillet has been reduced. The main objective was to investigate if intake of vitamin D3 enriched salmon or vitamin D3 tablets decreased bone biomarkers (urinary N-telopeptides, deoxypyridinoline, serum bone-specific alkaline phosphatase, and osteocalcin) compared to a low vitamin D3 intake. The 122 healthy postmenopausal women included in this 12 weeks intervention trial were randomized into four groups: three salmon groups (150 grams/two times/week) and one tablet group (800 IU vitamin D and 1000 mg calcium/day). The salmon groups also received calcium supplements. The salmon had three different vitamin D3/vitamin K1 combinations: high D3+high K1, low D3+high K1, or high D3+low K1. Increased intake of salmon containing high levels of vitamin D3 (0.35-0.38 mg/kg/fillet) and supplements with the same weekly contribution had a positive influence on bone health as measured by bone biomarkers in postmenopausal women. Consequently, an increased level of vitamin D3 at least to original level in feed for salmonids will contribute to an improved vitamin D3 status and may improve human bone health.

In vivo testing of a biodegradable woven fabric made of bioactive glass fibers and PLGA80--a pilot study in the rabbit.

PubMed

Alm, Jessica J; Frantzén, Janek P A; Moritz, Niko; Lankinen, Petteri; Tukiainen, Mikko; Kellomäki, Minna; Aro, Hannu T

2010-05-01

The purpose of this study was to perform an intra-animal comparison of biodegradable woven fabrics made of bioactive glass (BG) fibers and poly(L-lactide-co-glycolide) 80/20 copolymer (PLGA(80)) fibers or PLGA(80) fibers alone, in surgical stabilization of bone graft. The BG fibers (BG 1-98) were aimed to enhance bone growth at site of bone grafting, whereas the PLGA component was intended to provide structural strength and flexibility to the fabric. Bone formation was analyzed qualitatively by histology and quantitatively by peripheral quantitative computed tomography (pQCT) at 12 weeks. The surgical handling properties of the control PLGA(80) fabric were more favorable. Both fabrics were integrated with the cortical bone surfaces, but BG fibers showed almost complete resorption. There were no signs of adverse local tissue reactions. As a proof of material integration and induced new bone formation, there was a significant increase in bone volume of the operated femurs compared with the contralateral intact bone (25% with BG/PLGA(80) fabric, p < 0.001 and 28% with the control PLGA(80) fabric, p = 0.006). This study failed to demonstrate the previously seen positive effect of BG 1-98 on osteogenesis, probably due to the changed resorption properties of BG in the form of fibers. Therefore, the feasibility and safety of BG as fibers needs to be reevaluated before use in clinical applications. (c) 2010 Wiley Periodicals, Inc.

Calcineurin/NFAT signaling in osteoblasts regulates bone mass.

PubMed

Winslow, Monte M; Pan, Minggui; Starbuck, Michael; Gallo, Elena M; Deng, Lei; Karsenty, Gerard; Crabtree, Gerald R

2006-06-01

Development and repair of the vertebrate skeleton requires the precise coordination of bone-forming osteoblasts and bone-resorbing osteoclasts. In diseases such as osteoporosis, bone resorption dominates over bone formation, suggesting a failure to harmonize osteoclast and osteoblast function. Here, we show that mice expressing a constitutively nuclear NFATc1 variant (NFATc1(nuc)) in osteoblasts develop high bone mass. NFATc1(nuc) mice have massive osteoblast overgrowth, enhanced osteoblast proliferation, and coordinated changes in the expression of Wnt signaling components. In contrast, viable NFATc1-deficient mice have defects in skull bone formation in addition to impaired osteoclast development. NFATc1(nuc) mice have increased osteoclastogenesis despite normal levels of RANKL and OPG, indicating that an additional NFAT-regulated mechanism influences osteoclastogenesis in vivo. Calcineurin/NFATc signaling in osteoblasts controls the expression of chemoattractants that attract monocytic osteoclast precursors, thereby coupling bone formation and bone resorption. Our results indicate that NFATc1 regulates bone mass by functioning in both osteoblasts and osteoclasts.

Osteoclastogenesis and Osteoclastic Resorption of Tricalcium Phosphate: Effect of Strontium and Magnesium Doping

PubMed Central

Roy, Mangal; Bose, Susmita

2012-01-01

Bone substitute materials are required to support the remodeling process, which consists of osteoclastic resorption and osteoblastic synthesis. Osteoclasts, the bone resorbing cells, generate from differentiation of hemopoietic mononuclear cells. In the present study we have evaluated the effects of 1.0 wt% strontium (Sr) and 1.0 wt% magnesium (Mg) doping in beta-tricalcium phosphate (β-TCP) on the differentiation of mononuclear cells into osteoclast-like cells and its resorptive activity. In vitro osteoclast-like cell formation, adhesion, and resorption were studied using osteoclast precursor RAW 264.7 cell, supplemented with receptor activator of nuclear factor κβ ligand (RANKL). Osteoclast-like cell formation was noticed on pure and Sr doped β-TCP samples at day 8 which was absent on Mg doped β-TCP samples indicating decrease in initial osteoclast differentiation due to Mg doping. After 21 days of culture, osteoclast-like cell formation was evident on all samples with osteoclastic markers such as actin ring, multiple nuclei, and presence of vitronectin receptor αvβ3 integrin. After osteoclast differentiation, all substrates showed osteoclast-like cell mediated degradation, however; significantly restricted for Mg doped β-TCP samples. Our present results indicated substrate chemistry controlled osteoclast differentiation and resorptive activity which can be used in designing TCP based resorbable bone substitutes with controlled degradation properties. PMID:22566212

Osteoclastogenesis and osteoclastic resorption of tricalcium phosphate: effect of strontium and magnesium doping.

PubMed

Roy, Mangal; Bose, Susmita

2012-09-01

Bone substitute materials are required to support the remodeling process, which consists of osteoclastic resorption and osteoblastic synthesis. Osteoclasts, the bone-resorbing cells, generate from differentiation of hemopoietic mononuclear cells. In the present study, we have evaluated the effects of 1.0 wt % strontium (Sr) and 1.0 wt % magnesium (Mg) doping in beta-tricalcium phosphate (β-TCP) on the differentiation of mononuclear cells into osteoclast-like cells and its resorptive activity. In vitro osteoclast-like cell formation, adhesion, and resorption were studied using osteoclast precursor RAW 264.7 cell, supplemented with receptor activator of nuclear factor κβ ligand (RANKL). Osteoclast-like cell formation was noticed on pure and Sr-doped β-TCP samples at day 8, which was absent on Mg-doped β-TCP samples indicating decrease in initial osteoclast differentiation due to Mg doping. After 21 days of culture, osteoclast-like cell formation was evident on all samples with osteoclastic markers such as actin ring, multiple nuclei, and presence of vitronectin receptor α(v)β(3) integrin. After osteoclast differentiation, all substrates showed osteoclast-like cell-mediated degradation, however, significantly restricted for Mg-doped β-TCP samples. Our present results indicated that substrate chemistry controlled osteoclast differentiation and resorptive activity, which can be used in designing TCP-based resorbable bone substitutes with controlled degradation properties. Copyright © 2012 Wiley Periodicals, Inc.

Calcium Kinetics During Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Wastney, Meryl E.; OBrien, Kimberly O.; Lane, Helen W.

1999-01-01

Bone loss is one of the most detrimental effects of space flight, threatening to limit the duration of human space missions. The ability to understand and counteract this loss will be critical for crew health and safety during and after extended-duration missions. The hypotheses to be tested in this project are that space flight alters calcium homeostasis and bone mineral metabolism, and that calcium homeostasis and bone mineral metabolism will return to baseline within days to weeks of return to Earth. These hypotheses will be evidenced by elevated rates of bone mineral resorption and decreased bone mineral deposition, decreased absorption of dietary calcium, altered calcitropic endocrine profiles, elevated excretion of calcium in urine and feces, and elevated excretion of markers of bone resorption. The second hypothesis will be evidenced by return of indices of calcium homeostasis and bone metabolism to preflight levels within days to weeks of return to Earth. Studies will be conducted on International Space Station astronauts before, during, and after extended-duration flights. Measurements of calcium kinetics, bone mass, and endocrine/biochemical markers of bone and calcium homeostasis will be conducted. Kinetic studies utilizing dual isotope tracer kinetic studies and mathematical modeling techniques will allow for determination of bone calcium deposition, bone calcium resorption, dietary calcium absorption and calcium excretion (both urinary and endogenous fecal excretion). These studies will build upon preliminary work conducted on the Russian Mir space station. The results from this project will be critical for clarifying how microgravity affects bone and calcium homeostasis, and will provide an important control point for assessment of countermeasure efficacy. These results are expected to aid in developing countermeasures for bone loss, both for space crews and for individuals on Earth who have metabolic bone diseases.

Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

PubMed

Langdahl, Bente; Ferrari, Serge; Dempster, David W

2016-12-01

The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that rediscovering a phenomenon that was first observed more half a century ago will have an important impact on our understanding of how new antifracture treatments work.

Bone Remodeling Monitor

NASA Technical Reports Server (NTRS)

Foucar, Charlie; Goldberg, Leslie; Hon, Bodin; Moore, Shannon; Williams, Evan

2009-01-01

The impact of bone loss due to different mechanical loadings in microgravity is a major concern for astronauts upon reintroduction to gravitational forces in exploration missions to the Moon and Mars. it has been shown that astronauts not only lose bone at differing rates, with levels up to 2% per month, but each astronaut will respond to bone loss treatments differently. Pre- and post-flight imaging techniques and frozen urine samples for post-flight laboratory immunoassays To develop a novel, non-invasive, highly . sensitive, portable, intuitive, and low-powered device to measure bone resorption levels in 'real time' to provide rapid and Individualized feedback to maximize the efficacy of bone loss countermeasures 1. Collect urine specimen and analyze the level of bone resorption marker, DPD (deoxypridinoline) excreted. 2. Antibodies specific to DPD conjugated with nanoshells and mixed with specimen, the change in absorbance from agglutination is measured by an optical device. 3. The concentration of DPD is displayed and recorded on a PDA

Simulation of multi-stage nonlinear bone remodeling induced by fixed partial dentures of different configurations: a comparative clinical and numerical study.

PubMed

Liao, Zhipeng; Yoda, Nobuhiro; Chen, Junning; Zheng, Keke; Sasaki, Keiichi; Swain, Michael V; Li, Qing

2017-04-01

This paper aimed to develop a clinically validated bone remodeling algorithm by integrating bone's dynamic properties in a multi-stage fashion based on a four-year clinical follow-up of implant treatment. The configurational effects of fixed partial dentures (FPDs) were explored using a multi-stage remodeling rule. Three-dimensional real-time occlusal loads during maximum voluntary clenching were measured with a piezoelectric force transducer and were incorporated into a computerized tomography-based finite element mandibular model. Virtual X-ray images were generated based on simulation and statistically correlated with clinical data using linear regressions. The strain energy density-driven remodeling parameters were regulated over the time frame considered. A linear single-stage bone remodeling algorithm, with a single set of constant remodeling parameters, was found to poorly fit with clinical data through linear regression (low [Formula: see text] and R), whereas a time-dependent multi-stage algorithm better simulated the remodeling process (high [Formula: see text] and R) against the clinical results. The three-implant-supported and distally cantilevered FPDs presented noticeable and continuous bone apposition, mainly adjacent to the cervical and apical regions. The bridged and mesially cantilevered FPDs showed bone resorption or no visible bone formation in some areas. Time-dependent variation of bone remodeling parameters is recommended to better correlate remodeling simulation with clinical follow-up. The position of FPD pontics plays a critical role in mechanobiological functionality and bone remodeling. Caution should be exercised when selecting the cantilever FPD due to the risk of overloading bone resorption.

Safflower bud inhibits RANKL-induced osteoclast differentiation and prevents bone loss in ovariectomized mice.

PubMed

Choi, Joo-Hee; Lim, Seul-Ki; Kim, Dong-Il; Park, Min-Jung; Kim, Young-Kuk; Lee, An-Chul; Kim, Young-Min; Yang, Soo-Jin; Park, Jong-Hwan

2017-10-15

The powder and extract of safflower seeds are known to be effective in the prevention of bone loss in ovariectomized animals. However, the inhibitory effect and molecular mechanisms of safflower bud (SB), the germinated safflower, on bone destruction is unclear. The present study was designed to investigate the inhibitory effect and molecular mechanism of SB on osteoclastic differentiation and on bone loss in ovarietomized (OVX) mice. Osteoclastogenesis was determined by TRAP staining, F-actin ring formation, and bone resorption assay. NF-κB and MAPKs activation was analyzed by transfection assay and Western blot, respectively. Real-time PCR was performed to examine the expression of osteoclastogenesis-related genes. Histological changes, increases in TRAP-positive cells, and cathepsin K expression were examined in the metaphysis of OVX mice. Density of bone marrow was evaluated by µCT. SB inhibited the RANKL-induced differentiation of BMDMs into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by SB in RANKL-treated BMDMs. In addition, SB decreased the activation of NF-κB and MAPKs and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. Feeding of SB-included diet prevented bone loss in OVX mice. The number of TRAP-positive cells and level of protein expression of cathepsin K was reduced and bone mineral density was increased in the metaphysis of mice fed SB compared with OVX mice. These findings suggest that SB can be a preventive and therapeutic candidate for destructive bone diseases. Copyright © 2017. Published by Elsevier GmbH.

Alendronate (ALN) combined with Osteoprotegerin (OPG) significantly improves mechanical properties of long bone than the single use of ALN or OPG in the ovariectomized rats

PubMed Central

2011-01-01

Background Alendronate (ALN) is the most common form of bisphosphonates used for the treatment of osteoporosis. Osteoprotegerin (OPG) has also been shown to reduce osteoporotic changes in both humans and experimental animals after systemic administration. The aim of this current study was to test if the anti-resorption effects of ALN may be enhanced when used in combination with OPG. Objectives To investigate the effects of ALN, OPG or combined on bone mass and bone mechanical properties in ovariectomized (OVX) rats. Methods OVX rats were treated with ALN, OPG-Fc, or OPG-Fc and ALN. Biochemical markers, trabecular bone mass, biomechanics, histomorphometry and RANKL expression in the bone tissues were examined following the treatments. Results The treatment of ALN, OPG-Fc and ALN+OPG-Fc all prevented bone loss in the OVX-rats, there was no statistical difference among the three treatment groups in terms of vertebrae BMD, mineralizing surfaces, mineral apposition rate, BFR/BS. The ALN+OPG-Fc treatment group had significantly increased the mechanical strength of lumber vertebral bodies and femoral shafts when compared to the ALN and OPG-Fc treatment groups. The RANKL protein expression in the vertebral bones was significantly decreased in the ALN and ALN+OPG-Fc treatment groups, suggesting the combined use of OPG-Fc and ALN might have amplified inhibition of bone resorption through inhibiting RANKL-dependent osteoclastogenesis. Conclusion The combined use of OPG-Fc and ALN may be a new treatment strategy for reversing bone loss and restoring bone quality in osteoprotic disorders. PMID:21752290

Changes in Structural-Mechanical Properties and Degradability of Collagen during Aging-associated Modifications*

PubMed Central

Panwar, Preety; Lamour, Guillaume; Mackenzie, Neil C. W.; Yang, Heejae; Ko, Frank; Li, Hongbin; Brömme, Dieter

2015-01-01

During aging, changes occur in the collagen network that contribute to various pathological phenotypes in the skeletal, vascular, and pulmonary systems. The aim of this study was to investigate the consequences of age-related modifications on the mechanical stability and in vitro proteolytic degradation of type I collagen. Analyzing mouse tail and bovine bone collagen, we found that collagen at both fibril and fiber levels varies in rigidity and Young's modulus due to different physiological changes, which correlate with changes in cathepsin K (CatK)-mediated degradation. A decreased susceptibility to CatK-mediated hydrolysis of fibrillar collagen was observed following mineralization and advanced glycation end product-associated modification. However, aging of bone increased CatK-mediated osteoclastic resorption by ∼27%, and negligible resorption was observed when osteoclasts were cultured on mineral-deficient bone. We observed significant differences in the excavations generated by osteoclasts and C-terminal telopeptide release during bone resorption under distinct conditions. Our data indicate that modification of collagen compromises its biomechanical integrity and affects CatK-mediated degradation both in bone and tissue, thus contributing to our understanding of extracellular matrix aging. PMID:26224630

The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects

NASA Technical Reports Server (NTRS)

Zerwekh, J. E.; Ruml, L. A.; Gottschalk, F.; Pak, C. Y.; Blomqvist, C. G. (Principal Investigator)

1998-01-01

This study was undertaken to examine the effects of 12 weeks of skeletal unloading on parameters of calcium homeostasis, calcitropic hormones, bone histology, and biochemical markers of bone turnover in 11 normal subjects (9 men, 2 women; 34 +/- 11 years of age). Following an ambulatory control evaluation, all subjects underwent 12 weeks of bed rest. An additional metabolic evaluation was performed after 12 days of reambulation. Bone mineral density declined at the spine (-2.9%, p = 0.092) and at the hip (-3.8%, p = 0.002 for the trochanter). Bed rest prompted a rapid, sustained, significant increase in urinary calcium and phosphorus as well as a significant increase in serum calcium. Urinary calcium increased from a pre-bed rest value of 5.3 mmol/day to values as high as 73 mmol/day during bed rest. Immunoreactive parathyroid hormone and serum 1,25-dihydroxyvitamin D declined significantly during bed rest, although the mean values remained within normal limits. Significant changes in bone histology included a suppression of osteoblastic surface for cancellous bone (3.1 +/- 1.3% to 1.9 +/- 1.5%, p = 0.0142) and increased bone resorption for both cancellous and cortical bone. Cortical eroded surface increased from 3.5 +/- 1.1% to 7.3 +/- 4.0% (p = 0.018) as did active osteoclastic surface (0.2 +/- 0.3% to 0.7 +/- 0.7%, p = 0.021). Cancellous eroded surface increased from 2.1 +/- 1.1% to 4.7 +/- 2.2% (p = 0.002), while mean active osteoclastic surface doubled (0.2 +/- 0.2% to 0.4 +/- 0.3%, p = 0.020). Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, and type I procollagen extension peptide) did not change significantly during bed rest. Urinary biochemical markers of bone resorption (hydroxyproline, deoxypyridinoline, and N-telopeptide of type I collagen) as well as a serum marker of bone resorption (type I collagen carboxytelopeptide) all demonstrated significant increases during bed rest which declined toward normal during reambulation. Thus, under the conditions of this study, the human skeleton appears to respond to unloading by a rapid and sustained increase in bone resorption and a more subtle decrease in bone formation.

Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD).

PubMed

Ng, Adeline H; Willett, Thomas L; Alman, Benjamin A; Grynpas, Marc D

2014-11-01

The etiology of Adynamic Bone Disease (ABD) is poorly understood but the hallmark of ABD is a lack of bone turnover. ABD occurs in renal osteodystrophy (ROD) and is suspected to occur in elderly patients on long-term anti-resorptive therapy. A major clinical concern of ABD is diminished bone quality and an increased fracture risk. To our knowledge, experimental animal models for ABD other than ROD-ABD have not been developed or studied. The objectives of this study were to develop a mouse model of ABD without the complications of renal ablation, and to characterize changes in bone quality in ABD relative to controls. To re-create the adynamic bone condition, 4-month old female Col2.3Δtk mice were treated with ganciclovir to specifically ablate osteoblasts, and pamidronate was used to inhibit osteoclastic resorption. Four groups of animals were used to characterize bone quality in ABD: Normal bone controls, No Formation controls, No Resorption controls, and an Adynamic group. After a 6-week treatment period, the animals were sacrificed and the bones were harvested for analyses. Bone quality assessments were conducted using established techniques including bone histology, quantitative backscattered electron imaging (qBEI), dual energy X-ray absorptiometry (DXA), microcomputed tomography (microCT), and biomechanical testing. Histomorphometry confirmed osteoblast-related hallmarks of ABD in our mouse model. Bone formation was near complete suppression in the No Formation and Adynamic specimens. Inhibition of bone resorption in the Adynamic group was confirmed by tartrate-resistant acid phosphatase (TRAP) stain. Normal bone mineral density and architecture were maintained in the Adynamic group, whereas the No Formation group showed a reduction in bone mineral content and trabecular thickness relative to the Adynamic group. As expected, the No Formation group had a more hypomineralized profile and the Adynamic group had a higher mean mineralization profile that is similar to suppressed bone turnover in human. This data confirms successful replication of the adynamic bone condition in a mouse without the complication of renal ablation. Our approach is the first model of ABD that uses pharmacological manipulation in a transgenic mouse to mimic the bone cellular dynamics observed in the human ABD condition. We plan to use our mouse model to investigate the adynamic bone condition in aging and to study changes to bone quality and fracture risk as a consequence of over-suppressed bone turnover. Copyright © 2014 Elsevier Inc. All rights reserved.

Horizontal Resorption of Fresh-Frozen Corticocancellous Bone Blocks in the Reconstruction of the Atrophic Maxilla at 5 Months

PubMed Central

Pereira, Eugénio; Messias, Ana; Dias, Ricardo; Judas, Fernando; Salvoni, Alexander; Guerra, Fernando

2015-01-01

Background Reliable implant-supported rehabilitation of an alveolar ridge needs sufficient volume of bone. In order to achieve a prosthetic-driven positioning, bone graft techniques may be required. Purpose This prospective cohort study aims to clinically evaluate the amount of resorption of corticocancellous fresh-frozen allografts bone blocks used in the reconstruction of the severe atrophic maxilla. Materials and Methods Twenty-two partial and totally edentulous patients underwent bone augmentation procedures with fresh-frozen allogenous blocks from the iliac crest under local anesthesia. Implants were inserted into the grafted sites after a healing period of 5 months. Final fixed prosthesis was delivered ± 4 months later. Ridge width analysis and measurements were performed with a caliper before and after grafting and at implant insertion. Bone biopsies were performed in 16 patients. Results A total of 98 onlay block allografts were used in 22 patients with an initial mean alveolar ridge width of 3.41 ± 1.36 mm. Early exposure of blocks was observed in four situations and one of these completely resorbed. Mean horizontal bone gain was 3.63 ± 1.28 mm (p < .01). Mean buccal bone resorption between allograph placement and the reopening stage was 0.49 ± 0.54 mm, meaning approximately 7.1% (95% confidence interval: [5.6%, 8.6%]) of total ridge width loss during the integration period. One hundred thirty dental implants were placed with good primary stability (≥ 30 Ncm). Four implants presented early failure before the prosthetic delivery (96.7% implant survival). All patients were successfully rehabilitated. Histomorphometric analysis revealed 20.9 ± 5.8% of vital bone in close contact to the remaining grafted bone. A positive strong correlation (adjusted R2 = 0.44, p = .003) was found between healing time and vital bone percentage. Conclusions Augmentation procedures performed using fresh-frozen allografts from the iliac crest are a suitable alternative in the reconstruction of the atrophic maxilla with low resorption rate at 5 months, allowing proper stability of dental implants followed by fixed prosthetic rehabilitation. PMID:25346211

Three-dimensional analysis of alveolar bone resorption by image processing of 3-D dental CT images

NASA Astrophysics Data System (ADS)

Nagao, Jiro; Kitasaka, Takayuki; Mori, Kensaku; Suenaga, Yasuhito; Yamada, Shohzoh; Naitoh, Munetaka

2006-03-01

We have developed a novel system that provides total support for assessment of alveolar bone resorption, caused by periodontitis, based on three-dimensional (3-D) dental CT images. In spite of the difficulty in perceiving the complex 3-D shape of resorption, dentists assessing resorption location and severity have been relying on two-dimensional radiography and probing, which merely provides one-dimensional information (depth) about resorption shape. However, there has been little work on assisting assessment of the disease by 3-D image processing and visualization techniques. This work provides quantitative evaluation results and figures for our system that measures the three-dimensional shape and spread of resorption. It has the following functions: (1) measures the depth of resorption by virtually simulating probing in the 3-D CT images, taking advantage of image processing of not suffering obstruction by teeth on the inter-proximal sides and much smaller measurement intervals than the conventional examination; (2) visualizes the disposition of the depth by movies and graphs; (3) produces a quantitative index and intuitive visual representation of the spread of resorption in the inter-radicular region in terms of area; and (4) calculates the volume of resorption as another severity index in the inter-radicular region and the region outside it. Experimental results in two cases of 3-D dental CT images and a comparison of the results with the clinical examination results and experts' measurements of the corresponding patients confirmed that the proposed system gives satisfying results, including 0.1 to 0.6mm of resorption measurement (probing) error and fairly intuitive presentation of measurement and calculation results.

A TNF receptor loop peptide mimic blocks RANK ligand–induced signaling, bone resorption, and bone loss

PubMed Central

Aoki, Kazuhiro; Saito, Hiroaki; Itzstein, Cecile; Ishiguro, Masaji; Shibata, Tatsuya; Blanque, Roland; Mian, Anower Hussain; Takahashi, Mariko; Suzuki, Yoshifumi; Yoshimatsu, Masako; Yamaguchi, Akira; Deprez, Pierre; Mollat, Patrick; Murali, Ramachandran; Ohya, Keiichi; Horne, William C.; Baron, Roland

2006-01-01

Activating receptor activator of NF-κB (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-α–induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF–induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-α promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF. PMID:16680194

RANKL, Osteopontin, and Osteoclast Homeostasis in a Hyper-Occlusion Mouse Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Cameron G.; Ito, Yoshihiro; Dangaria, Smit

2010-11-15

The biological mechanisms that maintain the position of teeth in their sockets establish a dynamic equilibrium between bone resorption and apposition. In order to reveal some of the dynamics involved in the tissue responses towards occlusal forces on periodontal ligament (PDL) and alveolar bone homeostasis, we developed the first mouse model of hyperocclusion. Swiss-Webster mice were kept in hyperocclusion for 0, 3, 6, and 9 d. Morphological and histological changes in the periodontium were assessed using micro-computed tomography (micro-CT) and ground sections with fluorescent detection of vital dye labels. Sections were stained for tartrate-resistant acid phosphatase, and the expression ofmore » receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteopontin (OPN) was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Traumatic occlusion resulted in enamel surface abrasion, inhibition of alveolar bone apposition, significant formation of osteoclasts at 3, 6 and 9 d, and upregulation of OPN and RANKL. Data from this study suggest that both OPN and RANKL contribute to the stimulation of bone resorption in the hyperocclusive state. In addition, we propose that the inhibition of alveolar bone apposition by occlusal forces is an important mechanism for the control of occlusal height that might work in synergy with RANKL-induced bone resorption to maintain normal occlusion.« less

RANKL, osteopontin, and osteoclast homeostasis in a hyperocclusion mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Cameron G.; Ito, Yoshihiro; Dangaria, Smit

2009-10-21

The biological mechanisms that maintain the position of teeth in their sockets establish a dynamic equilibrium between bone resorption and apposition. In order to reveal some of the dynamics involved in the tissue responses towards occlusal forces on periodontal ligament (PDL) and alveolar bone homeostasis, we developed the first mouse model of hyperocclusion. Swiss-Webster mice were kept in hyperocclusion for 0, 3, 6, and 9 d. Morphological and histological changes in the periodontium were assessed using micro-computed tomography (micro-CT) and ground sections with fluorescent detection of vital dye labels. Sections were stained for tartrate-resistant acid phosphatase, and the expression ofmore » receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteopontin (OPN) was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Traumatic occlusion resulted in enamel surface abrasion, inhibition of alveolar bone apposition, significant formation of osteoclasts at 3, 6 and 9 d, and upregulation of OPN and RANKL. Data from this study suggest that both OPN and RANKL contribute to the stimulation of bone resorption in the hyperocclusive state. In addition, we propose that the inhibition of alveolar bone apposition by occlusal forces is an important mechanism for the control of occlusal height that might work in synergy with RANKL-induced bone resorption to maintain normal occlusion.« less

Predisposing factors to severe external root resorption associated to orthodontic treatment.

PubMed

Picanço, Gracemia Vasconcelos; de Freitas, Karina Maria Salvatore; Cançado, Rodrigo Hermont; Valarelli, Fabricio Pinelli; Picanço, Paulo Roberto Barroso; Feijão, Camila Pontes

2013-01-01

The aim of this study was to evaluate predisposing factors among patients who developed moderate or severe external root resorption (Malmgren's grades 3 and 4), on the maxillary incisors, during fixed orthodontic treatment in the permanent dentition. Ninety-nine patients who underwent orthodontic treatment with fixed edgewise appliances were selected. Patients were divided into two groups: G1 - 50 patients with no root resorption or presenting only apical irregularities (Malmgren's grades 0 and 1) at the end of the treatment, with mean initial age of 16.79 years and mean treatment time of 3.21 years; G2 - 49 patients presenting moderate or severe root resorption (Malmgren's grades 3 and 4) at the end of treatment on the maxillary incisors, with mean initial age of 19.92 years and mean treatment time of 3.98 years. Periapical radiographs and lateral cephalograms were evaluated. Factors that could influence the occurrence of severe root resorption were also recorded. Statistical analysis included chi-square tests, Fisher's exact test and independent t tests. The results demonstrated significant difference between the groups for the variables: Extractions, initial degree of root resorption, root length and crown/root ratio at the beginning, and cortical thickness of the alveolar bone. It can be concluded that: Presence of root resorption before the beginning of treatment, extractions, reduced root length, decreased crown/root ratio and thin alveolar bone represent risk factors for severe root resorption in maxillary incisors during orthodontic treatment.

Impregnation of bone chips with alendronate and cefazolin, combined with demineralized bone matrix: a bone chamber study in goats

PubMed Central

2012-01-01

Background Bone grafts from bone banks might be mixed with bisphosphonates to inhibit the osteoclastic response. This inhibition prevents the osteoclasts to resorb the allograft bone before new bone has been formed by the osteoblasts, which might prevent instability. Since bisphosphonates may not only inhibit osteoclasts, but also osteoblasts and thus bone formation, we studied different bisphosphonate concentrations combined with allograft bone. We investigated whether locally applied alendronate has an optimum dose with respect to bone resorption and formation. Further, we questioned whether the addition of demineralized bone matrix (DBM), would stimulate bone formation. Finally, we studied the effect of high levels of antibiotics on bone allograft healing, since mixing allograft bone with antibiotics might reduce the infection risk. Methods 25 goats received eight bone conduction chambers in the cortical bone of the proximal medial tibia. Five concentrations of alendronate (0, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, and 10 mg/mL) were tested in combination with allograft bone and supplemented with cefazolin (200 μg/mL). Allograft not supplemented with alendronate and cefazolin served as control. In addition, allograft mixed with demineralized bone matrix, with and without alendronate, was tested. After 12 weeks, graft bone area and new bone area were determined with manual point counting. Results Graft resorption decreased significantly (p < 0.001) with increasing alendronate concentration. The area of new bone in the 1 mg/mL alendronate group was significantly (p = 0.002) higher when compared to the 10 mg/mL group. No differences could be observed between the group without alendronate, but with demineralized bone, and the control groups. Conclusions A dose-response relationship for local application of alendronate has been shown in this study. Most new bone was present at 1 mg/mL alendronate. Local application of cefazolin had no effect on bone remodelling. PMID:22443362

The circulating concentration and ratio of total and high molecular weight adiponectin in post-menopausal women with and without osteoporosis and its association with body mass index and biochemical markers of bone metabolism.

PubMed

Sodi, R; Hazell, M J; Durham, B H; Rees, C; Ranganath, L R; Fraser, W D

2009-09-01

There is increasing evidence suggesting that adiponectin plays a role in the regulation of bone metabolism. This was a cross-sectional study of 34 post-menopausal women with and 37 without osteoporosis. All subjects had body mass index (BMI), bone mineral density (BMD), total-, high molecular weight (HMW)-adiponectin and their ratio, osteoprotegerin (OPG), a marker of bone resorption (betaCTX) and formation (P1NP) measured. We observed a positive correlation between BMI and BMD (r=0.44, p<0.001). When normalised for BMI, total-, HMW-adiponectin concentrations and HMW/total-adiponectin ratio were significantly lower in obese compared to lean subjects but there was no difference between those with or without osteoporosis. There were significant negative correlations between HMW/total-adiponectin ratio and BMI (r=-0.27, p=0.030) and with OPG (r=-0.44, p<0.001). Our data suggests that there is no significant difference in the circulating concentration of fasting early morning total- or HMW-adiponectin in post-menopausal women with or without osteoporosis. The correlation between HMW/total-adiponectin ratio and OPG may indicate that adiponectin could influence bone metabolism by altering osteoblast production of OPG thereby affecting osteoclasts mediated bone resorption.

Decoronation followed by dental implants placement: fundamentals, applications and explanations

PubMed Central

Consolaro, Alberto; Ribeiro, Paulo Domingos; Cardoso, Maurício A.; Miranda, Dario A. Oliveira; Salfatis, Monica

2018-01-01

ABSTRACT Dental arches areas with teeth presenting dentoalveolar ankylosis and replacement root resorption can be considered as presenting normal bone, in full physiological remodeling process; and osseointegrated implants can be successfully placed. Bone remodeling will promote osseointegration, regardless of presenting ankylosis and/or replacement root resorption. After 1 to 10 years, all dental tissues will have been replaced by bone. The site, angulation and ideal positioning in the space to place the implant should be dictated exclusively by the clinical convenience, associated with previous planning. One of the advantages of decoronation followed by dental implants placement in ankylosed teeth with replacement resorption is the maintenance of bone volume in the region, both vertical and horizontal. If possible, the buccal part of the root, even if thin, should be preserved in the preparation of the cavity for the implant, as this will maintain gingival tissues looking fully normal for long periods. In the selection of cases for decoronation, the absence of microbial contamination in the region - represented by chronic periapical lesions, presence of fistula, old unconsolidated root fractures and active advanced periodontal disease - is important. Such situations are contraindications to decoronation. However, the occurrence of dentoalveolar ankylosis and replacement resorption without contamination should neither change the planning for implant installation, nor the criteria for choosing the type and brand of dental implant to be used. Failure to decoronate and use dental implants has never been reported. PMID:29791693

Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nurmio, Mirja, E-mail: Mirja.Nurmio@utu.fi; Department of Pediatrics, University of Turku; Joki, Henna, E-mail: Henna.Joki@utu.fi

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered)) . Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bonemore » physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research Highlights: > 3-Day imatinib treatment. > Causes growth plate anomalies in young rats. > Causes biomechanical changes and significant bone loss at distal trabecular bone. > Results in loss of osteoclasts at osteochondral junction.« less

Therapeutic potentials of naringin on polymethylmethacrylate induced osteoclastogenesis and osteolysis, in vitro and in vivo assessments

PubMed Central

Li, Nianhu; Xu, Zhanwang; Wooley, Paul H; Zhang, Jianxin; Yang, Shang-You

2014-01-01

Wear debris associated periprosthetic osteolysis represents a major pathological process associated with the aseptic loosening of joint prostheses. Naringin is a major flavonoid identified in grapefruit. Studies have shown that naringin possesses many pharmacological properties including effects on bone metabolism. The current study evaluated the influence of naringin on wear debris induced osteoclastic bone resorption both in vitro and in vivo. The osteoclast precursor cell line RAW 264.7 was cultured and stimulated with polymethylmethacrylate (PMMA) particles followed by treatment with naringin at several doses. Tartrate resistant acid phosphatase (TRAP), calcium release, and gene expression profiles of TRAP, cathepsin K, and receptor activator of nuclear factor-kappa B were sequentially evaluated. PMMA challenged murine air pouch and the load bearing tibia titanium pin-implantation mouse models were used to evaluate the effects of naringin in controlling PMMA induced bone resorption. Histological analyses and biomechanical pullout tests were performed following the animal experimentation. The in vitro data clearly demonstrated the inhibitory effects of naringin in PMMA induced osteoclastogenesis. The naringin dose of 10 μg/mL exhibited the most significant influence on the suppression of TRAP activities. Naringin treatment also markedly decreased calcium release in the stimulated cell culture medium. The short-term air pouch mouse study revealed that local injection of naringin ameliorated the PMMA induced inflammatory tissue response and subsequent bone resorption. The long-term tibia pin-implantation mouse model study suggested that daily oral gavage of naringin at 300 mg/kg dosage for 30 days significantly alleviated the periprosthetic bone resorption. A significant increase of periprosthetic bone volume and regaining of the pin stability were found in naringin treated mice. Overall, this study suggests that naringin may serve as a potential therapeutic agent to treat wear debris associated osteolysis. PMID:24376342

Cathepsin K expression and activity in canine osteosarcoma.

PubMed

Schmit, J M; Pondenis, H C; Barger, A M; Borst, L B; Garrett, L D; Wypij, J M; Neumann, Z L; Fan, T M

2012-01-01

Cathepsin K (CatK) is a lysosomal protease with collagenolytic activity, and its secretion by osteoclasts is responsible for degrading organic bone matrix. People with pathologic bone resorption have higher circulating CatK concentrations. Canine osteosarcoma (OS) cells will possess CatK, and its secretion will be cytokine inducible. Circulating CatK concentrations will be increased in dogs with OS, and will be a surrogate marker of bone resorption. Fifty-one dogs with appendicular OS and 18 age- and weight-matched healthy control dogs. In a prospective study, expressions of CatK mRNA and protein were investigated in OS cells. The inducible secretion and proteolytic activity of CatK from OS cells was assessed in vitro. Serum CatK concentrations were quantified in normal dogs and dogs with OS and its utility as a bone resorption marker was evaluated in dogs with OS treated with palliative radiation and antiresorptive agents. Canine OS cells contain preformed CatK within cytoplasmic vesicles. In OS cells, TGFβ1 induced the secretion of CatK, which degraded bone-derived type I collagen in vitro. CatK concentrations were higher in dogs with OS than healthy dogs (11.3 ± 5.2 pmol/L versus 8.1 ± 5.0 pmol/L, P = .03). In a subset of dogs with OS, pretreatment CatK concentrations gradually decreased after palliative radiation and antiresorptive treatment, from 9.3 ± 3.2 pmol/L to 5.0 ± 3.1 pmol/L, P = .03. Canine OS is associated with pathologic bone resorption, and CatK inhibitors might aid in the management of canine OS-related malignant osteolysis. Copyright © 2011 by the American College of Veterinary Internal Medicine.

Mechanical and Histological Effects of Resorbable Blasting Media Surface Treatment on the Initial Stability of Orthodontic Mini-Implants

PubMed Central

2016-01-01

Introduction. This study aimed to evaluate the effects of resorbable blasting media (RBM) treatment on early stability of orthodontic mini-implants by mechanical, histomorphometric, and histological analyses. Methods. Ninety-six (64 for mechanical study and 32 for histological study and histomorphometric analysis) titanium orthodontic mini-implants (OMIs) with machined (machined group) or RBM-treated (CaP) surface (RBM group) were implanted in the tibiae of 24 rabbits. Maximum initial torque (MIT) was measured during insertion, and maximum removal torque (MRT) and removal angular momentum (RAM) were measured at 2 and 4 weeks after implantation. Bone-to-implant contact (BIC) and bone area (BA) were analyzed at 4 weeks after implantation. Results. RBM group exhibited significantly lower MIT and significantly higher MRT and RAM at 2 weeks than machined group. No significant difference in MRT, RAM, and BIC between the two groups was noted at 4 weeks, although BA was significantly higher in RBM group than in machined group. RBM group showed little bone resorption, whereas machined group showed new bone formation after bone resorption. Conclusions. RBM surface treatment can provide early stability of OMIs around 2 weeks after insertion, whereas stability of machined surface OMIs may decrease in early stages because of bone resorption, although it can subsequently recover by new bone apposition. PMID:26942200

Retrospective Study of Serum Sclerostin Measurements in Bed Rest Subjects

NASA Technical Reports Server (NTRS)

Spatz, J. M.; Fields, E. E.; Yu, E. W.; Divieti, Pajevic P.; Bouxsein, M. L.; Sibonga, M. L.; Zwart, S. R.; Smith, S. M.

2011-01-01

Animal models and human studies suggest that osteocytes regulate the skeleton s response to mechanical unloading at the cellular level in part by an increase in sclerostin, an inhibitor of the anabolic Wnt pathway. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. Thus, we determined changes in serum sclerostin and bone turnover markers in healthy adult men who participated in a controlled bed rest study. Seven healthy adult men (31 +/- 3 yrs old) underwent 90-day six-degree head down tilt bed rest at the University of Texas Medical Branch in Galveston's Institute for Translational Sciences - Clinical Research Center (ITS-CRC). Serum sclerostin, PTH, serum markers of bone turnover (bone specific alkaline phosphatase, RANKL/OPG, and osteocalcin), urinary calcium and phosphorus excretion, and 24 hour pooled urinary markers of bone resorption (NTX, DPD, PYD) were evaluated pre-bed rest (BL), bed rest day 28 (BR-28), bed rest day 60 (BR-60), and bed rest day 90 (BR-90). In addition, bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry (DXA) at BL, BR-60, and post bed rest day 5 (BR+5). Data are reported as mean +/- standard deviation. We used repeated measures ANOVA to compare baseline values to BR-28, BR-60, and BR-90. RESULTS Consistent with prior reports, BMD declined significantly (1-2% per month) at weight-bearing skeletal sites (spine, hip, femur neck, and calcaneus). Serum sclerostin levels were elevated above BL at BR-28 (+29% +/- 20%, p = 0.003), BR-60 (+42% +/- 31%, p < 0.001), and BR-90 (22% +/- 21%, p = 0.07). Serum PTH levels were reduced at BR-28 (-17% +/- 16%, p = 0.02), BR-60 (-24% +/- 14%, p = 0.03), and returned to baseline at BR-90 (-21% +/- 21%, p = 0.14). Serum bone turnover markers did not change, however urinary bone resorption markers and calcium were significantly elevated following bed rest (p < 0.01). CONCLUSION We observed an increase of serum sclerostin associated with decreased serum PTH and elevated bone resorption markers in otherwise healthy men subjected to long-term immobilization.

DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats.

PubMed

Glorie, Lorenzo; Behets, Geert J; Baerts, Lesley; De Meester, Ingrid; D'Haese, Patrick C; Verhulst, Anja

2014-09-01

Dipeptidyl peptidase IV (DPP IV) modulates protein activity by removing dipeptides. DPP IV inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. DPP IV substrates not only increase insulin secretion but also affect bone metabolism. In this study, the effect of DPP IV inhibitor sitagliptin on bone was evaluated in normal and streptozotocin-induced diabetic rats. This study included 64 male Wistar rats divided into four groups (n = 16): two diabetic and two control groups. One diabetic and one control group received sitagliptin through drinking water. Tibiae were scanned every 3 wk using an in vivo μCT scanner. After 6 and 12 wk, rats were euthanized for histomorphometric analysis of bone parameters. The mechanical resistance of femora to fracture was assessed using a three-point bending test, and serum levels of bone metabolic markers were measured. Efficient DPP IV inhibition was achieved in sitagliptin-treated groups. Trabecular bone loss, the decrease in trabecular number, and the increase in trabecular spacing was attenuated through sitagliptin treatment in diabetic rats, as shown by in vivo μCT. Bone histomorphometry was in line with these results. μCT analysis furthermore showed that sitagliptin prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora during three-point bending. Finally, the serum levels of the resorption marker CTX-I were significantly lower in sitagliptin-treated diabetic animals compared with untreated diabetic animals. In conclusion, sitagliptin treatment attenuates bone loss and increases bone strength in diabetic rats probably through the reduction of bone resorption and independent of glycemic management. Copyright © 2014 the American Physiological Society.

Diamagnetic levitation promotes osteoclast differentiation from RAW264.7 cells.

PubMed

Sun, Yu-Long; Chen, Zhi-Hao; Chen, Xiao-Hu; Yin, Chong; Li, Di-Jie; Ma, Xiao-Li; Zhao, Fan; Zhang, Ge; Shang, Peng; Qian, Ai-Rong

2015-03-01

The superconducting magnet with a high magnetic force field can levitate diamagnetic materials. In this study, a specially designed superconducting magnet with large gradient high magnetic field (LGHMF), which provides three apparent gravity levels (μg, 1 g, and 2 g), was used to study its influence on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation from preosteoclast cell line RAW264.7. The effects of LGHMF on the viability, nitric oxide (NO) production, morphology in RAW264.7 cells were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the Griess method, and the immunofluorescence staining, respectively. The changes induced by LGHMF in osteoclast formation, mRNA expression, and bone resorption were determined by tartrate-resistant acid phosphatase staining, semiquantity PCR, and bone resorption test, respectively. The results showed that: 1) LGHMF had no lethal effect on osteoclast precursors but attenuated NO release in RAW264.7 cells. 2) Diamagnetic levitation (μg) enhanced both the formation and bone resorption capacity of osteoclast. Moreover, diamagnetic levitation up-regulated mRNA expression of RANK, Cathepsin K, MMP-9, and NFATc1, while down-regulated RunX2 in comparison with controls. Furthermore, diamagnetic levitation induced obvious morphological alterations in osteoclast, including active cytoplasmic peripheral pseudopodial expansion, formation of pedosome belt, and aggregation of actin ring. 3) Magnetic field produced by LGHMF attenuated osteoclast resorption activity. Collectively, LGHMF with combined effects has multiple effects on osteoclast, which attenuated osteoclast resorption with magnetic field, whereas promoted osteoclast differentiation with diamagnetic levitation. Therefore, these findings indicate that diamagnetic levitation could be used as a novel ground-based microgravity simulator, which facilitates bone cell research of weightlessness condition.

Efficacy of Bone Source™ and Cementek™ in comparison with Endobon™ in critical size metaphyseal defects, using a minipig model.

PubMed

Spies, Christian K G; Schnürer, Stefan; Gotterbarm, Tobias; Breusch, Steffen J

2010-01-01

To examine and compare biocompatibility, osteocompatibility, rate of resorption, and remodelling dynamics of 2 calcium phosphate cements in comparison with a well-established hydroxyapatite ceramic. In a randomised fashion, Bone Source™, Cementek™, and Endobon™ were implanted bilaterally into the proximal metaphyseal tibiae of 35 Göttinger minipigs in a direct right vs. left intra-individual comparison. Fluorescent labelling was used. Histological and morphometric evaluations were carried out at 6, 12, and 52 weeks. All bone substitutes showed good biocompatibility, bioactivity, and osteoconductivity. Endobon™ was not degraded over the follow-up period. Cementek™ was degraded constantly and significantly over the time intervals, whereas Bone Source™ was degraded mainly from the 6 week to 12 week interval. After 52 weeks, a significant difference of residual material within the defect zone was detected between all substitutes, with the highest resorption rate for Cementek™. Bone Source™ was least degraded. Defects filled with Endobon™ were characterised by a significantly continuous bony ingrowth over the time intervals. Bone formation within the defects filled with Cementek™ and Bone Source™ showed significant peaks 12 weeks after implantation. After 52 weeks, a significant difference in the amount of new bone within the defect area was detected, with the highest levels for Endobon™, followed by Cementek™. After 1 year a restitution ad integrum could not be observed in any treatment group. The ceramic Endobon™ showed the expected response histologically. Based on its porosity it excelled in osteoconductivity. Concerning the calcium phosphate cements, a thorough osseous incorporation seemed to inhibit further degradation of both bone substitute materials.

Osteoinductive effects of glyceollins on adult mesenchymal stromal/stem cells from adipose tissue and bone marrow

USDA-ARS?s Scientific Manuscript database

Osteoporosis is characterized by destruction of bone architecture, resulting in decreased bone mass density (BMD) and increased fracture susceptibility. While current therapies focus on reducing bone resorption, the development of therapies to regenerate bone may also be beneficial. Promising anabol...

Skeletal response to short-term weightlessness

NASA Technical Reports Server (NTRS)

Wronski, T. J.; Morey-Holton, E. R.

1986-01-01

Male Sprague Dawley rats were placed in orbit for 7 days aboard the space shuttle. Bone histomorphometry was performed in the long bones and lumbar vertebrae of flight rats and compared to data derived from ground based control rats. Trabecular bone mass was not altered during the first week of weightlessness. Strong trends were observed in flight rats for decreased periosteal bone formation in the tibial diaphysis, reduced osteoblast size in the proximal tibia, and decreased osteoblast surface and number in the lumbar vertebra. Histologic indices of bone resorption was relatively normal in flight rats. The results indicate that 7 day of weightlessness are not of sufficient duration to induce histologicaly detectable loss of trabecular bone in rats. However, cortical and trabecular bone formation appear to be diminished during the first week of space flight.

A study on OPG/RANK/RANKL axis in osteoporotic bile duct-ligated rats and the involvement of nitrergic and opioidergic systems.

PubMed

Doustimotlagh, Amir Hossein; Dehpour, Ahmad Reza; Etemad-Moghadam, Shahroo; Alaeddini, Mojgan; Ostadhadi, Sattar; Golestani, Abolfazl

2018-06-01

Chronic liver disease (CLD) affects millions of people and its impact on bone loss has become a subject of interest. Nitric oxide and endogenous opioids are suggested to increase during cholestasis/cirrhosis and may impact bone resorption by different mechanisms. The receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL)/osteoprotegerin (OPG) signaling pathway regulates bone resorption, but its role in metabolic bone disease subsequent to CLD is unknown. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss relative to the RANK/RANKL/OPG pathway, in bile duct-ligated (BDL) rats. Eighty BDL/sham-operated (SO) rats received injections of 3 mg/kg/day Nω-Nitro-L-arginine methyl ester ± naltrexone (10 mg/kg/day) or saline for 28 days. Plasma bone turnover markers, OPG, RANK, and RANKL along with mRNA expression levels of the latter three were assessed. Plasma bone turnover markers and OPG level increased, but RANKL decreased in the BDL group compared with their SO controls (both: P ≤ 0.05). Administration of naltrexone reduced bone turnover markers and OPG level while increased RANKL content in comparison to BDL rats ( P ≤ 0.05). As compared to untreated BDL rats, nitric oxide inhibition showed no effect on bone turnover marker i.e. OPG, RANK, and RANKL levels. BDL significantly increased RANK mRNA, but had no significant effect on RANKL and OPG mRNA expression. The lack of association between plasma levels and quantitative gene expression of RANKL and OPG suggests an indirect function of these markers in BDL rats. Considering that opioid receptor blockage by naltrexone in BDL animals caused a significant decrease in OPG and an increase in RANKL plasma contents, it could be postulated that the opioidergic system may have a regulatory effect on these bone markers.

Influence of exercise on bone remodeling-related hormones and cytokines in ovariectomized rats: a model of postmenopausal osteoporosis.

PubMed

Li, Lihui; Chen, Xi; Lv, Shuang; Dong, Miaomiao; Zhang, Li; Tu, Jiaheng; Yang, Jie; Zhang, Lingli; Song, Yinan; Xu, Leiting; Zou, Jun

2014-01-01

This study aims to explore the effects of exercise on postmenopausal osteoporosis and the mechanisms by which exercise affects bone remodeling. Sixty-three Wistar female rats were randomly divided into five groups: (1) control group, (2) sham-operated group, (3) OVX (Ovariectomy) group, (4) DES-OVX (Diethylstilbestrol-OVX) group, and (5) Ex-OVX (Exercise-OVX) group. The rat osteoporosis model was established through ovariectomy. The Ex-OVX rats were made to run 251.2 meters every day, 6 d/wk for 3 months in a running wheel. Trabecular bone volume (TBV%), total resorption surface (TRS%), trabecular formation surface (TFS%), mineralization rate (MAR), bone cortex mineralization rate (mAR), and osteoid seam width (OSW) were determined by bone histomorphometry. The mRNA and protein levels of interleukin-1β (IL-1β2), interleukin-6 (IL-6), and cyclooxygenase-2 (Cox-2) were determined by in situ hybridization and immunohistochemistry, respectively. Serum levels of estrogen estradiol (E2), calcitonin (CT), osteocalcin (BGP), and parathyroid hormone (PTH) were determined by ELISA assays. The investigation revealed that compared to the control and the sham-operated groups, the OVX group showed significantly lower levels of TBV%, E2, and CT, but much higher levels of TRS%, TFS%, MAR, OSW, BGP, and PTH. The Ex-OVX group showed increased TBV% and serum levels of E2 and CT compared to the OVX group. Ovariectomy also led to a significant increase in IL-1β mRNA and protein levels in the bone marrow and IL-6 and Cox-2 protein levels in tibias. In addition, the Ex-OVX group showed lower levels of IL-1 mRNA and protein, IL-6 mRNA, and Cox-2 mRNA and protein than those in the OVX group. The upshot of the study suggests that exercise can significantly increase bone mass in postmenopausal osteoporosis rat models by inhibiting bone resorption and increasing bone formation, especially in trabecular bones.

Expression of extracellular calcium (Ca2+o)-sensing receptor in human peripheral blood monocytes

NASA Technical Reports Server (NTRS)

Yamaguchi, T.; Olozak, I.; Chattopadhyay, N.; Butters, R. R.; Kifor, O.; Scadden, D. T.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

1998-01-01

The calcium-sensing receptor (CaR) is a G protein-coupled receptor playing key roles in extracellular calcium ion (Ca2+o) homeostasis in parathyroid gland and kidney. Macrophage-like mononuclear cells appear at sites of osteoclastic bone resorption during bone turnover and may play a role in the "reversal" phase of skeletal remodeling that follows osteoclastic resorption and precedes osteoblastic bone formation. Bone resorption produces substantial local increases in Ca2+o that could provide a signal for such mononuclear cells present locally within the bone marrow microenvironment. Indeed, previous studies by other investigators have shown that raising Ca2+o either in vivo or in vitro stimulated the release of interleukin-6 (IL-6) from human peripheral blood monocytes, suggesting that these cells express a Ca2+o-sensing mechanism. In these earlier studies, however, the use of reverse transcription-polymerase chain reaction (RT-PCR) failed to detect transcripts for the CaR previously cloned from parathyroid and kidney in peripheral blood monocytes. Since we recently found that non-specific esterase-positive, putative monocytes isolated from murine bone marrow express the CaR, we reevaluated the expression of this receptor in human peripheral blood monocytes. Immunocytochemistry, flow cytometry, and Western blot analysis, performed using a polyclonal antiserum specific for the CaR, detected CaR protein in human monocytes. In addition, the use of RT-PCR with CaR-specific primers, followed by nucleotide sequencing of the amplified products, identified CaR transcripts in the cells. Therefore, taken together, our data show that human peripheral blood monocytes possess both CaR protein and mRNA very similar if not identical to those expressed in parathyroid and kidney that could mediate the previously described, direct effects of Ca2+o on these cells. Furthermore, since mononuclear cells isolated from bone marrow also express the CaR, the latter might play some role in the "reversal" phase of bone remodeling, sensing local changes in Ca2+o resulting from osteoclastic bone resorption and secreting osteotropic cytokines or performing other Ca2+o-regulated functions that contribute to the control of bone turnover.

Inhibition of markers of bone resorption by consumption of vitamin D and calcium-fortified soft plain cheese by institutionalised elderly women.

PubMed

Bonjour, Jean-Philippe; Benoit, Valérie; Pourchaire, Olivier; Ferry, Monique; Rousseau, Brigitte; Souberbielle, Jean-Claude

2009-10-01

Acceleration of bone remodelling increases the risk of fragility fractures. The objective of the present study was to explore in elderly women whether a vitamin D and Ca-fortified dairy product providing about 17-25 % of the recommended intakes in vitamin D, Ca and proteins would reduce secondary hyperparathyroidism and bone remodelling in a way that may attenuate age-related bone loss in the long term. Thirty-seven institutionalised women, aged 84.8 (sd 8.1) years, with low serum 25-hydroxyvitamin D (5.5 (sd 1.7) ng/ml) were enrolled into a multicentre open trial to consume during 1 month two servings of soft plain cheese made of semi-skimmed milk providing daily 686 kJ (164 kcal), 2.5 microg vitamin D, 302 mg Ca and 14.2 g proteins. The primary endpoint was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX), selected as a marker of bone resorption. Thirty-five subjects remained compliant. Mean serum changes were: 25-hydroyvitamin D, +14.5 % (P = 0.0051); parathyroid hormone (PTH), - 12.3 % (P = 0.0011); CTX, - 7.5 % (P = 0.01); tartrate-resistant acid phosphatase isoform 5b (TRAP 5b), - 9.9 % (P < 0.0001); albumin, +6.2 % (P < 0.0001); insulin-like growth factor-I (IGF-I),+16.9 % (P < 0.0001); osteocalcin, +8.3 % (P = 0.0166); amino-terminal propeptide of type 1 procollagen (P1NP),+19.3 % (P = 0.0031). The present open trial suggests that fortified soft plain cheese consumed by elderly women with vitamin D insufficiency can reduce bone resorption markers by positively influencing Ca and protein economy, as expressed by decreased PTH and increased IGF-I, respectively. The rise in the bone formation marker P1NP could be explained by a protein-mediated increase in IGF-I. Thus, such a dietary intervention might uncouple, at least transiently, bone resorption from bone formation and thereby attenuate age-related bone loss.

"Ruffled border" formation on a CaP-free substrate: A first step towards osteoclast-recruiting bone-grafts materials able to re-establish bone turn-over.

PubMed

Merolli, Antonio; Fung, Stephanie; Murthy, N Sanjeeva; Pashuck, E Thomas; Mao, Yong; Wu, Xiaohuan; Steele, Joseph A M; Martin, Daniel; Moghe, Prabhas V; Bromage, Timothy; Kohn, Joachim

2018-03-21

Osteoclasts are large multinucleated giant cells that actively resorb bone during the physiological bone turnover (BTO), which is the continuous cycle of bone resorption (by osteoclasts) followed by new bone formation (by osteoblasts). Osteoclasts secrete chemotactic signals to recruit cells for regeneration of vasculature and bone. We hypothesize that a biomaterial that attracts osteoclasts and re-establishes BTO will induce a better healing response than currently used bone graft materials. While the majority of bone regeneration efforts have focused on maximizing bone deposition, the novelty in this approach is the focus on stimulating osteoclastic resorption as the starter for BTO and its concurrent new vascularized bone formation. A biodegradable tyrosine-derived polycarbonate, E1001(1k), was chosen as the polymer base due to its ability to support bone regeneration in vivo. The polymer was functionalized with a RGD peptide or collagen I, or blended with β-tricalcium phosphate. Osteoclast attachment and early stages of active resorption were observed on all substrates. The transparency of E1001(1k) in combination with high resolution confocal imaging enabled visualization of morphological features of osteoclast activation such as the formation of the "actin ring" and the "ruffled border", which previously required destructive forms of imaging such as transmission electron microscopy. The significance of these results is twofold: (1) E1001(1k) is suitable for osteoclast attachment and supports osteoclast maturation, making it a base polymer that can be further modified to optimize stimulation of BTO and (2) the transparency of this polymer makes it a suitable analytical tool for studying osteoclast behavior.

ADRA2A is involved in neuro-endocrine regulation of bone resorption

PubMed Central

Mlakar, Vid; Jurkovic Mlakar, Simona; Zupan, Janja; Komadina, Radko; Prezelj, Janez; Marc, Janja

2015-01-01

Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of α2A-AR in bone. The aim of this study was to investigate the presence of α2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate α2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in α2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A-AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A-AR mRNA level in human bone samples through the stability of mRNA. α2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that α2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in α2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis. PMID:25818344

Marginal Bone Remodeling around healing Abutment vs Final Abutment Placement at Second Stage Implant Surgery: A 12-month Randomized Clinical Trial.

PubMed

Nader, Nabih; Aboulhosn, Maissa; Berberi, Antoine; Manal, Cordahi; Younes, Ronald

2016-01-01

The periimplant bone level has been used as one of the criteria to assess the success of dental implants. It has been documented that the bone supporting two-piece implants undergoes resorption first following the second-stage surgery and later on further to abutment connection and delivery of the final prosthesis. The aim of this multicentric randomized clinical trial was to evaluate the crestal bone resorption around internal connection dental implants using a new surgical protocol that aims to respect the biological distance, relying on the benefit of a friction fit connection abutment (test group) compared with implants receiving conventional healing abutments at second-stage surgery (control group). A total of partially edentulous patients were consecutively treated at two private clinics, with two adjacent two-stage implants. Three months after the first surgery, one of the implants was randomly allocated to the control group and was uncovered using a healing abutment, while the other implant received a standard final abutment and was seated and tightened to 30 Ncm. At each step of the prosthetic try-in, the abutment in the test group was removed and then retightened to 30 Ncm. Horizontal bone changes were assessed using periapical radiographs immediately after implant placement and at 3 (second-stage surgery), 6, 9 and 12 months follow-up examinations. At 12 months follow-up, no implant failure was reported in both groups. In the control group, the mean periimplant bone resorption was 0.249 ± 0.362 at M3, 0.773 ± 0.413 at M6, 0.904 ± 0.36 at M9 and 1.047 ± 0.395 at M12. The test group revealed a statistically significant lower marginal bone loss of 20.88% at M3 (0.197 ± 0.262), 22.25% at M6 (0.601 ± 0.386), 24.23% at M9 (0.685 ± 0.341) and 19.2% at M9 (0.846 ± 0.454). The results revealed that bone loss increased over time, with the greatest change in bone loss occurring between 3 and 6 months. Alveolar bone loss was significantly greater in the control condition than the test condition. The results of this prospective study demonstrated the benefit of placing a prosthetic component with a stable connection at second-stage surgery, in terms of reduced marginal bone remodeling when compared with conventional procedure. The use of a stable connection in a healing component during try-in stages prior to final restoration placement leads to less periimplant marginal bone loss.

[In vitro study on bone resorption of odontogenic cysts and ameloblastomas].

PubMed

Gao, Li; Li, Tie-jun

2005-05-01

To investigate the effect of bone resorption by odontogenic cysts and ameloblastomas in vitro. Fragments of odontogenic cysts (14 odontogenic keratocysts, 6 inflamed odontogenic keratocysts, 5 dentigerous cysts) and ameloblastomas (n = 7) were incubated in vitro for 24 h. The supernatant was then removed into the culture system of SD rat calvaria. After incubation (48 h), the calcium contents of the media were measured by atom spectrophotometer. The supernatant of odontogenic cysts and ameloblastomas was measured for the bone resorption related factors such as IL-6, TNF-alpha, PGE(2), bone Gla-containing protein (BGP) and calcitonin (CT) by a radioimmunoassay system. The calcium released in the calvaria culture media by all the odontogenic lesions was significantly higher than that in the blank controls (P < 0.01). The inflamed odontogenic keratocyst group had a significantly higher calcium concentration than odontogenic keratocyst and ameloblastoma groups (P < 0.05). In addition, the concentration of IL-6, TNF-alpha, PGE(2) and CT in the culture media of all odontogenic lesions were significantly higher than that of the blank controls (P < 0.05). IL-6 concentration in the inflamed and non-inflamed odontogenic keratocyst groups were significantly higher than that of ameloblastoma group (P < 0.05). CT concentration in the inflamed odontogenic keratocyst was significantly higher than those of odontogenic keratocyst and dentigerous cyst groups (P < 0.05). Correlation and regression analysis showed that IL-6 was significantly correlated with the calcium content (P < 0.01). The odontogenic lesions could promote bone resorption in vitro and it is likely to be related to some of the cytokines secreted by the lesions.

Immunolocalization of bone-resorptive cytokines in rat pulp and periapical lesions following surgical pulp exposure.

PubMed

Tani-Ishii, N; Wang, C Y; Stashenko, P

1995-08-01

The bone-resorptive cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) have been implicated in the pathogenesis of many chronic inflammatory diseases, including pulpitis and apical periodontitis.To further elucidate their role in these disorders, we have identified cells that express IL-1 alpha and TNF alpha in infected pulps and in developing rat periapical lesions after surgical pulp exposure. As detected by immunohistochemistry, IL-1 alpha- and TNF alpha-positive cells were present as early as 2 days after pulp exposure in both the pulp and periapical region. The numbers of cytokine-expressing cells increased up to day 4 in the pulp and up to day 30 in the periapex. In contrast, cells expressing IL-1 beta and TNF beta, the homologous forms of these mediators, were not found in pulp or periapical lesions during this period. Cells expressing IL-1 alpha and TNF alpha were identified primarily as macrophages and fibroblasts, with occasional staining of polymorphonuclear leukocytes. Osteoblasts and osteoclasts were also positive, whereas lymphocytes were negative. In general, cytokine-expressing cells were located proximal to abscesses and the root apex. These findings demonstrate that cells that express bone-resorptive cytokines IL-1 alpha and TNF alpha are present immediately after pulp exposure in this model, which supports the hypothesis that these mediators play a key role in pulpal and periapical pathogenesis, including the concomitant bone destruction. They also indicate that both resident connective tissue cells as well as infiltrating cells express bone-resorptive cytokines in response to infection in these lesions.

Strategy for prevention of hip fractures in patients with Parkinson's disease.

PubMed

Iwamoto, Jun; Sato, Yoshihiro; Takeda, Tsuyoshi; Matsumoto, Hideo

2012-09-18

Hypovitaminosis D and K due to malnutrition or sunlight deprivation, increased bone resorption due to immobilization, low bone mineral density (BMD) and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Parkinson's disease. The purpose of the present study was to clarify the efficacy of interventions intended to prevent hip fractures in elderly patients with Parkinson's disease. PubMed was used to search the literature for randomized controlled trials (RCTs) regarding Parkinson's disease and hip fractures. The inclusion criteria were 50 or more subjects per group and a study period of 1 year or longer. Five RCTs were identified and the relative risk and 95% confidence interval were calculated for individual RCTs. Sunlight exposure increased serum hydroxyvitamin D [25(OH)D] concentration, improved motor function, decreased bone resorption and increased BMD. Alendronate or risedronate with vitamin D supplementation increased serum 25(OH)D concentration, strongly decreased bone resorption and increased BMD. Menatetrenone (vitamin K(2)) decreased serum undercarboxylated osteocalcin concentration, decreased bone resorption and increased BMD. Sunlight exposure (men and women), menatetrenone (women), alendronate and risedronate with vitamin D supplementation (women) significantly reduced the incidence of hip fractures. The respective RRs (95% confidence intervals) according to the intention-to-treat analysis were 0.27 (0.08, 0.96), 0.13 (0.02, 0.97), 0.29 (0.10, 0.85) and 0.20 (0.06, 0.68). Interventions, including sunlight exposure, menatetrenone and oral bisphosphonates with vitamin D supplementation, have a protective effect against hip fractures elderly patients with Parkinson's disease.

Impaired osteoblast function in osteoporosis: comparison between calcium balance and dynamic histomorphometry.

PubMed

Arlot, M; Edouard, C; Meunier, P J; Neer, R M; Reeve, J

1984-09-01

Osteoblast function was investigated in 27 patients with idiopathic osteoporosis. Transiliac bone biopsy specimens were taken after double labelling with tetracycline, and metabolic calcium balance was studied almost simultaneously. Many of the patients showed poor double labelling of their otherwise unremarkable trabecular osteoid, suggesting impaired formation of bone at many of these surfaces. This phenomenon was not accompanied by increased width of osteoid seams (as seen in osteomalacia), indicating that formation of the matrix and its mineralisation were in equilibrium. For the first time, highly significant positive correlations (p less than 0.01) were found between indices of bone formation, determined by labelling with tetracycline, and calcium balance. Thus some patients with osteoporosis who are rapidly losing bone have low rates of formation of trabecular bone both by individual osteoblasts and in relation to available bone surfaces. As histological indices of bone resorption also independently correlated strongly and inversely (p less than 0.01) with calcium balance the rate of initiation of new basic multicellular units by osteoclastic resorption of trabecular surfaces (or the depth of resorption at these surfaces) also appears to be an important determinant of mineral balance. The mechanisms that regulate the effective life span of mature osteoblasts require further investigation, particularly as some promising treatments that can increase trabecular bone volume in osteoporosis, such as parathyroid peptide hPTH (1-34) and sodium fluoride, must work through a reversal of osteoblastic depression.

Growth-Associated Changes in the Periodontal Bone and Molar Teeth of Male Rats

PubMed Central

García, María F; Moreno, Hilda; Rigalli, Alfredo; Puche, Rodolfo C

2009-01-01

Here we report quantitative data associating periodontal bone variables of young conventional rats with the growth process. The hemimandibles of male rats (IIM/Fm stock, 2 to 15 wk of age.) were excised and submitted to conventional morphologic, radiologic, and histologic evaluation. The length, area, or X-ray absorbance of various regions or structures was measured on digital images of radiographs by using an image-analysis program. The sum of periodontal bone areas undergoing resorption (interproximal + intraradicular) increased until 9 or 10 wk of age and decreased thereafter. Mineral accretion rates and mineral density asymptotes were not significantly different among molars. The mineral density of resorption areas in alveolar bone fitted sinusoidal kinetics, indicative of the ‘instability’ of the tissue due to its high metabolic activity. Mineral accretion rates and mineral density asymptotes were not significantly different among molars. The proportion of root length within alveolar bone exhibited a biphasic curve (minimum at 5 wk of age), due to differences in the growth rates of variables involved in its calculation (distance between the cementoenamel junction to the apex and height of the resorption areas). The distance between the cementoenamel junction and alveolar bone crest over time fitted a sigmoidal function with a point of inflection that did not differ significantly from that of body or mandible dry weight. In summary, the growth process appears to affect periodontal bone support and the distance between the cementoenamel junction and alveolar bone crest in male rats. PMID:19807966

Analysis of Miscellaneous Human Osteological Remains Recovered from Multi-County Areas of South Dakota

DTIC Science & Technology

1988-11-01

apical abscessing, and/or when the alveolar bone displayed minimal resorption or other bony changes which accompany periodontal disease. All other cases... periodontal resorption while the opposite was true for those individuals with excessive deposits. Apical abscessing, another common dental pathology...similar to those seen in other northern Plains populations. Periodontal disease as measured by alveolar resorption ranged from mild to severe. Apical

Feasibility of SH2 Binding as a Prognostic and Diagnostic Indicator: Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

DTIC Science & Technology

2005-08-01

osteoclastic bone resorption, respectively. Despite formidable difficulties in drug design due to the lability and poor cell permeability of negatively...with LysO?,D6, generally been treated with two categories of drugs : bone displacing water molecules found in the previous X-ray resorption inhibitors...and Dpp [236-238]. cancer drugs , of which only 12 were shown to have survival Researchers from Aventis reported the superimposition benefit in

Investigation of strontium accumulation on ovariectomized Sprague-Dawley rat tibia by micro-PIXE

NASA Astrophysics Data System (ADS)

Li, X.; Li, Y.; Jin, W.; Zheng, Y.; Rong, C.; Lyu, H.; Shen, H.

2014-08-01

Strontium ranelate is a newly developed drug effective in osteoporosis treatment by depressing bone resorption and maintaining bone formation. Strontium accumulation and distribution are determined in bones of rat after strontium ranelate administration by using micro-PIXE. The investigated rats are divided into four groups: (A) control, (B) ovariectomized, (C) ovariectomized followed with strontium chloride, (D) ovariectomized followed with strontium ranelate. It was found that strontium ranelate would result in increasing trabecular volume and decreasing bone resorption to treat osteoporosis. There are similar contours of calcium and strontium in two-dimensional images, while the strontium is not evenly distributed in the bone. It supports the conclusion that strontium has an affinity for bone and it is capable of replacing calcium atoms as a part of the strontium mechanism in the osteoporosis treatment. The results related to biochemistry are also discussed.

Resorption behavior of a nanostructured bone substitute: in vitro investigation and clinical application.

PubMed

Reichert, Christoph; Götz, Werner; Reimann, Susanne; Keilig, Ludger; Hagner, Martin; Bourauel, Christoph; Jäger, Andreas

2013-03-01

To develop an in vitro assay for quantitative analysis of the degradation to which a bone substitute is exposed by osteoclasts. The aim of establishing this method was to improve the predictability of carrying out tooth movements via bone substitutes and to provide a basis for verification in exemplary clinical cases. After populating a bone substitute (NanoBone®; ArtOss, Germany) with osteoclastic cells, inductively-coupled mass spectrometry was used to evaluate changing calcium levels in the culture medium as a marker of resorption activity. It was observed that calcium levels increased substantially in the culture medium with the cells populating the bone substitute. This in vitro assay is a valid method that can assist clinicians in selecting the appropriate materials for certain patients. While tooth movements occurring through this material were successful, uncertainty about the approach will remain as long-term results are not available.

Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate

PubMed Central

Pederson, Larry; Ruan, Ming; Westendorf, Jennifer J.; Khosla, Sundeep; Oursler, Merry Jo

2008-01-01

Under most conditions, resorbed bone is nearly precisely replaced in location and amount by new bone. Thus, it has long been recognized that bone loss through osteoclast-mediated bone resorption and bone replacement through osteoblast-mediated bone formation are tightly coupled processes. Abundant data conclusively demonstrate that osteoblasts direct osteoclast differentiation. Key questions remain, however, as to how osteoblasts are recruited to the resorption site and how the amount of bone produced is so precisely controlled. We hypothesized that osteoclasts play a crucial role in the promotion of bone formation. We found that osteoclast conditioned medium stimulates human mesenchymal stem (hMS) cell migration and differentiation toward the osteoblast lineage as measured by mineralized nodule formation in vitro. We identified candidate osteoclast-derived coupling factors using the Affymetrix microarray. We observed significant induction of sphingosine kinase 1 (SPHK1), which catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (S1P), in mature multinucleated osteoclasts as compared with preosteoclasts. S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. Stimulation of hMS cell nodule formation by osteoclast conditioned media was attenuated by the Wnt antagonist Dkk1, a BMP6-neutralizing antibody, and by a S1P antagonist. BMP6 antibodies and the S1P antagonist, but not Dkk1, reduced osteoclast conditioned media-induced hMS chemokinesis. In summary, our findings indicate that osteoclasts may recruit osteoprogenitors to the site of bone remodeling through SIP and BMP6 and stimulate bone formation through increased activation of Wnt/BMP pathways. PMID:19075223

Non-canonical Wnt4 prevents skeletal aging and inflammation by inhibiting NF-κB

PubMed Central

Yu, Bo; Chang, Jia; Liu, Yunsong; Li, Jiong; Kevork, Kareena; Al-Hezaimi, Khalid; Graves, Dana T; Park, No-Hee; Wang, Cun-Yu

2014-01-01

Aging-related bone loss and osteoporosis affect millions of patients worldwide. Chronic inflammation associated with aging and arthritis promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuated bone loss in osteoporosis and skeletal aging by inhibiting nuclear factor-kappa B (NF-κB) via non-canonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 could inhibit osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited transforming growth factor beta-activated kinase 1-mediated NF-κB activation in macrophages and osteoclast precursors independent of β-catenin. Moreover, recombinant Wnt4 proteins were able to alleviate osteoporotic bone loss and inflammation by inhibiting NF-κB in vivo. Taken together, our results suggest that Wnt4 might be used as a therapeutic agent for treating osteoporosis by attenuating NF-κB. PMID:25108526

Odanacatib, effects of 16-month treatment and discontinuation of therapy on bone mass, turnover and strength in the ovariectomized rabbit model of osteopenia.

PubMed

Duong, Le T; Crawford, Randy; Scott, Kevin; Winkelmann, Christopher T; Wu, Gouxin; Szczerba, Pete; Gentile, Michael A

2016-12-01

Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7.5μM·h 0-24 , in food) or ALN (0.2mg/kg/wk, s.c.) and compared to vehicle-treated OVX- (OVX+Veh) or Sham-operated animals. After 8months, treatment was discontinued in half of the ODN group. ODN treatment increased in vivo LV aBMD and trabecular (Tb) vBMD until reaching plateau at month 12 by 16% and 23% vs. baseline, respectively, comparable levels to that in Sham and significantly above OVX+Veh. LV BMD was also higher in ALN that plateaued around month 8 to levels below that in ODN or Sham. ODN treatment resulted in higher BMD, structure and improved biomechanical strength of LV and central femur (CF) to levels similar to Sham. ALN generally showed less robust efficacy compared to ODN. Neither ODN nor ALN influenced material properties at these bone sites following ODN or ALN treatment for 7 remodeling cycles in rabbits. ODN and ALN persistently reduced the bone resorption marker urinary helical peptide over study duration. While ALN reduced the bone formation marker BSAP, ODN treatment did not affect this marker. ODN also preserved histomorphometry-based bone formation indices in LV trabecular, CF endocortical and intracortical surfaces, at the levels of OVX+Veh. Discontinuation of ODN returned bone mass, structure and strength parameters to the comparable respective levels in OVX+Veh. Together, these data demonstrate efficacy and bone safety profile of ODN and suggests the potential long-term benefits of this agent over ALN with respect to accrued bone mass without long-term effects on bone formation. Copyright © 2016 Elsevier Inc. All rights reserved.

Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma

PubMed Central

Liu, Huan; Liu, Zhiqiang; Du, Juan; He, Jin; Lin, Pei; Amini, Behrang; Starbuck, Michael W.; Novane, Nora; Shah, Jatin J.; Davis, Richard E.; Hou, Jian; Gagel, Robert F.; Yang, Jing

2016-01-01

Myelomatous bone disease is characterized by the development of lytic bone lesions and a concomitant reduction in bone formation, leading to chronic bone pain and fractures. To understand the underlying mechanism, we investigated the contribution of myeloma-expressed thymidine phosphorylase (TP) to bone lesions. In osteoblast progenitors, TP upregulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP upregulated the methylation of IRF8, thereby enhanced expression of NFATc1, leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2DDR. Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K/Akt signaling, and increased DNMT3A expression, resulting in hypermethylation of RUNX2, osterix, and IRF8. This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients. As TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications. PMID:27559096

Denosumab: an investigational drug for the management of postmenopausal osteoporosis

PubMed Central

Lewiecki, E Michael

2008-01-01

Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor-κB ligand (RANKL), a cytokine member of the tumor necrosis factor family. RANKL, the principal mediator of osteoclastic bone resorption, plays a major role in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with bone loss. Denosumab inhibits the action of RANKL, thereby reducing the differentiation, activity, and survival of osteoclasts, and lowering the rate of bone resorption. Clinical trials have shown that denosumab increases bone mineral density (BMD) and reduces bone turnover in postmenopausal women with low BMD. Studies to evaluate the fracture risk benefit and long-term safety of denosumab in women with postmenopausal osteoporosis (PMO) are ongoing. Denosumab is a potential treatment for PMO and other skeletal disorders. PMID:19707445

Severe hypocalcemia following bisphosphonate treatment in a patient with Paget's disease of bone.

PubMed

Whitson, Heather E; Lobaugh, Bruce; Lyles, Kenneth W

2006-10-01

Bisphosphonate therapy is a common and effective treatment for Paget's disease of bone, osteoporosis, hypercalcemia of malignancy and cancer metastatic to bone. Clinically significant hypocalcemia has not been reported in patients with Paget's disease of bone and normal parathyroid function treated with an aminobisphosphonate. We treated a 52-year-old woman with polyostotic Paget's disease of bone (serum alkaline phosphatase level-1971 IU/L [normal 31-110 IU/L]), who had not previously received bisphosphonates, with daily oral 30 mg risedronate, oral 1000 mg elemental calcium and oral 400 IU cholecalciferol. After 10 days of treatment, she developed severe hypocalcemia (5.4 mg/dL [normal 8.7-10.2 mg/dL]), requiring hospitalization and support with 5 days of intravenous calcium gluconate. On the day risedronate treatment began, her PTH was low normal at 14 pg/mL (normal 12-72 pg/mL), consistent with a relatively suppressed PTH axis due to high bone turnover. Her vitamin D level was within normal limits (serum 25(OH)D 19 ng/mL [normal 8-38 ng/mL]), although possibly not optimally repleted. We hypothesize that this case represents an example of hungry bone syndrome in a patient with extensive Paget's disease of bone who received risedronate, causing acute suppression of bone resorption while elevated bone formation rates continued. In the year following her recovery, the patient was successfully treated with slowly titrated anti-resorptive therapy (subcutaneous calcitonin followed by titrated doses of risedronate), and is now clinically well. Physicians should be aware of the potential for hypocalcemia when patients with polyostotic Paget's disease and markedly elevated indicators of bone remodeling are initiated on powerful anti-resorptive therapy.

Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity on multiple myeloma bone disease.

PubMed

Muller, Joséphine; Bolomsky, Arnold; Dubois, Sophie; Duray, Elodie; Stangelberger, Kathrin; Plougonven, Erwan; Lejeune, Margaux; Léonard, Angélique; Marty, Caroline; Hempel, Ute; Baron, Frédéric; Beguin, Yves; Cohen-Solal, Martine; Ludwig, Heinz; Heusschen, Roy; Caers, Jo

2018-05-10

Multiple myeloma bone disease is characterized by an uncoupling of bone remodeling in the multiple myeloma microenvironment, resulting in the development of lytic bone lesions. Most myeloma patients suffer from these bone lesions, which not only causes morbidity but also negatively impacts survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that MELK plays a central role in proliferation-associated high-risk multiple myeloma and its inhibition with OTSSP167 resulted in decreased tumor load. MELK inhibition in bone cells has not yet been explored, although some reports suggest factors downstream of MELK stimulate osteoclast activity and inhibit osteoblast activity, which makes MELK inhibition a promising therapeutic approach. Therefore, we assessed the effect of OTSSP167 on bone cell activity and the development of myeloma-induced bone disease. OTSSP167 inhibited osteoclast activity in vitro by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature osteoclasts. In addition, OTSSP167 stimulated matrix deposition and mineralization by osteoblasts in vitro. This combined anti-resorptive and osteoblast-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in myeloma-bearing mice. Immunohistomorphometric analyses corroborated our in vitro findings. In conclusion, we show that OTSSP167 has a direct effect on myeloma-induced bone disease in addition to its anti-multiple myeloma effect, which warrants further clinical development of MELK inhibition in multiple myeloma. Copyright © 2018, Ferrata Storti Foundation.

Radiographic evaluation of bone adaptation adjacent to percutaneous osseointegrated prostheses in a sheep model.

PubMed

Jeyapalina, Sujee; Beck, James Peter; Bachus, Kent N; Chalayon, Ornusa; Bloebaum, Roy D

2014-10-01

Percutaneous osseointegrated prostheses (POPs) are being investigated as an alternative to conventional socket suspension and require a radiographic followup in translational studies to confirm that design objectives are being met. In this 12-month animal study, we determined (1) radiographic signs of osseointegration and (2) radiographic signs of periprosthetic bone hypertrophy and resorption (adaptation) and (3) confirmed them with the histologic evidence of host bone osseointegration and adaptation around a novel, distally porous-coated titanium POP with a collar. A POP device was designed to fit the right metacarpal bone of sheep. Amputation and implantation surgeries (n = 14) were performed, and plane-film radiographs were collected quarterly for 12 months. Radiographs were assessed for osseointegration (fixation) and bone adaptation (resorption and hypertrophy). The cortical wall and medullary canal widths were used to compute the cortical index and expressed as a percentage. Based on the cortical index changes and histologic evaluations, bone adaptation was quantified. Radiographic data showed signs of osseointegration including those with incomplete seating against the collar attachment. Cortical index data indicated distal cortical wall thinning if the collar was not seated distally. When implants were bound proximally, bone resorbed distally and the diaphyseal cortex hypertrophied. Histopathologic evidence and cortical index measurements confirmed the radiographic indications of adaptation and osseointegration. Distal bone loading, through collar attachment and porous coating, limited the distal bone resorption. Serial radiographic studies, in either animal models or preclinical trials for new POP devices, will help to determine which designs are likely to be safe over time and avoid implant failures.

Effect of spaceflight hardware on the skeletal properties of ground control mice

NASA Astrophysics Data System (ADS)

Bateman, Ted; Lloyd, Shane; Dunlap, Alex; Ferguson, Virginia; Simske, Steven; Stodieck, Louis; Livingston, Eric

Introduction: Spaceflight experiments using mouse or rat models require habitats that are specifically designed for the microgravity environment. During spaceflight, rodents are housed in a specially designed stainless steel meshed cage with gravity-independent food and water delivery systems and constant airflow to push floating urine and feces towards a waste filter. Differences in the housing environment alone, not even considering the spaceflight environment itself, may lead to physiological changes in the animals contained within. It is important to characterize these cage differences so that results from spaceflight experiments can be more reliably compared to studies from other laboratories. Methods: For this study, we examined the effect of NASA's Animal Enclosure Module (AEM) spaceflight hardware on the skeletal properties of 8-week-old female C57BL/6J mice. This 13-day experiment, conducted on the ground, modeled the flight experiment profile of the CBTM-01 payload on STS-108, with standard vivarium-housed mice being compared to AEM-housed mice (n = 12/group). Functional differences were compared via mechanical testing, micro-hardness indentation, microcomputed tomography, and mineral/matrix composition. Cellular changes were examined by serum chemistry, histology, quantitative histomorphometry, and RT-PCR. A Student's t-test was utilized, with the level of Type I error set at 95 Results: There was no change in elastic, maximum, or fracture force mechanical properties at the femur mid-diaphysis, however, structural stiffness was -17.5 Conclusions: Housing mice in the AEM spaceflight hardware had minimal effects on femur cortical bone properties. However, trabecular bone at the proximal tibia in AEM mice experi-enced large increases in microarchitecture and mineral composition. Increases in bone density were accompanied by reductions in bone-forming osteoblasts and bone-resorbing osteoclasts, representing a general decline in bone turnover at this site. Serum markers suggest a systemic decline in bone formation. The increase in trabecular bone formation rate is likely a result of the reduced resorptive activity; normal levels of bone resorption in vivarium mice likely removed portions of the bone label that were not removed in the AEM housed mice. This is supported by a greater mineralizing surface in AEM mice, with no change in mineral apposition rate.

Effects of clodronate on early alveolar bone remodeling and root resorption related to orthodontic forces: a histomorphometric analysis.

PubMed

Choi, Josefina; Baek, Seung-Hak; Lee, Jae-Il; Chang, Young-Il

2010-11-01

The objective of this study was to evaluate the short-term effects of clodronate, a first-generation bisphosphonate, on early alveolar bone remodeling and root resorption related to orthodontic tooth movement. The samples consisted of 54 sex-matched Wistar rats (weight, 180-230 g) allocated to the 2.5 mmol/L clodronate, 10 mmol/L clodronate, and control groups (n = 18 for each group). After application of a nickel-titanium closed-coil spring (force, 60 g) between the maxillary central incisor and first molar, 2.5 mmol/L of clodronate, 10 mmol/L of clodronate, or saline solution was injected into the subperiosteum adjacent to the maxillary first molar every third day. All animals received tetracycline, calcein, and alizarin red by intraperitoneal injection at 1, 6, and 14 days, respectively. The amounts of tooth movement were measured at 3, 6, 9, 12, and 15 days. The animals were killed at 4, 7, and 17 days. Histomorphometric analyses of bone mineral appositional rate, labeled surface, percentage of root resorption area, and number of root resorption lacunae of the mesiobuccal root of the maxillary first molar at 4, 7, and 17 days were done. One-way analysis of variance (ANOVA) with the post-hoc test were done for statistical analyses. Rats in the 10 mmol/L clodronate group had significant decreases of tooth movement (12 and 15 days, P <0.05) and percentages of root resorption area and numbers of root resorption lacunae (7 day, P <0.05), and increases of labeled surface and mineral appositional rates (17 day, P <0.05) over those of the 2.5 mmol/L clodronate and control groups. Although clodronate might decrease root resorption related to orthodontic tooth movement, patients should be informed about a possible decrease in the amount of tooth movement and a prolonged period of orthodontic treatment. Copyright © 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

The effect of the heights and thicknesses of the remaining root segments on buccal bone resorption in the socket-shield technique: An experimental study in dogs.

PubMed

Tan, Zhen; Kang, Jian; Liu, Wenjia; Wang, Hang

2018-06-01

To date only a few studies have been done on the use of the socket-shield technique for preserving the resorption of the buccal bone in aesthetically sensitive sites. Besides, there have been no further studies on the effect of the heights and thicknesses of the remaining root segments on buccal bone resorption when using this method. The aim of this study was to evaluate the effect of different heights and thicknesses of the remaining root segments on bone resorption in the socket-shield technique. Four healthy female beagle dogs were used in this study. The third premolar (P3) and the fourth premolar (P4) on both sides of the mandible were hemisected in the buccal-lingual direction, and the clinical crown of the distal root was beheaded. In the experimental groups, the roots were worn down in the apical direction until they were located at the buccal crestal level (Group A) or 1 mm higher than that level (Group B). In the control group, the distal root segments were extracted. Then, implant placement was performed into the distal root. After 3 months of healing, the specimens were prepared for histological diagnosis. There was no difference between Group A and Group B when using the socket-shield technique, but the results of both groups were better than those of the control group. The height of the root segments has little effect on the bone absorption of alveolar bone, while the bone absorption was strongly influenced by the thickness of the root segments. More precisely, the absorption may decrease if the thickness of the root fragment increases, when the thickness of the root plate is in the 0.5-1.5 mm range. © 2018 Wiley Periodicals, Inc.

Genistein supplementation increases bone turnover but does not prevent alcohol-induced bone loss in male mice

USDA-ARS?s Scientific Manuscript database

Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy prote...

Calcium Kinetics During Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.; OBrien, K. O.; Abrams, S. A.; Wastney, M. E.

2005-01-01

Bone loss during space flight is one of the most critical challenges to astronaut health on space exploration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract bone loss during space flight, and will have relevance for other clinical situations that impair weight-bearing activity. Bone health is a product of the balance between bone formation and bone resorption. Early space research could not clearly identify which of these was the main process altered in bone loss, but identification of the collagen crosslinks in the 1990s made possible a clear understanding that the impact of space flight was greater on bone resorption, with bone formation being unchanged or only slightly decreased. Calcium kinetics data showed that bone resorption was greater during flight than before flight (668 plus or minus 130 vs. 427 plus or minus 153 mg/d, p less than 0.001), and clearly documented that true intestinal calcium absorption was lower during flight than before flight (233 plus or minus 87 vs. 460 plus or minus 47 mg/d, p less than 0.01). Weightlessness had a detrimental effect on the balance in bone turnover: the difference between daily calcium balance during flight (-234 plus or minus 102 mg/d) and calcium balance before flight (63 plus or minus 75 mg/d) approached 300 mg/d (p less than 0.01). These data demonstrate that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption. Examining the changes in bone and calcium homeostasis in the initial days and weeks of space flight, as well as at later times on missions longer than 6 months, is critical to understanding the nature of bone adaptation to weightlessness. To increase knowledge of these changes, we studied bone adaptation to space flight on the 16-day Space Shuttle Columbia (STS-107) mission. When the brave and talented crew of Columbia were lost during reentry on the tragic morning of February 1, 2003, in a much smaller matter, the scientific products of this experiment, successfully obtained on orbit, were lost as well. As we begin to plan for missions back to the Moon, and even off to Mars, many questions remain to be answered. Counteracting bone loss is one of the greatest challenges. Calcium kinetics studies provide a valuable tool for assessing this loss, and evaluating countermeasures.

Reduced bone resorption by intake of dietary vitamin D and K from tailor-made Atlantic salmon: a randomized intervention trial

PubMed Central

Graff, Ingvild Eide; Øyen, Jannike; Kjellevold, Marian; Frøyland, Livar; Gjesdal, Clara Gram; Almås, Bjørg; Rosenlund, Grethe; Lie, Øyvind

2016-01-01

Suboptimal vitamin D status is common among humans, and might increase bone resorption with subsequent negative effects on bone health. Fatty fish, including Atlantic salmon, is an important dietary vitamin D source. However, due to a considerable change in fish feed composition, the contribution of vitamin D from salmon fillet has been reduced. The main objective was to investigate if intake of vitamin D3 enriched salmon or vitamin D3 tablets decreased bone biomarkers (urinary N-telopeptides, deoxypyridinoline, serum bone-specific alkaline phosphatase, and osteocalcin) compared to a low vitamin D3 intake. The 122 healthy postmenopausal women included in this 12 weeks intervention trial were randomized into four groups: three salmon groups (150 grams/two times/week) and one tablet group (800 IU vitamin D and 1000 mg calcium/day). The salmon groups also received calcium supplements. The salmon had three different vitamin D3/vitamin K1 combinations: high D3+high K1, low D3+high K1, or high D3+low K1. Increased intake of salmon containing high levels of vitamin D3 (0.35-0.38 mg/kg/fillet) and supplements with the same weekly contribution had a positive influence on bone health as measured by bone biomarkers in postmenopausal women. Consequently, an increased level of vitamin D3 at least to original level in feed for salmonids will contribute to an improved vitamin D3 status and may improve human bone health. PMID:27542236

Novel curcumin analogue UBS109 potently stimulates osteoblastogenesis and suppresses osteoclastogenesis: involvement in Smad activation and NF-κB inhibition.

PubMed

Yamaguchi, Masayoshi; Moore, Terry W; Sun, Aiming; Snyder, James P; Shoji, Mamoru

2012-08-01

Bone homeostasis is maintained through a balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss is induced due to decreased osteoblastic bone formation and increased osteoclastic bone resorption with various pathologic states. Osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public health problem. Pharmacologic and functional food factors may play a role in the prevention of bone loss with aging. This study was undertaken to determine the effect of curcumin analogues (curcumin, EF31, ECMN909, and UBS109), which were newly synthesized, on osteoblastogenesis and osteoclastogenesis in vitro. Among these compounds, UBS109 had a unique stimulatory effect on osteoblastic differentiation and mineralization. UBS109 stimulated both basal and bone morphogenic protein-2 (BMP2)-increased Smad-luciferase activity, the Smad signaling of which is related to osteoblastogenesis. Such an effect was not seen with other compounds. Moreover, UBS109 potently suppressed tumor necrosis factor-α (TNF-α)-increased osteoblastic nuclear factor kappa B (NF-κB)-luciferase activity. In addition, EF31, ECMN909, and UBS109 had a suppressive effect on osteoclastogenesis as compared with that of curcumin. ECMN909 and UBS109 potently inhibited the receptor activator of NF-κB (RANK) ligand (RANKL)-increased preosteoclastic NF-κB-luciferase activity, in which NF-κB signaling plays a pivotal role in osteoclastogenesis. In the present study, curcumin analogue UBS109 was found to have a stimulating effect on osteoblastogenesis and a suppressive effect on osteoclastogenesis in vitro, suggesting an anabolic effect of the compound on bone mass.

Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus.

PubMed

Catalano, A; Morabito, N; Di Vieste, G; Pintaudi, B; Cucinotta, D; Lasco, A; Di Benedetto, A

2013-05-01

Several studies have reported increased fracture risk in Type 1 diabetes mellitus (T1DM). Quantitative Ultrasound (QUS) provides information on the structure and elastic properties of bone, which are important determinants of fracture risk, along with bone mineral density. To study phalangeal sites by QUS, examine bone turnover markers and analyze association between these factors with metabolic control in a population of pre-menopausal women with T1DM. Thirty-five T1DM pre-menopausal women (mean age 34.5 ± 6.8 yr) attending the Diabetic Outpatients Clinic in the Department of Internal Medicine, University of Messina, were consecutively enrolled and divided into two groups, taking into account the mean value of glycated hemoglobin in the last three years. Twenty healthy age-matched women served as controls. Phalangeal ultrasound measurements [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), TScore, Z-Score] were performed using a DBM Sonic Bone Profiler. Osteocalcin and deoxypyridinoline served as markers of bone formation and bone resorption, respectively. T1DM women with poor metabolic control showed lower phalangeal QUS values compared to healthy controls (p<0.01) and T1DM women with good metabolic control (p<0.05). No significant differences in QUS measurements were detected between T1DM women with good metabolic control and healthy controls. Lower bone formation and increased bone resorption, although not statistically significant, were observed in patients with poor metabolic control in comparison to patients with good metabolic control. Poor metabolic control may worsen the quality of bone in T1DM. Phalangeal QUS could be considered as a tool to screen T1DM women for osteoporosis in pre-menopausal age.

Allografts with autogenous platelet-rich plasma for tibial defect reconstruction: a rabbit study.

PubMed

Nather, Aziz; Wong, Keng Lin; David, Vikram; Pereira, Barry P

2012-12-01

To evaluate the effect of autogenous platelet-rich plasma (PRP) for fresh-frozen allografts in tibial defect reconstruction in rabbits. 40 adult New Zealand white rabbits underwent tibial defect reconstruction with autografts (n=12), allografts without PRP (n=12), or allografts with PRP (n=12) and were observed for 12, 16, and 24 weeks (4 for each period). Tibias of the remaining 4 rabbits were used as donor allografts, and the remaining allografts were procured from recipient rabbits. A 1.5- cm cortical segment of the tibia was osteotomised, and then fixed with a 9-hole mini-compression plate and 2 cerclage wires. Allografts were stripped off the periosteum and soft tissues and medullary contents, and then stored in a freezer at -80 ºC. All allografts were deep frozen for at least 4 weeks before transplantation. 7 ml of whole blood was drawn to prepare 1 ml of PRP. The PRP was then mixed with 1.0 ml of human thrombin to form a platelet gel. The PRP gel was then packed into the medullary canal of the allograft and applied on the cortical surface before tibial defect reconstruction. Rabbits were sacrificed at 12, 16, and 24 weeks. The specimens were assessed for bone union at host-graft junctions and for bone resorption, new bone formation, callus encasement, and viable osteocyte counts. There were 4 specimens in each group at each observation period. Osteoid bridging the gap at host-graft junctions was noted in all specimens in the autograft and allograft-with-PRP groups at week 12 and in the allograft-without-PRP group at week 24. Bone union in allografts without PRP was delayed. All indices for biological incorporation (resorption index, new bone formation index, callus encasement index, and viable osteocyte count) were significantly greater in the autograft than allograft-without-PRP groups, except for the resorption index at week 24, whereas the differences were not significant between the autograft and allograft-with-PRP groups. The differences between the 2 allograft groups were usually not significant, except for the resorption index. PRP-augmented allografts behaved similarly to autografts for tibial defect reconstruction in rabbits. PRP increased bone union and bone resorption.

Clinical use of the resorbable bioscaffold poly lactic co-glycolic acid (PLGA) in post-extraction socket for maintaining the alveolar height: A prospective study.

PubMed

Hoda, Nadeemul; Saifi, Aamir Malick; Giraddi, Girish B

2016-01-01

A common sequel of tooth extraction is alveolar bone resorption. It makes the placement of dental implants difficult and creates an esthetic problem for the fabrication of conventional prostheses. Therefore, alveolar bone following tooth extraction should be preserved. The present prospective study was conducted to evaluate the efficacy of the resorbable bioscaffold poly lactic co-glycolic acid (PLGA) in maintaining the alveolar height in post-extraction socket. 20 patients were selected based on inclusion and exclusion criteria and were randomly divided into two groups: cases and control comprising of 10 patients each. Atraumatic tooth extraction was done in all patients. PLGA bioscaffold was placed in cases and socket was closed with 3-0 vicryl. In control group, socket was directly closed with 3-0 vicryl. The patients were kept on follow-up and complications such as dry socket, pain, and swelling were recorded. IOPA were taken at 1st, 4th, 12th, and 24th week to record changes in the height of alveolar bone. The radiographic measurements were compared and the differences were statistically analyzed. Reduction in alveolar bone height after placement of PLGA bioscaffold was significantly less in cases as compared to controls at 4th, 12th, and 24th week following extraction. No complications were observed throughout the follow-up period. PLGA scaffold significantly reduces bone resorption. Application is very simple and can be easily performed in a dental setup. However, PLGA scaffold adds significantly to the cost of treatment.

Effects of epidermal growth factor on bone formation and resorption in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marie, P.J.; Hott, M.; Perheentupa, J.

1990-02-01

The effects of mouse epidermal growth factor (EGF) on bone formation and resorption were examined in male mice. EGF administration (2-200 ng.g-1.day-1 ip for 7 days) induced a dose-dependent rise in plasma EGF levels that remained within physiological range. Histomorphometric analysis of caudal vertebrae showed that EGF (20 and 200 ng.g-1.day-1) reduced the endosteal matrix and mineral appositional rates after 5 days of treatment as measured by double (3H)proline labeling and double tetracycline labeling, respectively. This effect was transitory and was not observed after 7 days of EGF administration. EGF administered for 7 days induced a dose-dependent increase in themore » periosteal osteoblastic and tetracycline double-labeled surfaces. At high dosage (200 ng.g-1.day-1) EGF administration increased the osteoclastic surface and the number of acid phosphatase-stained osteoclasts, although plasma calcium remained normal. The results show that EGF administration at physiological doses induces distinct effects on endosteal and periosteal bone formation and that the effects are dependent on EGF dosage and duration of treatment. This study indicates that EGF at physiological dosage stimulates periosteal bone formation and increases endosteal bone resorption in the growing mouse.« less

Cortisol Secretory Parameters in Young Exercisers in Relation to LH Secretion and Bone Parameters

PubMed Central

Ackerman, Kathryn E.; Patel, Kamal T.; Guereca, Gabriela; Pierce, Lisa; Herzog, David B.; Misra, Madhusmita

2012-01-01

Objective Amenorrhoea and low bone density are common in excessive exercisers, yet endocrine factors that differentiate adolescent amenorrhoeic exercisers (AE) from eumenorrhoeic exercisers (EE) are unclear. We have previously reported that high ghrelin and low leptin predict lower LH secretion in AE. Leptin and ghrelin impact cortisol secretion, and hypercortisolaemia can inhibit LH pulsatility. We hypothesized that higher cortisol secretion in young endurance weight-bearing AE compared with EE and non-exercisers predicts lower LH secretion, lower levels of a bone formation marker and higher levels of a bone resorption marker. Design Cross-sectional Subjects We studied 21 AE, 18 EE and 20 non-exercisers 14–21 years (BMI 10th–90th%iles). Measurements Subjects underwent frequent sampling (11 p.m. to 7 a.m.) to assess cortisol, ghrelin, leptin and LH secretory dynamics. Fasting levels of a bone formation (P1NP) and bone resorption (CTX) marker were measured. Results BMI did not differ among groups. Cortisol pulse amplitude, mass, half-life and area under the curve (AUC) were highest in AE (p=0.04, 0.007, 0.04 and 0.003) and were associated inversely with fat mass (r=−0.29, −0.28 and −0.35, p=0.03, 0.04 and 0.007). We observed inverse associations between cortisol and LH AUC (r= −0.36, p=0.008), which persisted after controlling for fat mass, leptin and ghrelin AUC. Cortisol correlated positively with CTX in EE and inversely with P1NP in non-exercisers. Conclusions Higher cortisol secretion in AE compared with EE and non-exercisers is associated with lower LH secretion. Effects of leptin and ghrelin on LH secretion may be mediated by increased cortisol. PMID:22671919

Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption.

PubMed

Wilson, Susan R; Peters, Christoph; Saftig, Paul; Brömme, Dieter

2009-01-23

Cathepsin K is responsible for the degradation of type I collagen in osteoclast-mediated bone resorption. Collagen fragments are known to be biologically active in a number of cell types. Here, we investigate their potential to regulate osteoclast activity. Mature murine osteoclasts were seeded on type I collagen for actin ring assays or dentine discs for resorption assays. Cells were treated with cathepsins K-, L-, or MMP-1-predigested type I collagen or soluble bone fragments for 24 h. The presence of actin rings was determined fluorescently by staining for actin. We found that the percentage of osteoclasts displaying actin rings and the area of resorbed dentine decreased significantly on addition of cathepsin K-digested type I collagen or bone fragments, but not with cathepsin L or MMP-1 digests. Counterintuitively, actin ring formation was found to decrease in the presence of the cysteine proteinase inhibitor LHVS and in cathepsin K-deficient osteoclasts. However, cathepsin L deficiency or the general MMP inhibitor GM6001 had no effect on the presence of actin rings. Predigestion of the collagen matrix with cathepsin K, but not by cathepsin L or MMP-1 resulted in an increased actin ring presence in cathepsin K-deficient osteoclasts. These studies suggest that cathepsin K interaction with type I collagen is required for 1) the release of cryptic Arg-Gly-Asp motifs during the initial attachment of osteoclasts and 2) termination of resorption via the creation of autocrine signals originating from type I collagen degradation.

Prostaglandin E2 Increased Rat Cortical Bone Mass When Administered Immediately Following Ovariectomy

NASA Technical Reports Server (NTRS)

Ke, Hua Zhu; Jee, Webster S.S.; Zeng, Qing Qiang; Li, Mei; Lin, Bai Yun

1993-01-01

To investigate the effects of ovariectomy and the simultaneous administration of prostaglandin E2 (PGE2) on rat tibial shaft cortical bone histomorphometry, thirty-five 3 month-old female Sprague-Dawley rats were either ovariectomized (OVX), or sham ovariectomy (sham-OVX). The OVX rats were divided into three groups and treated with 0, 1 and 6 mg PGE2/kg/day for 90 days. The double fluorescent labeled undecalcified tibial shaft cross sections (proximal to the tibiofibular junction) of all the subjects were used for histomorphometry analysis. No differences in cross-sectional area and cortical bone area were found between sham-OVX and OVX controls, but OVX increased marrow area, intracortical porosity area and endocortical eroded perimeter. Periosteal and endocortical bone formation rates decreased with aging yet OVX prevented these changes. These OVX-induced increases in marrow area and endocortical eroded perimeter were prevented by 1 mg PGE2/kg/day treatment and added bone to periosteal and endocortical surfaces and to the marrow cavity. At the 6 mg/kg/day dose level, PGE2-treated OVX rats increased total tissue area, cortical bone area, marrow trabmular bone area, minimal cortical width and intracortical porosity area, and decreased marrow area compared to basal, sham-OVX and OVX controls. In addition, periosteal bone formation was elevated in the 6 mg PGE2/kg/day-treated OVX rats compared to OVX controls. Endocortical eroded perimeter increased from basal and sham-OVX control levels, but decreased from OVX control levels in the 6 mg PGE2/kg/day-treated OVX rats. Our study confirmed that ovariectomy does not cause osteopenia in tibial shaft cortical bone in rats, but it does stimulate endocortical bone resorption and enlarges marrow area. The new findings from the present study demonstrate that PGE2 prevents the OVX-induced increases in endocortical bone resorption and marrow area and adds additional bone to periosteal and endocortical surfaces and to marrow cavity to increase total bone mass in the tibial shaft of OVX rats when given immediately following ovafiectomy.

Mice lacking bone sialoprotein (BSP) lose bone after ovariectomy and display skeletal site-specific response to intermittent PTH treatment.

PubMed

Wade-Gueye, Ndéye Marième; Boudiffa, Maya; Laroche, Norbert; Vanden-Bossche, Arnaud; Fournier, Carole; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie-Hélène; Malaval, Luc

2010-11-01

Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP(-/-)) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP(+/+)) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP(+/+) and BSP(-/-) mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP(-/-) mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP(+/+) but not BSP(-/-) mice. PTH increased cortical thickness and bone area in BSP(+/+) but not BSP(-/-) mice and stimulated the bone formation rate specifically in the endosteum of BSP(+/+) mice and the periosteum of BSP(-/-) mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP(-/-) mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP(-/-) mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in compensating for the absence of BSP.

Periodontitis contributes to aberrant metabolism in type 2 diabetes mellitus rats by stimulating the expression of adipokines.

PubMed

Luo, S; Yang, X; Wang, D; Ni, J; Wu, J; Xu, Z; Xuan, D; Zhang, J

2016-08-01

Periodontitis has been associated with type 2 diabetes mellitus. We investigated the effects of local aberrant secretion of adipokines in diabetic rats on systemic metabolism. Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka rats were used as a diabetic model and associated control, respectively. Periodontitis was induced using a silk ligature for 36 wk. Rats were grouped into OLETF with (OP+) or without (OP-) periodontitis and Long-Evans Tokushima Otsuka with (LP+) or without (LP-) periodontitis. Alveolar bone resorption and destruction were evaluated by micro-computed tomography and hematoxylin and eosin staining. After 20 wk of periodontitis induction, lipids, insulin, interleukin-1, leptin and plasminogen activator inhibitor-1 were analyzed, and mRNA expressions of NF-κB, Mark8, TLR2 and -4, IKBKB and Nampt were evaluated by quantitative polymerase chain reaction in adipose tissue. After ligation, OLETF rats exhibited typical periodontitis lesions with the clinical features of type 2 diabetes mellitus. When compared with the OP(-) group, the area under curve of the oral glucose tolerance test and homeostatic model assessment-insulin resistance values were significantly higher in the OP(+) group. Micro-computed tomography showed that the OP(+) group had more bone resorption than the OP(-) group. When compared with the OP(-) group, the OP(+) group also exhibited higher total cholesterol (p < 0.05), leptin (p < 0.05), insulin (p > 0.05) and higher expression of Nampt (p < 0.05) and IKBKB (p < 0.05). The LP(+) group had a trend towards higher bone resorption when compared with the LP(-) group. Additionally, no difference in white adipose tissues or adipokines was found between LP(+) and LP(-) rats. Chronic periodontitis can alter lipid profiles in affected rats, elevate adipose tissue expression of Nampt and affect the metabolism of adipose tissue through the NF-κB pathway to inflame diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Scanning electron microscopy of bone: instrument, specimen, and issues.

PubMed

Boyde, A; Jones, S J

1996-02-01

There are many ways available now to maximise and analyse the information that can be obtained on the structure and constitution of bone using SEM. This paper considers a range of methods and the problems that arise relating to instrumentation and methodology as they apply to the use of SEM in the study of bone. In addition to the review content, some novel technical approaches to the SEM of bone are considered here for the first time; these include low kV imaging for the detection of new surface bone packets (and residual demineralized matrix after resorption), low kV BSE imaging of uncoated, embedded, and unembedded samples, environmental SEM for the study of wet tissue, low distortion, very low magnification imaging for the study of cancellous bone architecture, the use of multiple detectors for fast electrons in improving the imaging of porous samples, and high resolution, low voltage imaging for the study of collagen degradation during bone resorption.

Study of Osteoclast Adhesion to Cortical Bone Surfaces: A Correlative Microscopy Approach for Concomitant Imaging of Cellular Dynamics and Surface Modifications

PubMed Central

2015-01-01

Bone remodeling relies on the coordinated functioning of osteoblasts, bone-forming cells, and osteoclasts, bone-resorbing cells. The effects of specific chemical and physical bone features on the osteoclast adhesive apparatus, the sealing zone ring, and their relation to resorption functionality are still not well-understood. We designed and implemented a correlative imaging method that enables monitoring of the same area of bone surface by time-lapse light microscopy, electron microscopy, and atomic force microscopy before, during, and after exposure to osteoclasts. We show that sealing zone rings preferentially develop around surface protrusions, with lateral dimensions of several micrometers, and ∼1 μm height. Direct overlay of sealing zone rings onto resorption pits on the bone surface shows that the rings adapt to pit morphology. The correlative procedure presented here is noninvasive and performed under ambient conditions, without the need for sample labeling. It can potentially be applied to study various aspects of cell-matrix interactions. PMID:26682493

Dried plum diet protects from bone loss caused by ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schreurs, A. -S.; Shirazi-Fard, Y.; Shahnazari, M.

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or antiinflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss.more » Dried plum was most effective in reducing the expression of genes related to bone resorption ( Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Furthermore, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth.« less

Computational biomechanics of bone's responses to dental prostheses - osseointegration, remodeling and resorption

NASA Astrophysics Data System (ADS)

Li, Wei; Rungsiyakull, Chaiy; Field, Clarice; Lin, Daniel; Zhang, Leo; Li, Qing; Swain, Michael

2010-06-01

Clinical and experimental studies showed that human bone has the ability to remodel itself to better adapt to its biomechanical environment by changing both its material properties and geometry. As a consequence of the rapid development and extensive applications of major dental restorations such as implantation and fixed partial denture (FPD), the effect of bone remodeling on the success of a dental restorative surgery is becoming critical for prosthetic design and pre-surgical assessment. This paper aims to provide a computational biomechanics framework to address dental bone's responses as a result of dental restoration. It explored three important issues of resorption, apposition and osseointegration in terms of remodeling simulation. The published remodeling data in long bones were regulated to drive the computational remodeling prediction for the dental bones by correlating the results to clinical data. It is anticipated that the study will provide a more predictive model of dental bone response and help develop a new design methodology for patient-specific dental prosthetic restoration.

Dried plum diet protects from bone loss caused by ionizing radiation

DOE PAGES

Schreurs, A. -S.; Shirazi-Fard, Y.; Shahnazari, M.; ...

2016-02-11

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or antiinflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss.more » Dried plum was most effective in reducing the expression of genes related to bone resorption ( Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Furthermore, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth.« less

Dried plum diet protects from bone loss caused by ionizing radiation

PubMed Central

Schreurs, A.-S.; Shirazi-Fard, Y.; Shahnazari, M.; Alwood, J. S.; Truong, T. A.; Tahimic, C. G. T.; Limoli, C. L.; Turner, N. D.; Halloran, B.; Globus, R. K.

2016-01-01

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or anti-inflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss. Dried plum was most effective in reducing the expression of genes related to bone resorption (Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Thus, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth. PMID:26867002

Triiodothyronine increases calcium loss in a bed rest antigravity model for space flight.

PubMed

Smith, Steven R; Lovejoy, Jennifer C; Bray, George A; Rood, Jennifer; Most, Marlene M; Ryan, Donna H

2008-12-01

Bed rest has been used as a model to simulate the effects of space flight on bone metabolism. Thyroid hormones accelerate bone metabolism. Thus, supraphysiologic doses of this hormone might be used as a model to accelerate bone metabolism during bed rest and potentially simulate space flight. The objective of the study was to quantitate the changes in bone turnover after low doses of triiodothyronine (T(3)) added to short-term bed rest. Nine men and 5 women were restricted to bed rest for 28 days with their heads positioned 6 degrees below their feet. Subjects were randomly assigned to receive either placebo or oral T(3) at doses of 50 to 75 microg/d in a single-blind fashion. Calcium balance was measured over 5-day periods; and T(3), thyroxine, thyroid-stimulating hormone, immunoreactive parathyroid hormone, osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline were measured weekly. Triiodothyronine increased 2-fold in the men and 5-fold in the women during treatment, suppressing both thyroxine and thyroid-stimulating hormone. Calcium balance was negative by 300 to 400 mg/d in the T(3)-treated volunteers, primarily because of the increased fecal loss that was not present in the placebo group. Urinary deoxypyridinoline to creatinine ratio, a marker of bone resorption, increased 60% in the placebo group during bed rest, but more than doubled in the T(3)-treated subjects (P < .01), suggesting that bone resorption was enhanced by treatment with T(3). Changes in serum osteocalcin and bone-specific alkaline phosphatase, markers of bone formation, were similar in T(3)- and placebo-treated subjects. Triiodothyronine increases bone resorption and fecal calcium loss in subjects at bed rest.

Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties

PubMed Central

Wang, Chiachien J.; Chen, I-Ping; Koczon-Jaremko, Boguslawa; Boskey, Adele L.; Ueki, Yasuyoshi; Kuhn, Liisa; Reichenberger, Ernst J.

2010-01-01

Cherubism is an autosomal dominant disorder in children characterized by unwarranted symmetrical bone resorption of the jaws with fibrous tissue deposition. Mutations causing cherubism have been identified in the adaptor protein SH3BP2. Knock-in mice with a Pro416Arg mutation in Sh3bp2 exhibit a generalized osteoporotic bone phenotype. In this study, we examined the effects of this “cherubism” mutation on spectroscopic indices of “bone quality” and on osteoblast differentiation. Fourier-transform infrared imaging (FTIRI) analysis of femurs from wild-type and Sh3bp2 knock-in mice showed decreased mineral content, decreased mineral crystallinity/crystal size, and increased collagen maturity in homozygous mutants. To assess osteoblast maturation in vivo, knock-in mice were crossed with transgenic mice over-expressing GFP driven by 3.6-kb or 2.3-kb Col1a1 promoter fragments. Reduced numbers of mature osteoblasts were observed in homozygous mice. Neonatal calvarial cultures, which were enriched for osteoblasts by depletion of hematopoietic cells (negative selection for Ter119- and CD45-positive cells) were investigated for osteoblast-specific gene expression and differentiation, which demonstrated that differentiation and mineralization in homozygous osteoblast cultures was impaired. Co-cultures with calvarial osteoblasts and bone marrow macrophages showed that mutant osteoblasts appear to increase osteoclastogenesis resulting in increased bone resorption on bone chips. In summary, the Sh3bp2 mutation in cherubism mice alters bone quality, reduces osteoblast function, and may contribute to excessive bone resorption by osteoclasts. Our data, together with previous osteoclast studies, demonstrate a critical role of Sh3bp2 in bone remodeling and osteoblast differentiation. PMID:20117257

Kinetic study of bone ingrowth and ceramic resorption associated with the implantation of different injectable calcium-phosphate bone substitutes.

PubMed

Gauthier, O; Bouler, J M; Weiss, P; Bosco, J; Daculsi, G; Aguado, E

1999-10-01

This study investigated the in vivo performance of two composite injectable bone substitutes (IBS), each with different calcium-phosphate particles granulometries [40-80 (IBS 40-80) and 200-500 microm (IBS 200-500)]. These biomaterials were obtained by associating a biphasic calcium-phosphate (BCP) ceramic mineral phase with a 3% aqueous solution of a cellulosic polymer (hydroxy-propyl-methyl-cellulose). Both materials were injected for periods of 2, 3, 8, or 12 weeks into bone defects at the distal end of rabbit femurs. Quantitative results on new bone formation, BCP resorption, and staining for tartrate-resistant acid phosphatase (TRAP) activity were studied for statistical purposes. Measurements with scanning electron microscopy and image analysis showed that the final rates of newly formed bone were similar for both tested IBS after 12 weeks of implantation. Bone colonization occurred more extensively during early implantation times for IBS 40-80 than for IBS 200-500. For the latter, BCP degradation occurred regularly throughout the implantation period, whereas it was very intensive during the first 2 weeks for IBS 40-80. Positive TRAP-stained degradation cells were significantly more numerous for IBS 40-80 than for IBS 200-500 regardless of implantation time. With the granulometry of either mineral phase, both tested IBS supported extensive bone colonization, which was greater than that previously reported for an equivalent block of macroporous BCP. The resorption-bone substitution process seemed to occur earlier and faster for IBS 40-80 than for IBS 200-500. Both tested IBS expressed similar biological efficiency, with conserved in vivo bioactivity and bone-filling ability. Copyright 1999 John Wiley & Sons, Inc.

The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.

PubMed

Hayami, Tadashi; Pickarski, Maureen; Wesolowski, Gregg A; McLane, Julia; Bone, Ashleigh; Destefano, James; Rodan, Gideon A; Duong, Le T

2004-04-01

It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.

N-acetylcysteine supplementation decreases osteoclast differentiation and increases bone mass in mice fed a high-fat diet

USDA-ARS?s Scientific Manuscript database

Studies have demonstrated that obesity induced by high-fat diets increases bone resorption, decreases trabecular bone mass, and reduces bone strength in various animal models. This study investigated whether N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, alters glutathione statu...

Increased physical activity ameliorates high fat diet-induced bone resorption in mice

USDA-ARS?s Scientific Manuscript database

It has been recognized that mechanical stresses associated with physical activity (PA) have beneficial effects on increasing bone mineral density (BMD) and improving bone quality. On the other hand, high fat diet (HFD) and obesity increase bone marrow adiposity leading to increased excretion of pro-...

Hypervitaminosis A and bone.

PubMed

Binkley, N; Krueger, D

2000-05-01

Animal, human, and in vitro data all indicate that excess vitamin A stimulates bone resorption and inhibits bone formation. This combination would be expected to produce bone loss and to contribute to osteoporosis development and may occur with relatively low vitamin A intake. It is possible that unappreciated hypervitaminosis A contributes to osteoporosis pathogenesis.

Fifty years of human space travel: implications for bone and calcium research

USDA-ARS?s Scientific Manuscript database

Calcium and bone metabolism remain key concerns for space travelers, and ground-based models of space flight have provided a vast literature to complement the smaller set of reports from flight studies. Increased bone resorption and largely unchanged bone formation result in the loss of calcium and ...

Pathophysiology and new strategies for the treatment of Legg-Calvé-Perthes disease.

PubMed

Kim, Harry K W

2012-04-04

Legg-Calvé-Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to permanent femoral head deformity and premature osteoarthritis. According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments have modest success rates of producing a good outcome with a spherical femoral head in older children with Legg-Calvé-Perthes disease. Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic necrosis. Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of the hip, contribute to the pathogenesis of the femoral head deformity. Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating bone formation appear promising in nonhuman preclinical studies.

Acute bone response to whole body vibration in healthy pre-pubertal boys

PubMed Central

Harrison, R.; Ward, K.; Lee, E.; Razaghi, H.; Horne, C.; Bishop, N.J.

2015-01-01

The skeleton responds to mechanical stimulation. We wished to ascertain the magnitude and speed of the growing skeleton’s response to a standardised form of mechanical stimulation, vibration. 36 prepubertal boys stood for 10 minutes in total on one of two vibrating platforms (high (>2 g) or low (<1 g) magnitude vibration) on either 1, 3 or 5 successive days (n=12 for each duration); 15 control subjects stood on an inactive platform. Blood samples were taken at intervals before and after vibration to measure bone formation (P1NP, osteocalcin) and resorption (CTx) markers as well as osteoprotegerin and sclerostin. There were no significant differences between platform and control groups in bone turnover markers immediately after vibration on days 1, 3 and 5. Combining platform groups, at day 8 P1NP increased by 25.1% (CI 12.3 to 38.0; paired t-test p=0.005) and bone resorption increased by 10.9% (CI 3.6 to 18.2; paired t-test p=0.009) compared to baseline. Osteocalcin, osteoprotogerin and sclerostin did not change significantly. The growing skeleton can respond quickly to vibration of either high or low magnitude. Further work is needed to determine the utility of such “stimulation-testing” in clinical practice. PMID:26032203

Acute bone response to whole body vibration in healthy pre-pubertal boys.

PubMed

Harrison, R; Ward, K; Lee, E; Razaghi, H; Horne, C; Bishop, N J

2015-06-01

The skeleton responds to mechanical stimulation. We wished to ascertain the magnitude and speed of the growing skeleton's response to a standardised form of mechanical stimulation, vibration. 36 prepubertal boys stood for 10 minutes in total on one of two vibrating platforms (high (>2 g) or low (<1 g) magnitude vibration) on either 1, 3 or 5 successive days (n=12 for each duration); 15 control subjects stood on an inactive platform. Blood samples were taken at intervals before and after vibration to measure bone formation (P1NP, osteocalcin) and resorption (CTx) markers as well as osteoprotegerin and sclerostin. There were no significant differences between platform and control groups in bone turnover markers immediately after vibration on days 1, 3 and 5. Combining platform groups, at day 8 P1NP increased by 25.1% (CI 12.3 to 38.0; paired t-test p=0.005) and bone resorption increased by 10.9% (CI 3.6 to 18.2; paired t-test p=0.009) compared to baseline. Osteocalcin, osteoprotogerin and sclerostin did not change significantly. The growing skeleton can respond quickly to vibration of either high or low magnitude. Further work is needed to determine the utility of such "stimulation-testing" in clinical practice.

Higher bone resorption excretion in South Asian women vs. White Caucasians and increased bone loss with higher seasonal cycling of vitamin D: Results from the D-FINES cohort study.

PubMed

Darling, A L; Hart, K H; Gossiel, F; Robertson, F; Hunt, J; Hill, T R; Johnsen, S; Berry, J L; Eastell, R; Vieth, R; Lanham-New, S A

2017-05-01

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n=373 women (four groups; South Asian postmenopausal n=44, South Asian premenopausal n=50, Caucasian postmenopausal n=144, Caucasian premenopausal n=135) (mean (±SD) age 48 (14) years; age range 18-79years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006-2007). A mixed between-within subjects ANOVA (n=192) showed a between subjects effect of the four groups (P<0.001) on uNTX concentration, but no significant main effect of season (P=0.163). Bonferroni adjusted Post hoc tests (P≤0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P=0.04) and spring (P=0.007), premenopausal Asian women had a 16 to 20nmolBCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD)=0.213 (0.015) and 95% CI (0.182, 0.245; P<0.001) in a non-linear mixed model (n=154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD)=-0.035 (0.004), and 95% CI (-0.043, -0.028; P<0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health. Copyright © 2017 Elsevier Inc. All rights reserved.

Decursin from Angelica gigas suppresses RANKL-induced osteoclast formation and bone loss.

PubMed

Wang, Xin; Zheng, Ting; Kang, Ju-Hee; Li, Hua; Cho, Hyewon; Jeon, Raok; Ryu, Jae-Ha; Yim, Mijung

2016-03-05

Osteoclasts are the only cells capable of breaking down bone matrix, and excessive activation of osteoclasts is responsible for bone-destructive diseases. In this study, we investigated the effects of decursin from extract of Angelica gigas root on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast formation using mouse bone marrow-derived macrophages (BMMs). Decursin inhibited RANKL-induced osteoclast formation without cytotoxicity. In particular, decursin maintains the characteristics of macrophages by blocking osteoclast differentiation by RANKL. Furthermore, the RANKL-stimulated bone resorption was diminished by decursin. Mechanistically, decursin blocked the RANKL-triggered ERK mitogen-activated protein kinases (MAPK) phosphorylation, which results in suppression of c-Fos and the nuclear factor of activated T cells (NFATc1) expression. In accordance with the in vitro study, decursin reduced lipopolysaccharide (LPS)- or ovariectomy (OVX)-induced bone loss in vivo. Therefore, decursin exerted an inhibitory effect on osteoclast formation and bone loss in vitro and in vivo. Decursin could be useful for the treatment of bone diseases associated with excessive bone resorption. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis

NASA Astrophysics Data System (ADS)

Sardone, Laura Donata

Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat Type 2 Diabetes Mellitus (T2DM). Clinical trials show that women taking RSG experience more limb fractures than patients taking other T2DM drugs. The purpose of this study is to understand how RSG (3mg/kg/day and 10mg/kg/day) and the bisphosphonate alendronate (0.7mg/kg/week) alter bone quality in the male, female and female ovariectomized (OVX) Zucker fatty rat model over a 12 week period. Bone quality was evaluated by mechanical testing of cortical and trabecular bone. Microarchitecture, bone mineral density (BMD), cortical bone porosity, bone formation/resorption and mineralization were also measured. Female OVX RSG10mg/kg rats had significantly lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented these negative effects in the OVX RSG model. Evidence of reduced bone formation and excess bone resorption was detected in female RSG-treated rats.

Interdependence of skeletal sclerosis and elevated circulating levels of 1,25-dihydroxyvitamin D in osteopetrotic (op and tl) rats.

PubMed

Popoff, S N; Osier, L K; Zerwekh, J E; Marks, S C

1994-01-01

Osteopetrosis describes a heterogeneous group of inherited, metabolic bone disorders characterized by reduced bone resorption which coexists with elevated circulating levels of 1,25-dihydroxyvitamin D [1,25(OH)2D]. To determine whether or not skeletal sclerosis and high concentrations of 1,25(OH)2D are interdependent, this study used two distinct, nonallelic osteopetrotic mutations in the rat, osteopetrosis (op) and toothless (tl). The op rat is a mutation in which skeletal sclerosis can be cured (mutant) or induced (normal) following the transfer of normal or mutant osteoclast progenitors, respectively. Although these procedures are ineffective in rats of tl stock, infusions of pharmacological doses of macrophage colony-stimulating factor (CSF-1) can stimulate bone resorption and eliminate most of the excess skeletal matrix in tl mutants. This study examined the effects of cure/induction in neonatal mutant/normal rats of op stock and CSF-1 infusions in mutant rats of tl stock on skeletal (bone resorption) and serum [1,25(OH)2D] parameters as a function of time after treatment. Osteopetrotic mutants transplanted (cured) with normal spleen cells demonstrated cellular changes in osteoclast phenotype within 2-3 days followed by histologic and radiographic evidence for increased bone resorption that culminated in a normal appearance of the skeleton by 4 weeks. The markedly elevated serum levels of 1,25(OH)2D observed in untreated mutants fell significantly in transplanted mutants by the end of the first week and were similar to those in normal littermates at 3 and 4 weeks. Normal littermates transplanted (induced) with mutant spleen cells showed a progressive increase in skeletal sclerosis paralleled by significant increases in circulating levels of 1,25(OH)2D.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption

NASA Technical Reports Server (NTRS)

Miyauchi, A.; Hruska, K. A.; Greenfield, E. M.; Duncan, R.; Alvarez, J.; Barattolo, R.; Colucci, S.; Zambonin-Zallone, A.; Teitelbaum, S. L.; Teti, A.

1990-01-01

The mechanisms of Ca2+ entry and their effects on cell function were investigated in cultured chicken osteoclasts and putative osteoclasts produced by fusion of mononuclear cell precursors. Voltage-gated Ca2+ channels (VGCC) were detected by the effects of membrane depolarization with K+, BAY K 8644, and dihydropyridine antagonists. K+ produced dose-dependent increases of cytosolic calcium ([Ca2+]i) in osteoclasts on glass coverslips. Half-maximal effects were achieved at 70 mM K+. The effects of K+ were completely inhibited by dihydropyridine derivative Ca2+ channel blocking agents. BAY K 8644 (5 X 10(-6) M), a VGCC agonist, stimulated Ca2+ entry which was inhibited by nicardipine. VGCCs were inactivated by the attachment of osteoclasts to bone, indicating a rapid phenotypic change in Ca2+ entry mechanisms associated with adhesion of osteoclasts to their resorption substrate. Increasing extracellular Ca2+ ([Ca2+]e) induced Ca2+ release from intracellular stores and Ca2+ influx. The Ca2+ release was blocked by dantrolene (10(-5) M), and the influx by La3+. The effects of [Ca2+]e on [Ca2+]i suggests the presence of a Ca2+ receptor on the osteoclast cell membrane that could be coupled to mechanisms regulating cell function. Expression of the [Ca2+]e effect on [Ca2+]i was similar in the presence or absence of bone matrix substrate. Each of the mechanisms producing increases in [Ca2+]i, (membrane depolarization, BAY K 8644, and [Ca2+]e) reduced expression of the osteoclast-specific adhesion structure, the podosome. The decrease in podosome expression was mirrored by a 50% decrease in bone resorptive activity. Thus, stimulated increases of osteoclast [Ca2+]i lead to cytoskeletal changes affecting cell adhesion and decreasing bone resorptive activity.

The in vivo behaviour of a sol-gel glass and a glass-ceramic during critical diaphyseal bone defects healing.

PubMed

Gil-Albarova, Jorge; Salinas, Antonio J; Bueno-Lozano, Antonio L; Román, Jesus; Aldini-Nicolo, Nicolo; García-Barea, Agustina; Giavaresi, Gianluca; Fini, Milena; Giardino, Roberto; Vallet-Regí, Maria

2005-07-01

The in vivo evaluation, in New Zealand rabbits, of a sol-gel glass 70% CaO-30% SiO2 (in mol%) and a glass-ceramic obtained from thermal treatment of the glass, both bioactive in Kokubo's simulated body fluid (SBF), is presented. Femoral bone diaphyseal critical defects were filled with: (i) sol-gel glass cylinders, (ii) glass-ceramic cylinders, or (iii) no material (control group). Osteosynthesis was done by means of anterior screwed plates with an associate intramedullar Kirschner wire. Each group included 10 mature rabbits, 9 months old. Follow-up was 6 months. After sacrifice, macroscopic study showed healing of bone defects, with bone coating over the cylinders, but without evidence of satisfactory repair in control group. Radiographic study showed good implant stability and periosteal growth and bone remodelling around and over the filled bone defect. The morphometric study showed minimum evidences of degradation or resorption in glass-ceramic cylinders, maintaining its original shape, but sol-gel glass cylinders showed abundant fragmentation and surface resorption. An intimate union of the new-formed bone to both materials was observed. Mechanical study showed the higher results in the glass-ceramic group, whereas sol-gel glass and control group showed no differences. The minimum degradation of glass-ceramic cylinders suggests their application in critical bone defects locations of transmission forces or load bearing. The performance of sol-gel glass cylinders suggests their usefulness in locations where a quick resorption should be preferable, considering the possibility of serving as drug or cells vehicle for both of them.

Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases.

PubMed

Callaway, Danielle A; Jiang, Jean X

2015-07-01

Osteoclasts are cells derived from bone marrow macrophages and are important in regulating bone resorption during bone homeostasis. Understanding what drives osteoclast differentiation and activity is important when studying diseases characterized by heightened bone resorption relative to formation, such as osteoporosis. In the last decade, studies have indicated that reactive oxygen species (ROS), including superoxide and hydrogen peroxide, are crucial components that regulate the differentiation process of osteoclasts. However, there are still many unanswered questions that remain. This review will examine the mechanisms by which ROS can be produced in osteoclasts as well as how it may affect osteoclast differentiation and activity through its actions on osteoclastogenesis signaling pathways. In addition, the contribution of ROS to the aging-associated disease of osteoporosis will be addressed and how targeting ROS may lead to the development of novel therapeutic treatment options.

The influence of resilient liner and clip attachments for bar-implant-retained mandibular overdentures on opposing maxillary ridge. A 5-year randomised clinical trial.

PubMed

Elsyad, M A; Ashmawy, T M; Faramawy, A G

2014-01-01

This study aimed to compare the influence of resilient liner and clip attachments for bar-implant-retained mandibular overdentures on opposing maxillary ridge after 5 years of denture wearing. Thirty edentulous male patients (mean age 62·5 years) received two implants in the anterior mandible after being allocated into two equal groups using balanced randomisation. After 3 months, implants were connected with resilient bars. New maxillary complete dentures were then constructed, and mandibular overdentures were retained to the bars with either clips (group I, GI) or silicone resilient liners (group II, GII). The prosthetic and soft tissue complications of the maxillary dentures were recorded 6 months (T6 m ), 1 year (T1), 3 years (T3) and 5 years (T5) after overdenture insertion. Traced rotational tomograms were used for measurements of maxillary alveolar bone loss. The proportional value between bone areas and areas of reference not subject to resorption was expressed as a ratio (R). Change in R immediately before (T0) and after 5 years (T5) of overdenture insertion was calculated. Maxillary denture relining times and frequency of flabby anterior maxillary ridge occurred significantly more often in GI compared with GII. The change of R in anterior part of maxilla was significantly higher than change of R in posterior part in both groups. GI showed significant resorption of anterior residual ridge compared with GII. Relining times and frequencies of flabby ridge were significantly correlated with change in R. Within the limitations of this study, resilient liner attachments for bar-implant-retained mandibular overdentures are associated with decreased resorption and flabbiness of maxillary anterior residual ridge and fewer maxillary denture relining times when compared with clip attachments. © 2013 John Wiley & Sons Ltd.

A High-Fat Diet Decreases Bone Mass in Growing Mice with Systemic Chronic Inflammation Induced by Low-Dose, Slow-Release Lipopolysaccharide Pellets.

PubMed

Cao, Jay J; Gregoire, Brian R; Shen, Chwan-Li

2017-10-01

Background: Chronic inflammation is associated with increased bone resorption and is linked to osteopenia, or low bone mass. Obesity is also associated with low-grade chronic upregulation of inflammatory cytokines. Objective: This study investigated the effect of high-fat (HF) diet-induced obesity on bone structure changes in growing mice with existing systemic chronic inflammation induced by low-dose, slow-release lipopolysaccharide (LPS). Methods: Forty-eight 6-wk-old female C57BL/6 mice were randomly assigned to 4 treatment groups ( n = 12/group) in a 2 × 2 factorial design-control (placebo) or LPS treatment (1.5 μ g/d)-and consumed either a normal-fat (NF, 10% of energy as fat) or an HF (45% of energy as fat) diet ad libitum for 13 wk. Bone structure, serum biomarkers of bone turnover, and osteoclast differentiation were measured. Results: No alterations were observed in final body weights, fat mass, or lean mass in response to LPS treatment. LPS treatment increased serum concentration of tartrate-resistant acid phosphatase (TRAP, a bone resorption marker) and bone marrow osteoclast differentiation and decreased femoral and lumbar vertebral bone volume (BV):total volume (TV) by 25% and 24%, respectively, compared with the placebo. Mice fed the HF diet had greater body weight at the end of the study ( P < 0.01) due to increased fat mass ( P < 0.01) than did mice fed the NF diet. The HF diet increased serum TRAP concentration, bone marrow osteoclast differentiation, and expression of tumor necrosis factor α, interleukin 1β and interleukin 6 in adipose tissue. Compared with the NF diet, the HF diet decreased BV:TV by 10% and 8% at femur and lumbar vertebrae, respectively, and the HF diet was detrimental to femoral and lumbar vertebral bone structure with decreased trabecular number and increased trabecular separation and structure model index. Conclusion: Results suggest that HF diets and systemic chronic inflammation have independent negative effects on bone structure in mice. © 2017 American Society for Nutrition.

Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711.

PubMed

Lindström, Erik; Rizoska, Biljana; Henderson, Ian; Terelius, Ylva; Jerling, Markus; Edenius, Charlotte; Grabowska, Urszula

2018-05-09

Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg. MIV-711 was a potent inhibitor of human cathepsin K (K i : 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC 50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data. MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.

Reduced energy availability: implications for bone health in physically active populations.

PubMed

Papageorgiou, Maria; Dolan, Eimear; Elliott-Sale, Kirsty J; Sale, Craig

2018-04-01

The present review critically evaluates existing literature on the effects of short- and long-term low energy availability (EA) on bone metabolism and health in physically active individuals. We reviewed the literature on the short-term effects of low EA on markers of bone metabolism and the long-term effects of low EA on outcomes relating to bone health (bone mass, microarchitecture and strength, bone metabolic markers and stress fracture injury risk) in physically active individuals. Available evidence indicates that short-term low EA may increase markers of bone resorption and decrease markers of bone formation in physically active women. Bone metabolic marker responses to low EA are less well known in physically active men. Cross-sectional studies investigating the effects of long-term low EA suggest that physically active individuals who have low EA present with lower bone mass, altered bone metabolism (favouring bone resorption), reduced bone strength and increased risk for stress fracture injuries. Reduced EA has a negative influence on bone in both the short- and long-term, and every effort should be made to reduce its occurrence in physically active individuals. Future interventions are needed to explore the effects of long-term reduced EA on bone health outcomes, while short-term low EA studies are also required to give insight into the pathophysiology of bone alterations.

Bioactive scaffold for bone tissue engineering: An in vivo study

NASA Astrophysics Data System (ADS)

Livingston, Treena Lynne

Massive bone loss of the proximal femur is a common problem in revision cases of total hip implants. Allograft is typically used to reconstruct the site for insertion of the new prosthesis. However, for long term fixation and function, it is desirable that the allograft becomes fully replaced by bone tissue and aids in the regeneration of bone to that site. However, allograft use is typically associated with delayed incorporation and poor remodeling. Due to these profound limitations, alternative approaches are needed. Tissue engineering is an attractive approach to designing improved graft materials. By combining osteogenic activity with a resorbable scaffold, bone formation can be stimulated while providing structure and stability to the limb during incorporation and remodeling of the scaffold. Porous, surface modified bioactive ceramic scaffolds (pSMC) have been developed which stimulate the expression of the osteoblastic phenotype and production of bone-like tissue in vitro. The scaffold and two tissue-engineered constructs, osteoprogenitor cells seeded onto scaffolds or cells expanded in culture to form bone tissue on the scaffolds prior to implantation, were investigated in a long bone defect model. The rate of incorporation was assessed. Both tissue-engineered constructs stimulated bone formation and comparable repair at 2 weeks. In a rat femoral window defect model, bone formation increased over time for all groups in concert with scaffold resorption, leading to a 40% increase in bone and 40% reduction of the scaffold in the defect by 12 weeks. Both tissue-engineered constructs enhanced the rate of mechanical repair of long bones due to better bony union with the host cortex. Long bones treated with tissue engineered constructs demonstrated a return in normal torsional properties by 4 weeks as compared to 12 weeks for long bones treated with pSMC. Culture expansion of cells to produce bone tissue in vitro did not accelerate incorporation over the treatment with cells seeded at the time of surgery. Porous, surface modified bioactive ceramic is a promising scaffold material for tissue-engineered bone repair. Bone formation and scaffold resorption act in concert for maintenance and improvement of the structural properties of the long bones over time. As determined histomorphometrically and mechanically, the rate of incorporation of the scaffold was enhanced with the tissue-engineered constructs.

Association between bone turnover, micronutrient intake, and blood lead levels in pre- and postmenopausal women, NHANES 1999-2002.

PubMed

Jackson, Leila W; Cromer, Barbara A; Panneerselvamm, Ashok

2010-11-01

Blood lead levels (BLLs) have been shown to increase during periods of high bone turnover such as pregnancy and menopause. We examined the associations between bone turnover and micronutrient intake with BLLs in women 20-85 years of age (n = 2,671) participating in the National Health and Nutrition Examination Survey, 1999-2002. Serum bone-specific alkaline phosphatase (BAP) and urinary cross-linked N-telopeptides (NTx) were measured as markers of bone formation and resorption, respectively. Lead was quantified in whole blood. The association between tertiles of BAP and NTx, and BLLs was examined using linear regression with natural log transformed BLLs as the dependent variable and interpreted as the percent difference in geometric mean BLLs. In adjusted analyses, mean BLLs among postmenopausal women in the upper tertiles of NTx and BAP were 34% [95% confidence interval (CI), 23%-45%] and 30% (95% CI, 17%-43%) higher than BLLs among women in the lowest tertiles of NTx and BAP, respectively. These associations were weaker, but remained statistically significant, among premenopausal women (NTx: 10%; 95% CI, 0.60%-19%; BAP: 14%; 95% CI, 6%-22%). Within tertiles of NTx and BAP, calcium intake above the Dietary Reference Intake (DRI), compared with below the DRI, was associated with lower mean BLLs among postmenopausal women but not premenopausal women, although most of the associations were not statistically significant. We observed similar associations for vitamin D supplement use. Bone resorption and bone formation were associated with a significant increase in BLLs among pre- and postmenopausal women.

Artificial Gravity as a Bone Loss Countermeasure in Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Smith, S. M.; Zwart, S. R.; Crawford, G. E.; Gillman, P. L.; LeBlanc, A.; Shackelford, L. C.; Heer, M. A.

2007-01-01

The impact of microgravity on the human body is a significant concern for space travelers. We report here initial results from a pilot study designed to explore the utility of artificial gravity (AG) as a countermeasure to the effects of microgravity, specifically to bone loss. After an initial phase of adaptation and testing, 15 male subjects underwent 21 days of 6 head-down bed rest to simulate the deconditioning associated with space flight. Eight of the subjects underwent 1 h of centrifugation (AG, 1 gz at the heart, 2.5 gz at the feet) each day for 21 days, while 7 of the subjects served as untreated controls (CN). Blood and urine were collected before, during, and after bed rest for bone marker determinations. At this point, preliminary data are available on the first 8 subjects (6 AG, and 2 CN). Comparing the last week of bed rest to before bed rest, urinary excretion of the bone resorption marker n-telopeptide increased 95 plus or minus 59% (mean plus or minus SD) in CN but only 32 plus or minus 26% in the AG group. Similar results were found for another resorption marker, helical peptide (increased 57 plus or minus 0% and 35 plus or minus 13% in CN and AG respectively). Bone-specific alkaline phosphatase, a bone formation marker, did not change during bed rest. At this point, sample analyses are continuing, including calcium tracer kinetic studies. These initial data demonstrate the potential effectiveness of short-radius, intermittent AG as a countermeasure to the bone deconditioning that occurs during bed rest.

Ibandronate and cementless total hip arthroplasty: densitometric measurement of periprosthetic bone mass and new therapeutic approach to the prevention of aseptic loosening

PubMed Central

Muratore, Maurizio; Quarta, Eugenio; Quarta, Laura; Calcagnile, Fabio; Grimaldi, Antonella; Orgiani, M. Antonio; Marsilio, Antonio; Rollo, Giuseppe

2012-01-01

Summary Studies of the mechanisms of periprosthetic bone loss have led to the development of pharmacologic strategies intended to enhance bone mass recovery after surgery and consequently prevent aseptic loosening and prolong the implant survival. Bisphosphonates, potent anti-resorptive drugs widely used in the treatment of osteoporosis and other disorders of bone metabolism, were shown to be particularly effective in reducing periprosthetic bone resorption in the first year after hip and knee arthroplasty, both cemented and cementless. Based on these results, we investigated the inhibitory effects of ibandronate on periprosthetic bone loss in a 2-year study of postmenopausal women that underwent cementless total hip arthroplasty. In the first 6 months both groups (A, treated with ibandronate 3 mg i.v. within five days after surgery and then with oral ibandronate 150 mg/month, plus calcium and vitamin D supplementation; and B, treated with calcium and vitamin D supplementation only) experienced bone loss, though to a lesser extent in group A. After 12 months, group A showed a remarkable BMD recovery, that was statistically significant versus baseline values (about +1, 74% of global BMD) and most evident in region R1 (+3, 81%) and R2 (+4, 12%); in group B, on the contrary, BMD values were unchanged compared with those at 6 months post-surgery. Quality of life scores also showed a greater improvement in group A, both at 6 and 12 months after surgery, likely because of the pain-reducing effects of ibandronate treatment. PMID:22783337

S-Ketoprofen Inhibits Tenotomy-Induced Bone Loss and Dynamics in Weanling Rats

NASA Technical Reports Server (NTRS)

Zeng, Q. Q.; Jee, W. S. S.; Ke, H. Z.; Wechter, W. J.

1993-01-01

The objects of this study were to determine whether S-ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), can prevent immobilization (tenotomy)-induced bone loss in weanling rats. Forty five 4 week-old Sprague-Dawley female rats were either sham-operated or subjected to knee tenotomy and treated simultaneously with 0, 0.02, 0.1, 0.5 or 2.5 mg of S-ketoprofen/kg per day for 21 days. We then studied double-fluorescent labeled proximal tibial longitudinal sections and tibial shaft cross sections using static and dynamic histomorphometry. Less cancellous bone mass in proximal tibial metaphyses was found in tenotomized controls than in basal (36%) and sham-operated (54%) controls. This was due to the inhibition of age-related bone gain and induced bone loss due to increased bone resorption and decreased bone formation. S-ketoprofen prevented both the inhibition of age-related bone gain and the stimulation of bone loss at the 2.5 mg/kg per day dose level, while it only prevented bone loss at the 0.5 mg/kg dose levels. In cancellous bone, dynamic histomorphometry showed that S-ketoprofen prevented the tenotomy induced decrease in bone formation and increase in bone resorption. In the tibial shaft, tenotomy inhibited the enlargement of total tissue area by depressing periosteal bone formation, and thus inhibited age-related cortical bone gain. S-ketoprofen treatment did not prevent this change at all dose levels, but reduced marrow cavity area to increase cortical bone area at the 0.1, 0.5 and 2.5 mg/kg per dose levels compared to tenotomy controls. However, the cortical bone area in the 0.1 and 0.5 mg dose-treated treated tenotomy rats was still lower than in the age-related controls. S-ketoprofen also prevented the increase in endocortical eroded perimeter induced by tenotomy. In summary, tenotomy inhibited age-related bone gain and stimulated bone loss in cancellous bone sites, and only inhibited age-related bone gain in cortical bone sites. S-ketoprofen treatment at the highest dose levels prevented the changes in cancellous bone, and reduced marrow area to increase cortical bone in the tibial shafts.

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice.

PubMed

Pereira, M; Jeyabalan, J; Jørgensen, C S; Hopkinson, M; Al-Jazzar, A; Roux, J P; Chavassieux, P; Orriss, I R; Cleasby, M E; Chenu, C

2015-12-01

Some anti-diabetic therapies can have adverse effects on bone health and increase fracture risk. In this study, we tested the skeletal effects of chronic administration of two Glucagon-like peptide-1 receptor agonists (GLP-1RA), increasingly used for type 2 diabetes treatment, in a model of osteoporosis associated bone loss and examined the expression and activation of GLP-1R in bone cells. Mice were ovariectomised (OVX) to induce bone loss and four weeks later they were treated with Liraglutide (LIR) 0.3mg/kg/day, Exenatide (Ex-4) 10 μg/kg/day or saline for four weeks. Mice were injected with calcein and alizarin red prior to euthanasia, to label bone-mineralising surfaces. Tibial micro-architecture was determined by micro-CT and bone formation and resorption parameters measured by histomorphometric analysis. Serum was collected to measure calcitonin and sclerostin levels, inhibitors of bone resorption and formation, respectively. GLP-1R mRNA and protein expression were evaluated in the bone, bone marrow and bone cells using RT-PCR and immunohistochemistry. Primary osteoclasts and osteoblasts were cultured to evaluate the effect of GLP-1RA on bone resorption and formation in vitro. GLP-1RA significantly increased trabecular bone mass, connectivity and structure parameters but had no effect on cortical bone. There was no effect of GLP-1RA on bone formation in vivo but an increase in osteoclast number and osteoclast surfaces was observed with Ex-4. GLP-1R was expressed in bone marrow cells, primary osteoclasts and osteoblasts and in late osteocytic cell line. Both Ex-4 and LIR stimulated osteoclastic differentiation in vitro but slightly reduced the area resorbed per osteoclast. They had no effect on bone nodule formation in vitro. Serum calcitonin levels were increased and sclerostin levels decreased by Ex-4 but not by LIR. Thus, GLP-1RA can have beneficial effects on bone and the expression of GLP-1R in bone cells may imply that these effects are exerted directly on the tissue. Copyright © 2015 Elsevier Inc. All rights reserved.

Tibial changes in experimental disuse osteoporosis in the monkey

NASA Technical Reports Server (NTRS)

Young, D. R.; Niklowitz, W. J.; Steele, C. R.

1983-01-01

The mechanical properties and structural changes in the monkey tibia with disuse osteoporosis and during subsequent recovery are investigated. Bone mending stiffness is evaluated in relation to microscopic changes in cortical bone and Norland bone mineral analysis. Restraint in the semireclined position is found to produce regional losses of bone most obviously in the anterior-proximal tibiae. After six months of restraint, the greatest losses of bone mineral in the proximal tibiae range from 23 percent to 31 percent; the largest changes in bone stiffness range from 36 percent to 40 percent. Approximately eight and one-half months of recovery are required to restore the normal bending properties. Even after 15 months of recovery, however, the bone mineral content does not necessarily return to normal levels. Histologically, resorption cavities in cortical bone are seen within one month of restraint; by two and one-half months of restraint there are large resorption cavities subperiosteally, endosteally, and intracortically. After 15 months of recovery, the cortex consists mainly of first-generation haversian systems. After 40 months, the cortex appears normal, with numerous secondary and tertiary generations of haversian systems.

Timing of cranioplasty after decompressive craniectomy for trauma.

PubMed

Piedra, Mark P; Nemecek, Andrew N; Ragel, Brian T

2014-01-01

The optimal timing of cranioplasty after decompressive craniectomy for trauma is unknown. The aim of this study was to determine if early cranioplasty after decompressive craniectomy for trauma reduces complications. Consecutive cases of patients who underwent autologous cranioplasty after decompressive craniectomy for trauma at a single Level I Trauma Center were studied in a retrospective 10 year data review. Associations of categorical variables were compared using Chi-square test or Fisher's exact test. A total of 157 patients were divided into early (<12 weeks; 78 patients) and late (≥12 weeks; 79 patients) cranioplasty cohorts. Baseline characteristics were similar between the two cohorts. Cranioplasty operative time was significantly shorter in the early (102 minutes) than the late (125 minutes) cranioplasty cohort (P = 0.0482). Overall complication rate in both cohorts was 35%. Infection rates were lower in the early (7.7%) than the late (14%) cranioplasty cohort as was bone graft resorption (15% early, 19% late), hydrocephalus rate (7.7% early, 1.3% late), and postoperative hematoma incidence (3.9% early, 1.3% late). However, these differences were not statistically significant. Patients <18 years of age were at higher risk of bone graft resorption than patients ≥18 years of age (OR 3.32, 95% CI 1.25-8.81; P = 0.0162). After decompressive craniectomy for trauma, early (<12 weeks) cranioplasty does not alter the incidence of complication rates. In patients <18 years of age, early (<12 weeks) cranioplasty increases the risk of bone resorption. Delaying cranioplasty (≥12 weeks) results in longer operative times and may increase costs.

An ex vivo evaluation of the efficacy of andrographolide in modulating differential expression of transcription factors and target genes in periodontal cells and its potential role in treating periodontal diseases.

PubMed

Ambili R; Janam, Prasanthila; Saneesh Babu, P S; Prasad, Manu; Vinod, D; Anil Kumar, P R; Kumary, T V; Asha Nair, S; Radhakrishna Pillai, M

2017-01-20

Andrographolide is a herbal extract traditionally used in South Asian countries for treating inflammatory diseases. To evaluate the efficacy of andrographolide in management of periodontal disease which is a highly prevalent oral disease. Periodontal ligament fibroblasts (PDLF) were cultured from healthy and diseased periodontium using explant culture methods. The safe dose of AG was determined using MTT assay. LPS (lipopolysaccharide) of the most important periodontopathogen, P gingivalis was used to activate NF-κB and STAT3 in PDLF. The efficacy of AG in inhibiting NF-κB and STAT3 was analyzed using immunofluorescence. Down regulation of expression of target genes of these transcription factors related to inflammation and bone resorption were analyzed using real time PCR. AG up to the concentration of 25μM was found to be safe as determined by MTT assay. Statistically significant activation of NF-κB and STAT3 in cultured PDLF was observed in diseased group compared to healthy controls before and after LPS challenge. 5μM AG pretreatment significantly inhibited activation of NF-κB and STAT3 and down regulated expression of inflammatory and bone resorptive genes in cultured PDLF. The findings of the present study propose the adjunctive use of a novel herbal drug andrographolide as a promising host modulation agent for periodontal therapy by inhibiting NF-κB and STAT3 activation and inhibition of inflammation and bone resorption related genes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mouse osteoblastic cell line (MC3T3-E1) expresses extracellular calcium (Ca2+o)-sensing receptor and its agonists stimulate chemotaxis and proliferation of MC3T3-E1 cells

NASA Technical Reports Server (NTRS)

Yamaguchi, T.; Chattopadhyay, N.; Kifor, O.; Butters, R. R. Jr; Sugimoto, T.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

1998-01-01

The calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays key roles in extracellular calcium ion (Ca2+o) homeostasis in parathyroid gland and kidney. Osteoblasts appear at sites of osteoclastic bone resorption during bone remodeling in the "reversal" phase following osteoclastic resorption and preceding bone formation. Bone resorption produces substantial local increases in Ca2+o that could provide a signal for osteoblasts in the vicinity, leading us to determine whether such osteoblasts express the CaR. In this study, we used the mouse osteoblastic, clonal cell line MC3T3-E1. Both immunocytochemistry and Western blot analysis, using an antiserum specific for the CaR, detected CaR protein in MC3T3-E1 cells. We also identified CaR transcripts in MC3T3-E1 cells by Northern analysis using a CaR-specific riboprobe and by reverse transcription-polymerase chain reaction with CaR-specific primers, followed by nucleotide sequencing of the amplified products. Exposure of MC3T3-E1 cells to high Ca2+o (up to 4.8 mM) or the polycationic CaR agonists, neomycin and gadolinium (Gd3+), stimulated both chemotaxis and DNA synthesis in MC3T3-E1 cells. Therefore, taken together, our data strongly suggest that the osteoblastic cell line MC3T3-E1 possesses both CaR protein and mRNA very similar, if not identical, to those in parathyroid and kidney. Furthermore, the CaR in these osteoblasts could play a key role in regulating bone turnover by stimulating the proliferation and migration of such cells to sites of bone resorption as a result of local release of Ca2+o.

Secondary osteoporosis.

PubMed

Gennari, C; Martini, G; Nuti, R

1998-06-01

Generalized osteoporosis currently represents a heterogeneous group of conditions with many different causes and pathogenetic mechanisms, that often are variably associated. The term "secondary" is applied to all patients with osteoporosis in whom the identifiable causal factors are other than menopause and aging. In this heterogeneous group of conditions, produced by many different pathogenetic mechanisms, a negative bone balance may be variably associated with low, normal or increased bone remodeling states. A consistent group of secondary osteoporosis is related to endocrinological or iatrogenic causes. Exogenous hypercortisolism may be considered an important risk factor for secondary osteoporosis in the community, and probably glucocorticoid-induced osteoporosis is the most common type of secondary osteoporosis. Supraphysiological doses of corticosteroids cause two abnormalities in bone metabolism: a relative increase in bone resorption, and a relative reduction in bone formation. Bone loss, mostly of trabecular bone, with its resultant fractures is the most incapacitating consequence of osteoporosis. The estimated incidence of fractures in patients prescribed corticosteroid is 30% to 50%. Osteoporosis is considered one of the potentially serious side effects of heparin therapy. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (over 4-5 months), and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts, and by enhancing the activity of individual osteoclasts. Hyperthyroidism is frequently associated with loss of trabecular and cortical bone; the enhanced bone turnover that develops in thyrotoxicosis is characterized by an increase in the number of osteoclasts and resorption sites, and an increase in the ratio of resorptive to formative bone surfaces, with the net result of bone loss. Despite these findings, the occurrence of pathological fractures in patients with hyperthyroidism is relatively low, and probably due to the fact that deficiencies in bone mass may be reversed by treatment of the thyroid disease. Most, but not all, studies on insulin-dependent diabetes mellitus (IDDM) report an association with osteopenia. In IDDM, the extent of bone loss is usually slight, which helps explain the discrepancy between the frequency of decreased bone mineral density, and the frequency of osteoporotic fractures in long-standing diabetes. Contradictory results have been obtained in non-insulin-dependent diabetes mellitus (NIDDM) patients. Increased rates of bone loss at the radius and lumbar spine were demonstrated either in patients with two-thirds gastric resection and Billroth II reconstruction, or in those with one-third resection and Billroth I anastomosis, and the metabolic bone disease following gastrectomy may consist also of osteomalacia or mixed pattern of osteoporosis-osteomalacia, with secondary hyperparathyroidism. Miscellaneous causes of secondary osteoporosis are also immobilization, pregnancy and lactation, and alcohol abuse.

The effect of two doses of dried plum on bone density and bone biomarkers in osteopenic postmenopausal women: a randomized, controlled trial.

PubMed

Hooshmand, S; Kern, M; Metti, D; Shamloufard, P; Chai, S C; Johnson, S A; Payton, M E; Arjmandi, B H

2016-07-01

Daily consumption of 50 g of dried plum (equivalent to 5-6 dried plums) for 6 months may be as effective as 100 g of dried plum in preventing bone loss in older, osteopenic postmenopausal women. To some extent, these results may be attributed to the inhibition of bone resorption with the concurrent maintenance of bone formation. The objective of our current study was to examine the possible dose-dependent effects of dried plum in preventing bone loss in older osteopenic postmenopausal women. Forty-eight osteopenic women (65-79 years old) were randomly assigned into one of three treatment groups for 6 months: (1) 50 g of dried plum; (2) 100 g of dried plum; and (3) control. Total body, hip, and lumbar bone mineral density (BMD) were evaluated at baseline and 6 months using dual-energy X-ray absorptiometry. Blood biomarkers including bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRAP-5b), high-sensitivity C-reactive protein (hs-CRP), insulin-like growth factor-1 (IGF-1), and sclerostin were measured at baseline, 3 months, and 6 months. Osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), calcium, phosphorous, and vitamin D were measured at baseline and 6 months. Both doses of dried plum were able to prevent the loss of total body BMD compared with that of the control group (P < 0.05). TRAP-5b, a marker of bone resorption, decreased at 3 months and this was sustained at 6 months in both 50 and 100 g dried plum groups (P < 0.01 and P < 0.04, respectively). Although there were no significant changes in BAP for either of the dried plum groups, the BAP/TRAP-5b ratio was significantly (P < 0.05) greater at 6 months in both dried plum groups whereas there were no changes in the control group. These results confirm the ability of dried plum to prevent the loss of total body BMD in older osteopenic postmenopausal women and suggest that a lower dose of dried plum (i.e., 50 g) may be as effective as 100 g of dried plum in preventing bone loss in older, osteopenic postmenopausal women. This may be due, in part, to the ability of dried plums to inhibit bone resorption. This clinical trial was registered at ClinicalTrials.gov: NCT02325895 .

Avascular Necrosis of the Femoral Head: Are Any Genes Involved?

PubMed Central

Pouya, Farzaneh; Kerachian, Mohammad Amin

2015-01-01

Avascular necrosis of the femoral head (ANFH) is a pathologic process that results from interruption of blood supply to the femur bone resulting in the death of bone cells and collapse of the femoral head. Nontraumatic ANFH continues to be a significant challenge to orthopedic surgeons. While the exact mechanisms remain elusive, many new insights have emerged from research in the last decade that has given us a clearer picture of the pathogenesis of nontraumatic ANFH. Progression to the end stage of ANFH appears to be related to five main mechanisms: hypercoagulable conditions, angiogenesis suppressions, hyperadipogenesis, heritable states, and switching the bone remodelling into bone resorption. Researchers have been examining the pathogenic mechanisms of ANFH but none of these theories have been firmly confirmed although some appear more plausible than the others. All of these factors can switch bone remodelling into bone resorption, which can further lead to ANFH progression ending up to femoral head collapse. PMID:26213697

Shell bone histology of the long-necked chelid Yaminuechelys (Testudines: Pleurodira) from the late Cretaceous—early Palaeocene of Patagonia with comments on the histogenesis of bone ornamentation

NASA Astrophysics Data System (ADS)

Jannello, Juan Marcos; Cerda, Ignacio A.; de la Fuente, Marcelo S.

2016-04-01

Yaminuechelys is a long-necked chelid turtle whose remains have been recovered from outcrops of the Santonian-Maastrichtian and Danian of South America. With the purpose of providing data about shell sculpturing origin and palaeoecology, the bone histology of several shell elements (including neural, costal, peripheral and plastral plates) of Yaminuechelys is described herein. Histological analysis reveals that Yaminuechelys shares with Chelidae the presence of interwoven structural fibre bundles in the external cortex, and parallel-fibred bone of the internal cortex. The presence of resorption lines in several samples indicates that the particular ornamentation of the external surfaces originated, at least in part, by focalized resorption and new bone deposition. This mechanism for ornamentation origin and maintenance is here described for the first time in a turtle. Compactness of the shell bones is consistent with an aquatic habitat, which supports previous hypothesis based on palaeoenvironmental and morphological data.

Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

NASA Technical Reports Server (NTRS)

Westerlind, K. C.; Wronski, T. J.; Ritman, E. L.; Luo, Z. P.; An, K. N.; Bell, N. H.; Turner, R. T.

1997-01-01

Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spaceflight and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is influenced by prevailing levels of mechanical strain.

Responsiveness of mouse calvaria to parathyroid hormone after explant cryopreservation: 45Ca release in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wezeman, F.H.; Dungan, D.D.

1986-08-01

Newborn mouse calvaria prelabeled with /sup 45/Ca and cryopreserved at -196 degrees C in serum-free medium containing dimethylsulfoxide were compared to unpreserved explants for response to parathyroid hormone during subsequent culture. After short-term cryopreservation followed by rapid thawing, the viable explants continued to release /sup 45/Ca to the culture medium but additions of parathyroid hormone to the medium did not cause increased bone resorption. The data suggest that cryopreservation and thawing impairs mechanisms responsible for parathyroid hormone action on bone cells.

Maintaining Restored Bone with Bisphoshonate in the Ovariectomized Rat Skeleton: Dynamic Histomorphometry of Changes in Bone Mass

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Tang, L.; Ke, H. Z.; Setterberg, R. B.; Kimmel, D. B.

1993-01-01

This experiment contains the crucial data for the Lose, Restore and Maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses ovariectomy (ox) to lose bone, an anabolic agent to restore bone mass and then switches to an anti-resorptive agent to maintain bone mass. We ox'd or sham-ox'd rats for 150 days (Loss Phase), treated them with 6 mg PGE2/kg/d for 75 days to restore lost cancellous bone mass (Restore Phase) and then stopped PGE2 treatment and began treatment with 1 or 5 micro-g/kg Risedronate, a bisphosphonate twice a week for 60 days (Maintain Phase). During the Loss Phase, cancellous bone volumes of the proximal tibial metaphysis (PTM) in the ox'd rat fell to 19% of initial controls. During the Restore Phase, the PTM bone volume in ox'd rats doubled. However, when PGE2 treatment was stopped, the PGE2-induced cancellous bone disappeared. In contrast, 5 micro-g of Risedronate inhibited the bone loss and maintained it at the PGE2 treatment level. The key dynamic histomorphometry value for the restore (R) and maintenance (M) phases was the ratio of bone formation to resorption rates. The ratio was elevated to 5.8 in the R phase and depressed to 0.4 for no and 1 micro-g Risedronate treated M phase and to a ratio of near unity of 1.1 for the 5 micro-g Risedronate treatment. These findings indicate that we were successful in maintaining the new PTM bone induced by PGE2 after discontinuing PGE2 by administering enough Risedronate, a resorption inhibitor. We concluded that the LRM concept is correct and such an approach should be considered when employing anabolic agents or growth factors in the treatment of osteoporosis. Continued use of an anabolic agent may not be appropriate because of cost, potential adverse side effects and a loss of efficacy.

ADRA2A is involved in neuro-endocrine regulation of bone resorption.

PubMed

Mlakar, Vid; Jurkovic Mlakar, Simona; Zupan, Janja; Komadina, Radko; Prezelj, Janez; Marc, Janja

2015-07-01

Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of α2A-AR in bone. The aim of this study was to investigate the presence of α2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate α2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in α2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A-AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A-AR mRNA level in human bone samples through the stability of mRNA. α2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that α2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in α2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Treatment of root fracture with accompanying resorption using cermet cement.

PubMed

Lui, J L

1992-02-01

A method of treating an apical root fracture with accompanying resorption at the junction of the fracture fragments using glass-cermet cement is described. Endodontically, the material had previously been used for repair of lateral resorptive root defects and retrograde root fillings. Complete bone regeneration was observed three years post-operatively following treatment of the root fracture in the conventional manner. The various advantages of glass-cermet cement as a root filling material used in the technique described are discussed.

The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs

PubMed Central

Sun, Yubo; Kiraly, Alex J.; Cox, Michael; Mauerhan, David R.; Hanley, Edward N.

2018-01-01

Phosphocitrate (PC) and its analogue, PC-β ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (P<0.05). These results indicated that articular chondrocytes in Hartley guinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program. PMID:29545850

Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn's disease: a prospective study.

PubMed

Ryan, B M; Russel, M G V M; Schurgers, L; Wichers, M; Sijbrandij, J; Stockbrugger, R W; Schoon, E

2004-10-15

Patients with Crohn's disease are at increased risk of osteoporosis. Disease activity and circulating proinflammatory cytokines are thought to play a role in this process. Infliximab, a chimaeric antitumour necrosis factor-alpha antibody is effective in the treatment of Crohn's disease. The aim of this study was to investigate the impact of treatment with infliximab on bone turnover in Crohn's disease patients. This was a prospective trial. Twenty-four patients with active Crohn's disease were treated with infliximab (5 mg/kg). Bone markers were assayed pre- and post-treatment. Bone formation was measured using serum bone-specific alkaline phosphatase and total osteocalcin and bone resorption using serum N-telopeptide cross-linked type 1 collagen. Infliximab therapy caused a significant increase in both markers of bone formation in patients with active Crohn's disease. No significant change in the bone resorption marker serum N-telopeptide cross-linked type 1 was found. Infliximab therapy had a significant beneficial effect on bone metabolism in patients with active Crohn's disease. These findings further support the theory that active ongoing inflammation and high levels of circulating cytokines play a pivotal role in the pathogenesis of bone loss in patients with Crohn's disease.

Effect of supplementary zinc on orthodontic tooth movement in a rat model

PubMed Central

Sadegh, Ahmad Akhoundi Mohammad; Rezvaneh, Ghazanfari; Shahroo, Etemad-Moghadam; Mojgan, Alaeddini; Azam, Khorshidian; Shahram, Rabbani; Reza, Shamshiri Ahmad; Nafiseh, Momeni

2016-01-01

ABSTRACT Introduction: Osteoclasts and osteoblasts are responsible for regulating bone homeostasis during which the trace element zinc has been shown to exert a cumulative effect on bone mass by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. Objective: The aim of the present study was to investigate the effects of zinc (Zn) on orthodontic tooth movement (OTM) in a rat model. Material and Methods: A total of 44 male Wistar rats were divided into four groups of 11 animals each and received 0, 1.5, 20 and 50 ppm Zn in distilled water for 60 days. In the last 21 days of the study, nickel-titanium closed coil springs were ligated between maxillary right incisors and first molars of all rats, and tooth movement was measured at the end of this period. Histological analysis of hematoxylin/eosin slides was performed to assess root resorption lacunae, osteoclast number and periodontal ligament (PDL) width. Results: Mean OTM was calculated as 51.8, 49.1, 35.5 and 45 µm in the 0, 1.5, 20 and 50 ppm zinc-receiving groups, respectively. There were no significant differences in neither OTM nor histological parameters among the study groups (p > 0.05). Conclusion: According to the results obtained in the current investigation, increase in supplementary zinc up to 50 ppm does not affect the rate of OTM neither bone and root resorption in rats. PMID:27275614

A theoretical framework for strain-related trabecular bone maintenance and adaptation.

PubMed

Ruimerman, R; Hilbers, P; van Rietbergen, B; Huiskes, R

2005-04-01

It is assumed that density and morphology of trabecular bone is partially controlled by mechanical forces. How these effects are expressed in the local metabolic functions of osteoclast resorption and osteoblast formation is not known. In order to investigate possible mechano-biological pathways for these mechanisms we have proposed a mathematical theory (Nature 405 (2000) 704). This theory is based on hypothetical osteocyte stimulation of osteoblast bone formation, as an effect of elevated strain in the bone matrix, and a role for microcracks and disuse in promoting osteoclast resorption. Applied in a 2-D Finite Element Analysis model, the theory explained the formation of trabecular patterns. In this article we present a 3-D FEA model based on the same theory and investigated its potential morphological predictability of metabolic reactions to mechanical loads. The computations simulated the development of trabecular morphological details during growth, relative to measurements in growing pigs, reasonably realistic. They confirmed that the proposed mechanisms also inherently lead to optimal stress transfer. Alternative loading directions produced new trabecular orientations. Reduction of load reduced trabecular thickness, connectivity and mass in the simulation, as is seen in disuse osteoporosis. Simulating the effects of estrogen deficiency through increased osteoclast resorption frequencies produced osteoporotic morphologies as well, as seen in post-menopausal osteoporosis. We conclude that the theory provides a suitable computational framework to investigate hypothetical relationships between bone loading and metabolic expressions.

Differentiation of osteoblast and osteoclast precursors on pure and silicon-substituted synthesized hydroxyapatites.

PubMed

Lehmann, Giorgia; Cacciotti, Ilaria; Palmero, Paola; Montanaro, Laura; Bianco, Alessandra; Campagnolo, Luisa; Camaioni, Antonella

2012-10-01

Calcium phosphate-based materials should show excellent bone-bonding and cell-mediated resorption characteristics at the same time, in order to be employed for bone replacement. In this perspective, pure (HAp) and silicon-substituted hydroxyapatite (Si-HAp, 1.4% wt) porous cylinders were prepared starting from synthesized powders and polyethylene spheres used as porogens, and investigated as supports for osteoblast and osteoclast progenitor differentiation. A systematic and detailed biological characterization is reported, in terms of cell adhesion, viability, proliferation, differentiation and bioresorption, aimed at proposing a complete and reliable picture of bone cell in vitro behavior, comprehensive of both the osteogenesis and the bone resorption processes. In order to achieve this purpose, cytocompatibility, differentiation and gene expression by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) were carried out using parietal bone-derived pre-osteoblasts obtained from neonatal mice and the bioresorption capability was assessed by seeding human peripheral blood monocytes, as osteoclast precursors. It resulted that both pure and Si-substituted HAps were able to promote differentiation of precursor cells in mature osteoblasts and osteoclasts. In particular, the Si-HAps enhanced the pre-osteoblast proliferation and showed higher osteoclast-mediated bioresorption capability, as supported by the presence of larger and more numerous resorption lacunae, whereas HAps promoted a more robust cell differentiation in terms of both osteocalcin gene expression by qRT-PCR and cell morphological evaluation by SEM analysis.

Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts.

PubMed

Kittaka, Mizuho; Mayahara, Kotoe; Mukai, Tomoyuki; Yoshimoto, Tetsuya; Yoshitaka, Teruhito; Gorski, Jeffrey P; Ueki, Yasuyoshi

2018-01-01

Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2 KI/KI ) with a homozygous gain-of-function mutation in the SH3-domain binding protein 2 (SH3BP2) was shown to develop auto-inflammatory joint destruction. Here, we demonstrate that Sh3bp2 KI/KI mice also deficient in the FBJ osteosarcoma oncogene (c-Fos) still exhibit noticeable bone erosion at the distal tibia even in the absence of osteoclasts at 12 weeks old. Levels of serum collagen I C-terminal telopeptide (ICTP), a marker of bone resorption generated by matrix metalloproteinases (MMPs), were elevated, whereas levels of serum cross-linked C-telopeptide (CTX), another resorption marker produced by cathepsin K, were not increased. Collagenolytic MMP levels were increased in the inflamed joints of the Sh3bp2 KI/KI mice deficient in c-Fos. Resorption pits contained a large number of F4/80+ macrophages and genetic depletion of macrophages rescued these erosive changes. Importantly, administration of NSC405020, an MMP14 inhibitor targeted to the hemopexin (PEX) domain, suppressed bone erosion in c-Fos-deficient Sh3bp2 KI/KI mice. After activation of the NF-κB pathway, macrophage colony-stimulating factor (M-CSF)-dependent macrophages from c-Fos-deficient Sh3bp2 KI/KI mice expressed increased amounts of MMP14 compared with wild-type macrophages. Interestingly, receptor activator of NF-κB ligand (RANKL)-deficient Sh3bp2 KI/KI mice failed to show notable bone erosion, whereas c-Fos deletion did restore bone erosion to the RANKL-deficient Sh3bp2 KI/KI mice, suggesting that osteolytic transformation of macrophages requires both loss-of-function of c-Fos and gain-of-function of SH3BP2 in this model. These data provide the first genetic evidence that cells other than osteoclasts can cause focal bone destruction in inflammatory bone disease and suggest that MMP14 is a key mediator conferring pathological bone-resorbing capacity on c-Fos-deficient Sh3bp2 KI/KI macrophages. In summary, the paradigm that osteoclasts are the exclusive cells executing inflammatory bone destruction may need to be reevaluated based on our findings with c-Fos-deficient cherubism mice lacking osteoclasts. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Bone Loss from High Repetitive High Force Loading is Prevented by Ibuprofen Treatment

PubMed Central

Jain, Nisha X.; Barr-Gillespie, Ann E.; Clark, Brian D.; Kietrys, David M.; Wade, Christine K.; Litvin, Judith; Popoff, Steven N.; Barbe, Mary F.

2014-01-01

We examined roles of loading and inflammation on forearm bones in a rat model of upper extremity overuse. Trabecular structure in distal radius and ulna was examined in three groups of young adult rats: 1) 5% food-restricted that underwent an initial training period of 10 min/day for 5 weeks to learn the repetitive task (TRHF); 2) rats that underwent the same training before performing a high repetition high force task, 2 hours/day for 12 weeks (HRHF); and 3) food-restricted only (FRC). Subsets were treated with oral ibuprofen (IBU). TRHF rats had increased trabecular bone volume and numbers, osteoblasts, and serum osteocalcin, indicative of bone adaptation. HRHF rats had constant muscle pulling forces, showed limited signs of bone adaptation, but many signs of bone resorption, including decreased trabecular bone volume and bone mineral density, increased osteoclasts and bone inflammatory cytokines, and reduced median nerve conduction velocity (15%). HRHF+IBU rats showed no trabecular resorptive changes, no increased osteoclasts or bone inflammatory cytokines, no nerve inflammation, preserved nerve conduction, and increased muscle voluntary pulling forces. Ibuprofen treatment preserved trabecular bone quality by reducing osteoclasts and bone inflammatory cytokines, and improving muscle pulling forces on bones as a result of reduced nerve inflammation. PMID:24583543

Does methamphetamine affect bone metabolism?

PubMed

Tomita, Masafumi; Katsuyama, Hironobu; Watanabe, Yoko; Okuyama, Toshiko; Fushimi, Shigeko; Ishikawa, Takaki; Nata, Masayuki; Miyamoto, Osamu

2014-05-07

There is a close relationship between the central nervous system activity and bone metabolism. Therefore, methamphetamine (METH), which stimulates the central nervous system, is expected to affect bone turnover. The aim of this study was to investigate the role of METH in bone metabolism. Mice were divided into 3 groups, the control group receiving saline injections, and the 5 and 10mg/kg METH groups (n=6 in each group). All groups received an injection of saline or METH every other day for 8 weeks. Bone mineral density (BMD) was assessed by X-ray computed tomography. We examined biochemical markers and histomorphometric changes in the second cancellous bone of the left femoral distal end. The animals that were administered 5mg/kg METH showed an increased locomotor activity, whereas those receiving 10mg/kg displayed an abnormal and stereotyped behavior. Serum calcium and phosphorus concentrations were normal compared to the controls, whereas the serum protein concentration was lower in the METH groups. BMD was unchanged in all groups. Bone formation markers such as alkaline phosphatase and osteocalcin significantly increased in the 5mg/kg METH group, but not in the 10mg/kg METH group. In contrast, bone resorption markers such as C-terminal telopeptides of type I collagen and tartrate-resistant acid phosphatase 5b did not change in any of the METH groups. Histomorphometric analyses were consistent with the biochemical markers data. A significant increase in osteoblasts, especially in type III osteoblasts, was observed in the 5mg/kg METH group, whereas other parameters of bone resorption and mineralization remained unchanged. These results indicate that bone remodeling in this group was unbalanced. In contrast, in the 10mg/kg METH group, some parameters of bone formation were significantly or slightly decreased, suggesting a low turnover metabolism. Taken together, our results suggest that METH had distinct dose-dependent effects on bone turnover and that METH might induce adverse effects, leading to osteoporosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo.

PubMed

Fujii, Toshiaki; Ishikawa, Mizuho; Kubo, Akiko; Tanaka, Yoshitaka

2015-12-01

SI-591[N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-2-furancarboxamide] is an orally bioavailable compound that was synthesized as one of several unique peptidomimetic compounds without a basic group. This compound was found to have the ability to inhibit cathepsin K, a lysosomal cysteine protease. Cathepsin K is known to be expressed in osteoclasts and involved in bone loss processes. In this study, SI-591 was shown to inhibit the activity of various purified cathepsin molecules at nanomolar concentrations but had high selectivity for cathepsin K over other subtypes including B and L. SI-591 also decreased the level of CTX-I, a bone resorption marker, which was released from osteoclasts in vitro in a dose-dependent manner. The mobilization of calcium from the bones to the blood stream is known to increase in rats fed with a low calcium diet; SI-591 inhibited this increase in serum calcium level at an oral dose of 3mg/kg. Furthermore, SI-591 significantly decreased the level of CTX-I and DPD, bone resorption markers, at oral doses of 10mg/kg or less in ovariectomized rats, while it did not affect the level of BGP, a bone formation marker. In addition, SI-591 prevented bone mineral density loss in the lumber vertebrae and femurs in ovariectomized rats. These results suggest that SI-591 inhibits bone resorption without affecting osteoblast maturation. Therefore, SI-591, a novel cathepsin K inhibitor, could be a promising agent for the treatment of postmenopausal osteoporosis. Copyright © 2015. Published by Elsevier Inc.

Bone Resorption and Environmental Exposure to Cadmium in Women: A Population Study

PubMed Central

Schutte, Rudolph; Nawrot, Tim S.; Richart, Tom; Thijs, Lutgarde; Vanderschueren, Dirk; Kuznetsova, Tatiana; Van Hecke, Etienne; Roels, Harry A.; Staessen, Jan A.

2008-01-01

Background Environmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction. Objective We sought evidence for a direct osteotoxic effect of cadmium in women. Methods We randomly recruited 294 women (mean age, 49.2 years) from a Flemish population with environmental cadmium exposure. We measured 24-hr urinary cadmium and blood cadmium as indexes of lifetime and recent exposure, respectively. We assessed the multivariate-adjusted association of exposure with specific markers of bone resorption, urinary hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), as well as with calcium excretion, various calciotropic hormones, and forearm bone density. Results In all women, the effect sizes associated with a doubling of lifetime exposure were 8.4% (p = 0.009) for HP, 6.9% (p = 0.10) for LP, 0.77 mmol/day (p = 0.003) for urinary calcium, –0.009 g/cm2 (p = 0.055) for proximal forearm bone density, and –16.8% (p = 0.065) for serum parathyroid hormone. In 144 postmenopausal women, the corresponding effect sizes were –0.01223 g/cm2 (p = 0.008) for distal forearm bone density, 4.7% (p = 0.064) for serum calcitonin, and 10.2% for bone-specific alkaline phosphatase. In all women, the effect sizes associated with a doubling of recent exposure were 7.2% (p = 0.001) for urinary HP, 7.2% (p = 0.021) for urinary LP, –9.0% (p = 0.097) for serum parathyroid hormone, and 5.5% (p = 0.008) for serum calcitonin. Only one woman had renal tubular dysfunction (urinary retinol-binding protein > 338 μg/day). Conclusions In the absence of renal tubular dysfunction, environmental exposure to cadmium increases bone resorption in women, suggesting a direct osteotoxic effect with increased calciuria and reactive changes in calciotropic hormones. PMID:18560534

Systemic Treatment with Strontium Ranelate Accelerates the Filling of a Bone Defect and Improves the Material Level Properties of the Healing Bone

PubMed Central

Zacchetti, Giovanna; Rizzoli, René

2014-01-01

Rapid bone defect filling with normal bone is a challenge in orthopaedics and dentistry. Strontium ranelate (SrRan) has been shown to in vitro decrease bone resorption and increase bone formation, and represents a potential agent with the capacity to accelerate bone defect filling. In this study, bone tibial defects of 2.5 mm in diameter were created in 6-month-old female rats orally fed SrRan (625 mg/kg/d; 5/7 days) or vehicle for 4, 8, or 12 weeks (10 rats per group per time point) from the time of surgery. Tibias were removed. Micro-architecture was determined by micro-computed tomography (µCT) and material level properties by nanoindentation analysis. µCT analysis showed that SrRan administration significantly improved microarchitecture of trabecular bone growing into the defect after 8 and 12 weeks of treatment compared to vehicle. SrRan treatment also accelerated the growth of cortical bone over the defect, but with different kinetics compared to trabecular bone, as the effects were already significant after 4 weeks. Nanoindentation analysis demonstrated that SrRan treatment significantly increased material level properties of both trabecular bone and cortical bone filling the defect compared to vehicle. SrRan accelerates the filling of bone defect by improving cortical and trabecular bone microarchitecture both quantitatively and qualitatively. PMID:25243150

The clinical utility of bone marker measurements in osteoporosis

PubMed Central

2013-01-01

Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3–6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases. PMID:23984630

Alveolar ridge reduction after tooth extraction in adolescents: an animal study

PubMed Central

Sun, Zongyang; Herring, Susan W.; Tee, Boon Ching; Gales, Jordan

2013-01-01

Objective The mechanism for tooth extraction induced residual alveolar ridge reduction (RRR) during adolescence is poorly understood. This study investigated the alveolar bone morphology, growth, resorption and functional loading at normal and extraction sites using an adolescent pig model. Design Sixteen 3-month-old pigs were divided into two groups – immediate post-extraction (IE) and 6-week post-extraction (SE). The IE group received an extraction of one deciduous mandibular molar, immediately followed by a final experiment to record masseter muscle EMGs and strains from the buccal surface of the extraction and contralateral non-extraction sites during function (mastication). The SE group was given the same tooth extraction, then kept for 6 weeks before the same final functional recording as the IE group. Both groups also received baseline (pre-extraction) EMGs and fluorescent vital stains 10 and 3 days before the final functional recording. Immediately after the final functional recording, animals were euthanized and alveolar bone specimens from extraction and contralateral non-extraction sites were collected and used to analyze alveolar bone morphology, apposition and resorption based on fluorescent and hematoxylin and eosin stained histological sections. Results At control sites (IE-extraction, IE-non-extraction and SE-non-extraction), the alveolar ridges grew gingivally and buccally. Bone formation characterized the buccal surface and lingual bundle bone, whereas resorption characterized the lingual surface and buccal bundle bone. The SE-extraction sites showed three major alterations: convergence of the buccal and lingual gingival crests, loss of apposition on the lingual bundle bone, and decelerated growth at the entire buccal surface. These alterations likely resulted from redirected crestal growth as part of the socket healing process, loss of tongue pressure to the lingual side of the teeth which normally provides mechanical stimulation for dental arch expansion, and masticatory underloading during the initial post-extraction period, respectively. Conclusions These data indicate that the initial phase of RRR in adolescents is a product of modified growth, not resorption, possibly because of decreased mechanical stimulation at the extraction site. PMID:23380583

Adaptation of Diaphyseal Structure with Aging and Increased Mechanical Usage in the Adult Rat: A Histomorphometrical and Biomechanical Study

NASA Technical Reports Server (NTRS)

Jee, Webster S. S.; Li, Xiao Jian; Schaffler, Mitchell B.

1991-01-01

The experimental increase in mechanical usage or overloading of the left hindlimb was produced by immobilization of the contralateral hindlimb. The right hindlimb was placed in a flexed position against the body and was immobilized using an elastic bandage. Some control animals were sacrificed initially at time zero and increased mechanical usage and age-matched control animals were sacrificed after 2, 10, 18, and 26 weeks of treatment. All animals received double bone fluorochrome labeling prior to sacrifice. Cortical bone histomorphometry and cross-sectional moments of inertia were determined. Marrow cavity enlargement and total cross-sectional area expansion represented the age-related cortical bone changes. Increased mechanical usage enhanced periosteal bone modeling in the formation mode and dampened endocortical bone remodeling and bone modeling in the resorption mode (resorption drift) to create a slight positive bone balance. These observations are in general agreement with Frost's postulate for mechanical effects on bone modeling and remodeling. The maximum moment of inertia did not change significantly in either control or overloaded tibial shafts. The minimum and polar moment of inertias in overloaded bones increases over those of controls at 18 and 26 weeks of the experiment.