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Sample records for accelerated bone resorption

  1. [Pharmacology of bone resorption inhibitor].

    PubMed

    Menuki, Kunitaka; Sakai, Akinori

    2015-10-01

    Currently, bone resorption inhibitor is mainly used for osteoporosis. A number of these agents have been developed. These pharmacological action are various. Bisphosphonate inhibit functions of the osteoclasts by inducing apoptosis. On the one hand, RANK-ligand inhibitor and selective estrogen receptor modulator inhibit formation of osteoclasts. It is important to understand these pharmacological action for the selection of the appropriate medicine. PMID:26529923

  2. Bone resorption, metastasis, and diphosphonates

    SciTech Connect

    Garattini, S.

    1985-01-01

    This book contains 17 selections. Some of the titles are: Radiotherapy of Bone Lesions; Methodological Problems; Treatment of Bone Metastasis with Antiresorptive Drugs; Control of Bone Cancer Pain; and Chemotherapy of Bone Metastases.

  3. Bone resorption in chronic otitis media.

    PubMed

    Maynard, J; Bumsted, R M; Huang, C C; Abramson, M

    1979-01-01

    Bone resorption is an important aspect of chronic otitis media contributing to many complications of this disease. It is postulated that the mechanism of this localized destructive process is chemical in origin. Collagenase, lysosomal enzymes, prostaglandins, and other cell mediators are thought to induce bone resorption, but the site of action and cellular origin of these substances remains unclear. In this report, we demonstrate the location and attempt to delineate the cellular origin of two enzymes, collagenase and the lysosomal enzyme acid phosphatase in guinea pig temporal bones and human ossicles from ears containing chronic otitis media. Tissue localization of these enzymes identifies sites of active bone resorption and demonstrates the cells initiating this process. Using immunohistochemical and immunocytochemical techniques, collagenase was seen surrounding mononuclear inflammatory cells of granulation tissue at bone resorbing margins and at the periphery of osteocyte lacunae adjacent to resorbing areas. Electron microscopic data suggests that collagenase is an extracellular enzyme foun at the periphery of osteocytes. In addition, abundant acid phosphatase activity was seen in the same cells that exhibited collagenase staining, lending credence to the destructive function of these cells. The chronic inflammatory reaction found in chronic otitis media appears to activate bone destruction through the dynamic activity of mononuclear inflammatory cells and stimulates bone cells to increase their destructive biochemical functions.

  4. 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.

  5. Peptidomimetic antagonists of alphavbeta3 inhibit bone resorption by inhibiting osteoclast bone resorptive activity, not osteoclast adhesion to bone.

    PubMed

    Carron, C P; Meyer, D M; Engleman, V W; Rico, J G; Ruminski, P G; Ornberg, R L; Westlin, W F; Nickols, G A

    2000-06-01

    Osteoclasts are actively motile on bone surfaces and undergo alternating cycles of migration and resorption. Osteoclast interaction with the extracellular matrix plays a key role in the osteoclast resorptive process and a substantial body of evidence suggests that integrin receptors are important in osteoclast function. These integrin receptors bind to the Arg-Gly-Asp (RGD) sequence found in a variety of extracellular matrix proteins and it is well established that the interaction of osteoclast alpha v beta 3 integrin with the RGD motif within bone matrix proteins is important in osteoclast-mediated bone resorption. In this study, we characterized the effects of two synthetic peptidomimetic antagonists of alpha v beta 3, SC-56631 and SC-65811, on rabbit osteoclast adhesion to purified matrix proteins and bone, and on bone resorption in vitro. SC-56631 and SC-65811 are potent inhibitors of vitronectin binding to purified alpha v beta 3. Both SC-56631 and SC-65811 inhibited osteoclast adhesion to osteopontin- and vitronectin-coated surfaces and time-lapse video microscopy showed that osteoclasts rapidly retract from osteopontin-coated surfaces when exposed to SC-56631 and SC-65811. SC-56631 and SC-65811 blocked osteoclast-mediated bone resorption in a dose-responsive manner. Further analysis showed that SC-65811 and SC-56631 reduced the number of resorption pits produced per osteoclast and the average pit size. SC-65811 was a more potent inhibitor of bone resorption and the combination of reduced pit number and size led to a 90% inhibition of bone resorption. Surprisingly, however, osteoclasts treated with SC-65811, SC-56631 or the disintegrin echistatin, at concentrations that inhibit bone resorption did not inhibit osteoclast adhesion to bone. These results suggest that alphavbeta3 antagonists inhibited bone resorption by decreasing osteoclast bone resorptive activity or efficiency but not by inhibiting osteoclast adhesion to bone per se.

  6. The effects of gallium nitrate on bone resorption.

    PubMed

    Bockman, Richard

    2003-04-01

    Gallium nitrate has been shown to be an effective treatment for patients with cancer-related hypercalcemia. Clinical studies have also suggested the drug may have considerably broader use in other diseases associated with accelerated bone loss including multiple myeloma, bone metastases, Paget's disease, and osteoporosis. The actions of gallium nitrate on bone are quite distinct from those of bisphosphonates. Preclinical studies show that gallium preferentially accumulates in trace amounts in metabolically active regions of bone. When present, gallium favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. The drug also acts on the cellular components of bone to reduce bone resorption by decreasing acid secretion by osteoclasts. This effect appears to be mediated by inhibition of the ATPase-dependent proton pump of the osteoclast's ruffled membrane. Gallium does not inhibit the development or recruitment of osteoclasts to bone tissue, unlike many bisphosphonates that may induce osteoclast apoptosis. Together, these pharmacologic actions may yield a skeletal system with increased calcium and phosphate content and improved biomechanical strength. Gallium nitrate has potent antiresorptive effects on bone that can be achieved at considerably lower doses than are currently used for cancer-related hypercalcemia. Parenteral and oral formulations of gallium appear to have high activity in bone resorptive disorders, and thus development should be vigorously pursued in these diseases. PMID:12776254

  7. Mechanisms of Bone Resorption in Periodontitis

    PubMed Central

    Hienz, Stefan A.; Paliwal, Sweta

    2015-01-01

    Alveolar bone loss is a hallmark of periodontitis progression and its prevention is a key clinical challenge in periodontal disease treatment. Bone destruction is mediated by the host immune and inflammatory response to the microbial challenge. However, the mechanisms by which the local immune response against periodontopathic bacteria disturbs the homeostatic balance of bone formation and resorption in favour of bone loss remain to be established. The osteoclast, the principal bone resorptive cell, differentiates from monocyte/macrophage precursors under the regulation of the critical cytokines macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. TNF-α, IL-1, and PGE2 also promote osteoclast activity, particularly in states of inflammatory osteolysis such as those found in periodontitis. The pathogenic processes of destructive inflammatory periodontal diseases are instigated by subgingival plaque microflora and factors such as lipopolysaccharides derived from specific pathogens. These are propagated by host inflammatory and immune cell influences, and the activation of T and B cells initiates the adaptive immune response via regulation of the Th1-Th2-Th17 regulatory axis. In summary, Th1-type T lymphocytes, B cell macrophages, and neutrophils promote bone loss through upregulated production of proinflammatory mediators and activation of the RANK-L expression pathways. PMID:26065002

  8. Overexpression of cathepsin K accelerates the resorption cycle and osteoblast differentiation in vitro.

    PubMed

    Morko, Jukka; Kiviranta, Riku; Mulari, Mika T K; Ivaska, Kaisa K; Väänänen, H Kalervo; Vuorio, Eero; Laitala-Leinonen, Tiina

    2009-04-01

    Bone resorption is a multistep process including osteoclast attachment, cytoskeletal reorganization, formation of four distinct plasma membrane domains, and matrix demineralization and degradation followed by cell detachment. The present study describes the intracellular mechanisms by which overexpression of cathepsin K in osteoclasts results in enhanced bone resorption. Osteoclasts and bone marrow-derived osteoclast and osteoblast precursors were isolated from mice homozygous (UTU17(+/+)) and negative for the transgene locus. Cells cultured on bovine cortical bone slices were analyzed by fluorescence and confocal laser scanning microscopy, and bone resorption was studied by measurements of biochemical resorption markers, morphometry, and FESEM. Excessive cathepsin K protein and enzyme activity were microscopically observed in various intracellular vesicles and in the resorption lacunae of cathepsin K-overexpressing osteoclasts. The number of cathepsin K-containing vesicles in UTU17(+/+) osteoclasts was highly increased, and co-localization with markers for the biosynthetic and transcytotic pathways was observed throughout the cytoplasm. As a functional consequence of cathepsin K overexpression, biochemical resorption markers were increased in culture media of UTU17(+/+) osteoclasts. Detailed morphometrical analysis of the erosion in bone slices indicated that the increased biosynthesis of cathepsin K was sufficient to accelerate the osteoclastic bone resorption cycle. Cathepsin K overexpression also enhanced osteogenesis and induced the formation of exceptionally small, actively resorbing osteoclasts from their bone marrow precursors in vitro. The present study describes for the first time how enhancement in one phase of the osteoclastic resorption cycle also stimulates its other phases and further demonstrate that tight control and temporal coupling of mesenchymal and hematopoietic bone cells in this multistep process.

  9. Gallium a unique anti-resorptive agent in bone: Preclinical studies on its mechanisms of action

    SciTech Connect

    Bockman, R.; Adelman, R.; Donnelly, R.; Brody, L.; Warrell, R. ); Jones, K.W. )

    1990-01-01

    The discovery of gallium as a new and unique agent for the treatment of metabolic bone disorders was in part fortuitous. Gallium is an exciting new therapeutic agent for the treatment of pathologic states characterized by accelerated bone resorption. Compared to other therapeutic metal compounds containing platinum or germanium, gallium affects its antiresorptive action without any evidence of a cytotoxic effect on bone cells. Gallium is unique amongst all therapeutically available antiresorptive agents in that it favors bone formation. 18 refs., 1 fig.

  10. Bone resorption: an actor of dental and periodontal development?

    PubMed Central

    Gama, Andrea; Navet, Benjamin; Vargas, Jorge William; Castaneda, Beatriz; Lézot, Frédéric

    2015-01-01

    Dental and periodontal tissue development is a complex process involving various cell-types. A finely orchestrated network of communications between these cells is implicated. During early development, communications between cells from the oral epithelium and the underlying mesenchyme govern the dental morphogenesis with successive bud, cap and bell stages. Later, interactions between epithelial and mesenchymal cells occur during dental root elongation. Root elongation and tooth eruption require resorption of surrounding alveolar bone to occur. For years, it was postulated that signaling molecules secreted by dental and periodontal cells control bone resorbing osteoclast precursor recruitment and differentiation. Reverse signaling originating from bone cells (osteoclasts and osteoblasts) toward dental cells was not suspected. Dental defects reported in osteopetrosis were associated with mechanical stress secondary to defective bone resorption. In the last decade, consequences of bone resorption over-activation on dental and periodontal tissue formation have been analyzed with transgenic animals (RANKTg and Opg−∕− mice). Results suggest the existence of signals originating from osteoclasts toward dental and periodontal cells. Meanwhile, experiments consisting in transitory inhibition of bone resorption during root elongation, achieved with bone resorption inhibitors having different mechanisms of action (bisphosphonates and RANKL blocking antibodies), have evidenced dental and periodontal defects that support the presence of signals originating bone cells toward dental cells. The aim of the present manuscript is to present the data we have collected in the last years that support the hypothesis of a role of bone resorption in dental and periodontal development. PMID:26594180

  11. Osteoclast-independent bone resorption by fibroblast-like cells

    PubMed Central

    Pap, Thomas; Claus, Anja; Ohtsu, Susumu; Hummel, Klaus M; Schwartz, Peter; Drynda, Susanne; Pap, Géza; Machner, Andreas; Stein, Bernhard; George, Michael; Gay, Renate E; Neumann, Wolfram; Gay, Steffen; Aicher, Wilhelm K

    2003-01-01

    To date, mesenchymal cells have only been associated with bone resorption indirectly, and it has been hypothesized that the degradation of bone is associated exclusively with specific functions of osteoclasts. Here we show, in aseptic prosthesis loosening, that aggressive fibroblasts at the bone surface actively contribute to bone resorption and that this is independent of osteoclasts. In two separate models (a severe combined immunodeficient mouse coimplantation model and a dentin pit formation assay), these cells produce signs of bone resorption that are similar to those in early osteoclastic resorption. In an animal model of aseptic prosthesis loosening (i.e. intracranially self-stimulated rats), it is shown that these fibroblasts acquire their ability to degrade bone early on in their differentiation. Upon stimulation, such fibroblasts readily release acidic components that lower the pH of their pericellular milieu. Through the use of specific inhibitors, pericellular acidification is shown to involve the action of vacuolar type ATPases. Although fibroblasts, as mesenchymal derived cells, are thought to be incapable of resorbing bone, the present study provides the first evidence to challenge this widely held belief. It is demonstrated that fibroblast-like cells, under pathological conditions, may not only enhance but also actively contribute to bone resorption. These cells should therefore be considered novel therapeutic targets in the treatment of bone destructive disorders. PMID:12723988

  12. Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells.

    PubMed

    Li, Ziqing; Li, Chaohong; Zhou, Yuhuan; Chen, Weishen; Luo, Guotian; Zhang, Ziji; Wang, Haixing; Zhang, Yangchun; Xu, Dongliang; Sheng, Puyi

    2016-03-01

    Advanced glycation end products (AGEs) disturb bone remodeling during aging, and this process is accelerated in diabetes. However, their role in modulation of osteoclast-induced bone resorption is controversial, with some studies indicating that AGEs enhance bone resorption and others showing the opposite effect. We determined whether AGEs present at different stages of osteoclast differentiation affect bone resorption differently. Based on increased levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK), we identified day 4 of induction as the dividing time of cell fusion stage and mature stage in RAW264.7 cell-derived osteoclast-like cells (OCLs). AGE-modified BSA (50-400 μg/ml) or control BSA (100 μg/ml) was then added at the beginning of each stage. Results showed that the presence of AGEs at the cell fusion stage reduced pit numbers, resorption area, and CTSK expression. Moreover, expression of receptor activator of nuclear factor-κB (RANK) as well as the number of TRAP-positive cells, nuclei per OCL, actin rings, and podosomes also decreased. However, the presence of AGEs at the mature stage enlarged the resorption area markedly and increased pit numbers slightly. Intriguingly, only the number of nuclei per OCL and podosomes increased. These data indicate that AGEs biphasically modulate bone resorption activity of OCLs in a differentiation stage-dependent manner. AGEs at the cell fusion stage reduce bone resorption dramatically, mainly via suppression of RANK expression in osteoclast precursors, whereas AGEs at the mature stage enhance bone resorption slightly, most likely by increasing the number of podosomes in mature OCLs.

  13. Hypoxic regulation of osteoclast differentiation and bone resorption activity

    PubMed Central

    Knowles, Helen J

    2015-01-01

    Bone integrity is maintained throughout life via the homeostatic actions of bone cells, namely, osteoclasts, which resorb bone, and osteoblasts, which produce bone. Disruption of this balance in favor of osteoclast activation results in pathological bone loss, which occurs in conditions including osteoporosis, rheumatoid arthritis, primary bone cancer, and cancer metastasis to bone. Hypoxia also plays a major role in these conditions, where it is associated with disease progression and poor prognosis. In recent years, considerable interest has arisen in the mechanisms whereby hypoxia and the hypoxia-inducible transcription factors, HIF-1α and HIF-2α, affect bone remodeling and bone pathologies. This review summarizes the current evidence for hypoxia-mediated regulation of osteoclast differentiation and bone resorption activity. Role(s) of HIF and HIF target genes in the formation of multinucleated osteoclasts from cells of the monocyte–macrophage lineage and in the activation of bone resorption by mature osteoclasts will be discussed. Specific attention will be paid to hypoxic metabolism and generation of ATP by osteoclasts. Hypoxia-driven increases in both glycolytic flux and mitochondrial metabolic activity, along with consequent generation of mitochondrial reactive oxygen species, have been found to be essential for osteoclast formation and resorption activity. Finally, evidence for the use of HIF inhibitors as potential therapeutic agents targeting bone resorption in osteolytic disease will be discussed. PMID:27774484

  14. Bone remodeling and hydroxyapatite resorption in coated primary hip prostheses.

    PubMed

    Tonino, Alphons J; van der Wal, Bart C H; Heyligers, Ide C; Grimm, Bernd

    2009-02-01

    Hydroxyapatite coatings for THA promote bone ongrowth, but bone and coating are exposed to stress shielding-driven osteoclastic resorption. We asked: (1) if the resorption of hydroxyapatite coating and bone ongrowth correlated with demographics; (2) if the resorption related to the stem level; and (3) what happens to the implant-bone interface when all hydroxyapatite coating is resorbed? We recovered 13 femoral components from cadaveric specimens 3.3 to 11.2 years after uneventful primary THA. Three cross sections (proximal, medial, distal) of the hydroxyapatite-coated proximal implant sleeve were analyzed by measuring the percentage of residual hydroxyapatite and bone ongrowth on the implant perimeter. Hydroxyapatite resorption was independent of patient age but increased with time in vivo and mostly was gone after 8 years. Bone ongrowth was independent of time in vivo but decreased with aging patients. Only in the most proximal section did less residual hydroxyapatite correlate with less bone ongrowth. Hydroxyapatite resorption, which was more proximal than distal, showed no adverse effects on the implant-bone interface.

  15. Stimulative effects of lead on bone resorption in organ culture.

    PubMed

    Miyahara, T; Komiyama, H; Miyanishi, A; Takata, M; Nagai, M; Kozuka, H; Hayashi, T; Yamamoto, M; Ito, Y; Odake, H

    1995-03-31

    To clarify whether hypercalcemia after injection of Pb to rats is due to biological bone resorption or physicochemical mineral dissolution, the effect of lead (Pb) on release of previously incorporated 45Ca in organ culture was investigated. Pb at 50 microM and above stimulated the release of 45Ca and hydroxyproline (Hyp). Pb did not stimulate 45Ca release from the bones inactivated by freezing and thawing. Eel calcitonin (ECT), bafilomycin A1 and scopadulcic acid B (SDB) inhibited Pb-stimulated 45Ca release. These results indicate that Pb-induced 45Ca release is due to osteoclastic bone resorption. Pb-stimulated bone resorption was inhibited by indomethacin and flurbiprofen. Pb stimulated the release of prostaglandin E2 (PGE2) from the bones into the media. There was significantly high correlation between 45Ca and PGE2 release. Pb-induced bone resorption was inferred to be mediated by PGE2. From these results, it was suggested that hypercalcemia after Pb injection might be caused by biological bone resorption.

  16. Factors connected with alveolar bone resorption among institutionalized elderly people.

    PubMed

    de Baat, C; Kalk, W; van 't Hof, M

    1993-10-01

    In this socio-dental investigation among 175 institutionalized somatically disabled edentulous elderly people correlations are described between the test subjects' degree of alveolar bone resorption, their gender and age, their duration of edentulousness, and the number of complete dentures worn. All test subjects were interviewed by dental students and clinically examined by dentists. The mandibular alveolar bone resorption was significantly stronger in women than in men and stronger in people who had been edentulous longer. The longer the test subjects had been edentulous and the greater their degree of mandibular alveolar bone resorption was, the more mandibular dentures they had worn. This study among institutionalized elderly people provides for the most part the same results as a previously presented study among much younger people. Obviously, in these respects there are no differences between these groups.

  17. Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity.

    PubMed

    Irie, Atsushi; Takami, Masamichi; Kubo, Hideo; Sekino-Suzuki, Naoko; Kasahara, Kohji; Sanai, Yutaka

    2007-08-01

    Heparin is a highly sulfated glycosaminoglycan and has been shown to activate osteoclastic bone resorption though how is not yet clear. Here we investigate the molecule involved in heparin-induced activation of osteoclasts using an in vitro osteoclast culture assay. The formation and activation of osteoclasts are induced by receptor activator of NFkappaB ligand (RANKL) on osteoblasts, and inhibited by osteoprotegerin (OPG), a decoy receptor of RANKL, which is secreted from osteoblasts. In a coculture of mouse bone marrow cells and osteoblasts treated with 1,25-dihydroxyvitamin D(3) and prostaglandin E(2) on dentin slices, the bone marrow cells differentiate into osteoclasts, and resorption pits are formed on the dentin slices. Addition of heparin, various glycosaminoglycans, and chemically modified heparins to the coculture reveals that heparin enhances the pit-forming activity of osteoclasts, and this effect of heparin on the activation of osteoclasts is dependent on its sugar chain structure. By contrast, mRNA expression levels of RANKL, RANK, and OPG in the coculture are not altered by heparin treatment. Furthermore, neither RANK nor RANKL binds to heparin, suggesting that heparin does not directly interact with these proteins. Instead, heparin specifically binds to OPG and prevents OPG-mediated inhibition of osteoclastic bone resorption in the coculture. Heparin treatment does not enhance osteoclastic bone resorption in a monoculture of osteoclasts derived from bone marrow cells, and in the coculture using osteoblasts from OPG-deficient mice. A (125)I-OPG binding assay showed that OPG binds to osteoblasts and that this binding is inhibited by the addition of heparin, suggesting that OPG binds to RANKL on the osteoblast membrane and that heparin blocks this interaction. These results demonstrate that heparin enhances osteoclastic bone resorption by inhibiting OPG activity.

  18. Study on bone resorption behavior of osteoclast under drug effect using 41Ca tracing

    NASA Astrophysics Data System (ADS)

    Kejun, Dong; Liyan, Lu; Ming, He; Yinggen, Ouyang; Yan, Xue; Chaoli, Li; Shaoyong, Wu; Xianggao, Wang; Hongtao, Shen; Jianjun, Gao; Wei, Wang; Dafu, Chen; Yonggang, Xing; Jian, Yuan; Shan, Jiang

    2013-01-01

    The mechanisms governing calcium fluxes during bone remodeling processes in Osteoporosis (OP) patients are poorly known. Understanding the changes of Osteoclasts (OC) during this dynamic transition is important to prevent and cure OP. The exploration of long-lived 41Ca (T1/2 = 1.04 × 105 years) tracer combined with AMS measurements leads to the possibility of monitoring the bone resorption behavior of OC in OP patients. In this work, the behavior of OC with the administration of Strontium Ranelate (SR), a drug for OP, was studied by using 41Ca labeled hydroxyapatite (HAP) to simulate the bone. AMS on the HI-13 tandem accelerator at CIAE was used to determine trace amounts of 41Ca. The results show that the technique of 41Ca tracing with AMS can be used to quantitatively monitor the behavior of OC in bone resorption under the effects of drugs. Experimental details and preliminary results will be presented.

  19. Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis.

    PubMed

    Appelman-Dijkstra, Natasha M; Papapoulos, Socrates E

    2015-07-01

    Bone remodeling, the fundamental process for bone renewal, is targeted by treatments of osteoporosis to correct the imbalance between bone resorption and bone formation and reduce the risk of fractures and associated clinical consequences. Currently available therapeutics affect bone resorption and bone formation in the same direction and either decrease (inhibitors of bone resorption) or increase (parathyroid hormone [PTH] peptides) bone remodeling. Studies of patients with rare bone diseases and genetically modified animal models demonstrated that bone resorption and bone formation may not necessarily be coupled, leading to identification of molecular targets in bone cells for the development of novel agents for the treatment of osteoporosis. Application of such agents to the treatment of women with low bone mass confirmed that bone resorption and bone formation can be modulated in different directions and so far two new classes of therapeutics for osteoporosis have been defined with distinct mechanisms of action. Such treatments, if combined with a favorable safety profile, will offer new therapeutic options and will improve the management of patients with osteoporosis.

  20. Different cysteine proteinases involved in bone resorption and osteoclast formation.

    PubMed

    Brage, M; Abrahamson, M; Lindström, V; Grubb, A; Lerner, U H

    2005-06-01

    Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.

  1. Chronic erythroid hyperplasia and accelerated bone turnover.

    PubMed

    Weinstein, R S; Lutcher, C L

    Bone atrophy is generally thought to be the etiology of the decreased skeletal mass and fractures found in patients with ineffective hematopoiesis and associated erythroid hyperplasia. A bone biopsy from a patient with chronic erythroid hyperplasia and diffuse cortical osteopenia revealed a normal trabecular bone volume, excess osteoid, numerous osteoblasts, and increased osteoclastic resorptive surface. The increased fractional labeled surfaces and widely spaced double tetracycline labels indicated accelerated bone turnover, despite demonstrable iron deposits at the calcification front and cement lines and a low serum level of 25-hydroxyvitamin D. The relationship between the expanded marrow space and trabecular bone suggests that local marrow factors may be responsible for the rapid bone remodeling.

  2. [The OPG/RANKL/RANK system and bone resorptive disease].

    PubMed

    Liu, Ji-Zhong; Ji, Zong-Ling; Chen, Su-Min

    2003-11-01

    The OPG/RANKL/RANK system plays an important role in osteoclastogenesis and represents a great progress in bone biology. RANKL, which expresses on the surface of osteoblast/stromal cells and activated T cells, binds to RANK on the osteoclastic precursors or mature osteoclasts, and promotes osteoclastogenesis and bone resorption. While osteoprotegerin (OPG), which is expressed by osteoblasts/stromal cells, strongly inhibits bone resorption by binding to its ligand RANKL and thereby blocks the interaction between BANKL and RANK. A number of cytokines and hormones exert their effects on bone metabolism by regulating the OPG/RANKL ratio in the bone marrow microenvironment. RANK is also expressed on mammary epithelial cells and RANKL expression in these cells is induced by pregnancy hormones, RANKL and RANK are essential for the formation of the lactating mammary gland and the transmission of maternal calcium to neonates in mammalian species. Modulation of these systems provides a unique opportunity to develop novel therapeutics to inhibit bone loss in osteoporosis, rheumatoid arthritis, and bone metastasis of cancer. Further research should be focused on the cooperation of OPG/RANKL/RANK system with other signal pathways and the interactions among bone remodeling, immune system and endocrinology system. Currently, the development of OPG analogues or compounds which may stimulate OPG expression is becoming an attractive industry which may be profitable to both patients and manufacturers. PMID:15971575

  3. Fluid pressure and flow as a cause of bone resorption

    PubMed Central

    Fahlgren, Anna

    2010-01-01

    Background Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability. Method To understand the roles of pressure and flow, we describe the 3-dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans. Results Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s). Interpretation The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability. PMID:20718695

  4. Evidence that Resorption of Bone by Rat Peritoneal Macrophages Occurs in an Acidic Environment

    NASA Technical Reports Server (NTRS)

    Blair, H. C.

    1985-01-01

    Skeletal loss in space, like any form of osteoporosis, reflects a relative imbalance of the activities of cells resorbing (degrading) or forming bone. Consequently, prevention of weightlessness induced bone loss may theoretically be accomplished by (1) stimulating bone formation or (2) inhibiting bone resorption. This approach, however, requires fundamental understanding of the mechanisms by which cells form or degrade bone, information not yet at hand. An issue central to bone resorption is the pH at which resorption takes place. The pH dependent spectral shift of a fluorescent dye (fluorescein isothiocyanate) conjugated to bone matrix was used to determine the pH at the resorptive cell bone matrix interface. Devitalized rat bone was used as the substrate, and rat peritoneal macrophages were used as the bone resorbing cells. The results suggest that bone resorption is the result of generation of an acidic microenvironment at the cell matrix junction.

  5. 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.

  6. Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion.

    PubMed

    Nabavi, Noushin; Khandani, Arian; Camirand, Anne; Harrison, Rene E

    2011-11-01

    Exposure to microgravity has been associated with several physiological changes in astronauts, including an osteoporosis-like loss in bone mass. Despite many in vivo and in vitro studies in both microgravity and simulated microgravity conditions, the mechanism for bone loss is still not clear. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to assess bone cell responses. In this work, we conduct a unique investigation of the effects of microgravity on bone-producing osteoblasts and, in parallel, on bone-resorbing osteoclasts. An increase in total number of discrete resorption pits is observed in osteoclasts that experienced microgravity versus ground controls. We further show that osteoblasts exposed to 5 days of microgravity have shorter and wavier microtubules (MTs), smaller and fewer focal adhesions, and thinner cortical actin and stress fibers. Space-flown osteoblasts present extended cell shapes as well as significantly more disrupted and often fragmented or condensed nuclei. The absence of gravitational forces therefore causes both an increase in bone resorption by osteoclasts, and a decrease in osteoblast cellular integrity. The observed effects on both major bone cell types likely accelerate bone loss in microgravity environments, and additionally offer a potential explanation to the development of disuse osteoporosis on Earth. PMID:21839189

  7. Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion.

    PubMed

    Nabavi, Noushin; Khandani, Arian; Camirand, Anne; Harrison, Rene E

    2011-11-01

    Exposure to microgravity has been associated with several physiological changes in astronauts, including an osteoporosis-like loss in bone mass. Despite many in vivo and in vitro studies in both microgravity and simulated microgravity conditions, the mechanism for bone loss is still not clear. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to assess bone cell responses. In this work, we conduct a unique investigation of the effects of microgravity on bone-producing osteoblasts and, in parallel, on bone-resorbing osteoclasts. An increase in total number of discrete resorption pits is observed in osteoclasts that experienced microgravity versus ground controls. We further show that osteoblasts exposed to 5 days of microgravity have shorter and wavier microtubules (MTs), smaller and fewer focal adhesions, and thinner cortical actin and stress fibers. Space-flown osteoblasts present extended cell shapes as well as significantly more disrupted and often fragmented or condensed nuclei. The absence of gravitational forces therefore causes both an increase in bone resorption by osteoclasts, and a decrease in osteoblast cellular integrity. The observed effects on both major bone cell types likely accelerate bone loss in microgravity environments, and additionally offer a potential explanation to the development of disuse osteoporosis on Earth.

  8. 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.

  9. Sinusoidal electromagnetic fields promote bone formation and inhibit bone resorption in rat femoral tissues in vitro.

    PubMed

    Zhou, Jian; Ma, Xiao-Ni; Gao, Yu-Hai; Yan, Juan-Li; Shi, Wen-Gui; Xian, Cory J; Chen, Ke-Ming

    2016-01-01

    Effects of sinusoidal electromagnetic fields (SEMFs) on bone metabolism have not yet been well defined. The present study investigated SEMF effects on bone formation and resorption in rat femur bone tissues in vitro. Cultured femur diaphyseal (cortical bone) and metaphyseal (trabecular bone) tissues were treated with 50 Hz 1.8 mT SEMFs 1.5 h per day for up to 12 days and treatment effects on bone formation and resorption markers and associated gene expression were examined. Treatment with SEMFs caused a significant increase in alkaline phosphatase (ALP) activity and inhibited the tartrate-resistant acid phosphatase (TRACP) activity in the femoral diaphyseal or metaphyseal tissues. SEMFs also significantly increased levels of mRNA expression of osterix (OSX), insulin-like growth factor (IGF-1) and ALP in the bone tissues. SEMF treatment decreased glucose content and increased lactic acid contents in the culture conditioned medium. In addition, treatment with SEMFs decreased mRNA expression levels of bone resorption-related genes TRACP, macrophage colony stimulating factor (M-CSF) and cathepsin K (CTSK) in the cultured bone tissues. In conclusion, the current study demonstrated that treatment with 1.8 mT SEMFs at 1.5 h per day promoted bone formation, increased metabolism and inhibited resorption in both metaphyseal and diaphyseal bone tissues in vitro.

  10. Molecular Aspects of Bone Resorption in β-Thalassemia Major

    PubMed Central

    Saki, Najmaldin; Abroun, Saeid; Salari, Fatemeh; Rahim, Fakher; Shahjahani, Mohammad; Javad, Mohammadi-Asl

    2015-01-01

    β-thalassemia is the most common single gene disorder worldwide, in which hemoglobin β-chain production is decreased. Today, the life expectancy of thalassemic patients is increased because of a variety of treatment methods; however treatment related complications have also increased. The most common side effect is osteoporosis, which usually occurs in early adulthood as a consequence of increased bone resorption. Increased bone resorption mainly results from factors such as delayed puberty, diabetes mellitus, hypothyroidism, ineffective hematopoiesis as well as hyperplasia of the bone marrow, parathyroid gland dysfunction, toxic effect of iron on osteoblasts, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) deficiency. These factors disrupt the balance between osteoblasts and osteoclasts by interfering with various molecular mechanisms and result in decreased bone density. Given the high prevalence of osteopenia and osteoporosis in thalassemic patients and complexity of their development process, the goal of this review is to evaluate the molecular aspects involved in osteopenia and osteoporosis in thalassemic patients, which may be useful for therapeutic purposes. PMID:26199898

  11. Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

    PubMed

    Miyazaki, Yusei; Niino, Masaaki; Kanazawa, Ippei; Suzuki, Masako; Mizuno, Masanori; Hisahara, Shin; Fukazawa, Toshiyuki; Takahashi, Eri; Amino, Itaru; Ochi, Ryutaro; Nakamura, Masakazu; Akimoto, Sachiko; Minami, Naoya; Fujiki, Naoto; Doi, Shizuki; Shimohama, Shun; Terayama, Yasuo; Kikuchi, Seiji

    2016-09-15

    Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients. PMID:27609272

  12. Echistatin is a potent inhibitor of bone resorption in culture.

    PubMed

    Sato, M; Sardana, M K; Grasser, W A; Garsky, V M; Murray, J M; Gould, R J

    1990-10-01

    The venom protein, s-echistatin, originally derived from the saw-scaled viper Echis carinatus, was found to be a potent inhibitor of bone resorption by isolated osteoclasts. This Arg24-Gly25-Asp26-(RGD)-containing protein inhibited the excavation of bone slices by rat osteoclasts (IC50 = 0.1 nM). It also inhibited the release of [3H]proline from labeled bone particles by chicken osteoclasts (IC50 = 100 nM). By comparison, the tetrapeptide Arg-Gly-Asp-Ser (RGDS) inhibited resorption by rat or chicken osteoclasts with an IC50 of 0.1 mM while ala24-echistatin was inactive. Video microscopy showed that rat osteoclast attachment to substrate was more sensitive to s-echistatin than was the attachment of mononuclear cells or chicken osteoclasts. The difference in sensitivity of rat and chicken osteoclasts to s-echistatin may be due to differences between receptors on rat and chicken osteoclasts for s-echistatin. Antibody localization of echistatin on these cells showed much greater echistatin binding to rat osteoclasts than to chicken osteoclasts. Laser scanning confocal microscopy after immunohistochemical staining showed that s-echistatin binds to osteoclasts, that s-echistatin receptors are most abundant at the osteoclast/glass interface, and that s-echistatin colocalizes with vinculin. Confocal interference reflection microscopy of osteoclasts incubated with s-echistatin, demonstrated colocalization of s-echistatin with the outer edges of clusters of grey contacts at the tips of some lamellipodia. Identification of the echistatin receptor as an integrin was confirmed by colocalization of echistatin fluorescence with staining for an alpha-like subunit. Attachment of bone particles labeled with [3H]proline to chicken osteoclasts confirmed that the mechanism of action of echistatin was to inhibit osteoclast binding to bone presumably by disrupting adhesion structures. These data demonstrate that osteoclasts bind to bone via an RGD-sequence as an obligatory step in bone

  13. Family 2 cystatins inhibit osteoclast-mediated bone resorption in calvarial bone explants.

    PubMed

    Brand, H S; Lerner, U H; Grubb, A; Beertsen, W; Nieuw Amerongen, A V; Everts, V

    2004-09-01

    Osteoclastic bone resorption depends on the activity of various proteolytic enzymes, in particular those belonging to the group of cysteine proteinases. Biochemical studies have shown that cystatins, naturally occurring inhibitors of these enzymes, inhibit bone matrix degradation. Since the mechanism by which cystatins exert this inhibitory effect is not completely resolved yet, we studied the effect of cystatins on bone resorption microscopically and by Ca-release measurements. Calvarial bone explants were cultured in the presence or absence of family 2 cystatins and processed for light and electron microscopic analysis, and the culture media were analyzed for calcium release. Both egg white cystatin and human cystatin C decreased calcium release into the medium significantly. Microscopic analyses of the bone explants demonstrated that in the presence of either inhibitor, a high percentage of osteoclasts was associated with demineralized non-degraded bone matrix. Following a 24-h incubation in the presence of cystatin C, 41% of the cells were adjacent to areas of demineralized non-degraded bone matrix, whereas in controls, this was only 6%. If bone explants were cultured with both PTH and cystatin C, 60% of the osteoclasts were associated with demineralized non-degraded bone matrix, compared to 27% for bones treated with PTH only (P < 0.01). Our study provides evidence that cystatins, the naturally occurring inhibitors of cysteine proteinases, reversibly inhibit bone matrix degradation in the resorption lacunae adjacent to osteoclasts. These findings suggest the involvement of cystatins in the modulation of osteoclastic bone degradation.

  14. Assessment of bone formation and bone resorption in osteoporosis: a comparison between tetracycline-based iliac histomorphometry and whole body /sup 85/Sr kinetics

    SciTech Connect

    Reeve, J.; Arlot, M.E.; Chavassieux, P.M.; Edouard, C.; Green, J.R.; Hesp, R.; Tellez, M.; Meunier, P.J.

    1987-12-01

    Bone formation and resorption have been measured in patients with idiopathic osteoporosis by histomorphometry of 7.5-mm trephine biopsies and in the whole body by 85Sr radiotracer methodology and calcium balances. The studies were synchronized and most were preceded by double in vivo tetracycline labeling. Correlations between histological and kinetic bone formation indices were better when better when based on the extent of double tetracycline labels than on measurements of osteoid by visible light microscopy. Correction of the kinetic data for long-term exchange, using 5 months' serial whole body counting of retained 85Sr, improved the fit of the kinetic to the histological data. A statistical analysis of the measurement uncertainties showed that the residual scatter in the best correlations (between exchange-corrected bone formation rates and double-labeled osteoid surface indices) could be attributed to measurement imprecision alone. The exchange-corrected resorption rate correlated fairly well with iliac trabecular resorption surfaces, and using a volume referent rather than a surface referent for the histological index improved the statistical fit when patients with therapeutically accelerated bone turnover were included. A much better correlation was obtained by including osteoid volume acting as an independent predictor of bone resorption in a bivariate regression with a resorption surface index. The residual errors could then be accounted for by known measurement uncertainties. Whereas osteoid taking a double label closely predicted the kinetic rate of bone formation, further analysis suggested that osteoid that took no label or a single label was more closely related to bone resorption, presumably as a secondary result of the coupling of bone formation to bone resorption.

  15. A supra-cellular model for coupling of bone resorption to formation during remodeling: lessons from two bone resorption inhibitors affecting bone formation differently.

    PubMed

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Pennypacker, Brenda L; Duong, Le T; Engelholm, Lars H; Delaissé, Jean-Marie

    2014-01-10

    The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is

  16. Heterotopic new bone formation causes resorption of the inductive bone matrix

    SciTech Connect

    Nilsson, O.S.; Persson, P.E.; Ekelund, A. )

    1990-08-01

    The bone matrix of growing rats was labeled by multiple injections of 3H-proline, and demineralized bone matrix (DBM) was prepared. The DBM was allotransplanted heterotopically into growing rats. New bone formation was induced in and around the implants. The new bone formation was accompanied by a decrease in the content of 3H; 20 and 30 days after implantation, 72% and 46%, respectively, of the activity remained in the implants. Daily injections of indomethacin (2 mg/kg) inhibited calcium uptake by about 20% at 20 and 30 days and inhibited the release of 3H from the DBM to a similar degree. Heterotopic bone induction by DBM is accompanied by matrix resorption, and inhibition of the new bone formation decreases the resorption of DBM.

  17. Effect of cadmium on bone resorption in cultured fetal bone

    SciTech Connect

    Miyahara, T.; Miyakoshi, M.; Kozuka, H.

    1980-08-01

    Itai-itai disease which occurred in Toyama Prefecture, Japan, was thought to be due, at least partly, to chronic cadmium poisoning. Patients suffered severe pain in the waist, back and joints as well as kyphosis spinal column. In addition, x-ray film of these patients revealed abnormalities in the humerus and ribs. These bone lesions have been considered to be caused secondarily by dysfunction of other tissues, especially that of the kidneys, but there are some reports that the bone lesions appear before the occurrence of pathological changes in the kidneys of Cd-administered rat. It is currently unclear whether bone lesions by Cd are due to the direct action on the bone or indirect action which is caused by dysfunction of the kidney or intestine. To clarify the direct action of Cd on the bone, we studied the effect of Cd on the ossification of chick-embryo cultured bones biochemically and histologically. The results showed that Cd inhibited the bone matrix formation and brought about a malfunction in the ossification process. In the present work the effect of Cd on demineralization was studied using /sup 45/Ca-prelabeled bone in tissue culture and low levels of Cd were found to stimulate /sup 45/Ca from the bone.

  18. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer.

    PubMed

    Taube, T; Elomaa, I; Blomqvist, C; Beneton, M N; Kanis, J A

    1994-01-01

    We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

  19. Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption.

    PubMed

    Su, Nan; Li, Xiaogang; Tang, Yubin; Yang, Jing; Wen, Xuan; Guo, Jingyuan; Tang, Junzhou; Du, Xiaolan; Chen, Lin

    2016-09-01

    Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled-hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts derived from wild-type and Fgfr3-deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3-deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3-deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption. © 2016 American Society for Bone and Mineral Research.

  20. Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption.

    PubMed

    Su, Nan; Li, Xiaogang; Tang, Yubin; Yang, Jing; Wen, Xuan; Guo, Jingyuan; Tang, Junzhou; Du, Xiaolan; Chen, Lin

    2016-09-01

    Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled-hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts derived from wild-type and Fgfr3-deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3-deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3-deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption. © 2016 American Society for Bone and Mineral Research. PMID:26990430

  1. Bone balance within a cortical BMU: local controls of bone resorption and formation.

    PubMed

    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.

  2. The influence of age on adaptive bone formation and bone resorption.

    PubMed

    Birkhold, Annette I; Razi, Hajar; Duda, Georg N; Weinkamer, Richard; Checa, Sara; Willie, Bettina M

    2014-11-01

    Bone is a tissue with enormous adaptive capacity, balancing resorption and formation processes. It is known that mechanical loading shifts this balance towards an increased formation, leading to enhanced bone mass and mechanical performance. What is not known is how this adaptive response to mechanical loading changes with age. Using dynamic micro-tomography, we show that structural adaptive changes of trabecular bone within the tibia of living mice subjected to two weeks of in vivo cyclic loading are altered by aging. Comparisons of 10, 26 and 78 weeks old animals reveal that the adaptive capacity diminishes. Strikingly, adaptation was asymmetric in that loading increases formation more than it reduces resorption. This asymmetry further shifts the (re)modeling balance towards a net bone loss with age. Loading results in a major increase in the surface area of mineralizing bone. Interestingly, the resorption thickness is independent of loading in trabecular bone in all age groups. This data suggests that during youth, mechanical stimulation induces the recruitment of bone modeling cells whereas in old age, only bone forming cells are affected. These findings provide mechanistic insights into the processes that guide skeletal aging in mice as well as in other mammals.

  3. Inhibition of bone resorption and growth of breast cancer in the bone microenvironment.

    PubMed

    Buijs, Jeroen T; Que, Ivo; Löwik, Clemens W G M; Papapoulos, Socrates E; van der Pluijm, Gabri

    2009-02-01

    Breast cancer frequently metastasizes to bone, where tumor cells induce osteoclasts to locally destroy bone. During bone resorption, growth factors are locally released that may support bone metastatic growth. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates and osteoprotegerin (OPG), are available for bone. We examined the hypothesis that inhibition of bone resorption by two different mechanisms may also affect the growth of cancer cells in bone. For this, we tested the effects of high doses of OPG and zoledronic acid (ZOL) on progression of MDA-231-B/Luc+ breast cancer cells in the bone microenvironment using whole body bioluminescent reporter imaging (BLI). Both treatments significantly inhibited the development of radiographically detectable osteolytic lesions. Histologic examination corroborated the radiographic findings, showing that both treatments preserved the integrity of bone trabeculae and prevented bone destruction (significantly higher trabecular bone volumes vs. vehicle). However, whereas practically no TRAcP-positive osteoclasts were observed in tibiae preparations of animals treated with Fc-OPG, TRAcP-positive osteoclasts were still present in the animals treated with ZOL. Intra-bone tumor burden was reduced with ZOL and Fc-OPG treatment. Although there appeared to be a trend for less overall total tumor burden upon treatment with both compounds, this was not significant as assessed by BLI and histomorphometric analysis due to the extramedullary growth of cancer cells which was not affected by these treatments. Collectively, anti-resorptive agents with different mechanisms of action - ZOL and OPG - significantly reduced cancer-induced osteolysis and intra-osseous tumor burden, but failed to restrain local tumor growth. However, interference with the bone micro-environmental growth support could still be of therapeutic relevance when given to patients early in the course of bone metastatic disease.

  4. Mushroom Extracts Decrease Bone Resorption and Improve Bone Formation.

    PubMed

    Erjavec, Igor; Brkljacic, Jelena; Vukicevic, Slobodan; Jakopovic, Boris; Jakopovich, Ivan

    2016-01-01

    Mushroom extracts have shown promising effects in the treatment of cancer and various chronic diseases. Osteoporosis is considered one of the most widespread chronic diseases, for which currently available therapies show mixed results. In this research we investigated the in vitro effects of water extracts of the culinary-medicinal mushrooms Trametes versicolor, Grifola frondosa, Lentinus edodes, and Pleurotus ostreatus on a MC3T3-E1 mouse osteoblast-like cell line, primary rat osteoblasts, and primary rat osteoclasts. In an animal osteoporosis model, rats were ovariectomized and then fed 2 mushroom blends of G. frondosa and L. edodes for 42 days. Bone loss was monitored using densitometry (dual-energy X-ray absorptiometry) and micro computed tomography. In the concentration test, mushroom extracts showed no toxic effect on MC3T3-E1 cells; a dose of 24 µg/mL showed the most proliferative effect. Mushroom extracts of T. versicolor, G. frondosa, and L. edodes inhibited osteoclast activity, whereas the extract of L. edodes increased osteoblast mineralization and the production of osteocalcin, a specific osteoblastic marker. In animals, mushroom extracts did not prevent trabecular bone loss in the long bones. However, we show for the first time that the treatment with a combination of extracts from L. edodes and G. frondosa significantly reduced trabecular bone loss at the lumbar spine. Inhibitory properties of extracts from L. edodes on osteoclasts and the promotion of osteoblasts in vitro, together with the potential to decrease lumbar spine bone loss in an animal osteoporosis model, indicate that medicinal mushroom extracts can be considered as a preventive treatment and/or a supplement to pharmacotherapy to enhance its effectiveness and ameliorate its harmful side effects. PMID:27649725

  5. Bone resorption is affected by follicular phase length in female rotating shift workers.

    PubMed Central

    Lohstroh, Pete N; Chen, Jiangang; Ba, Jianming; Ryan, Louise M; Xu, Xiping; Overstreet, James W; Lasley, Bill L

    2003-01-01

    Stressors as subtle as night work or shift work can lead to irregular menstrual cycles, and changes in reproductive hormone profiles can adversely affect bone health. This study was conducted to determine if stresses associated with the disruption of regular work schedule can induce alterations in ovarian function which, in turn, are associated with transient bone resorption. Urine samples from 12 rotating shift workers from a textile mill in Anqing, China, were collected in 1996-1998 during pairs of sequential menstrual cycles, of which one was longer than the other (28.4 vs. 37.4 days). Longer cycles were characterized by a prolonged follicular phase. Work schedules during the luteal-follicular phase transition (LFPT) preceding each of the two cycles were evaluated. All but one of the shorter cycles were associated with regular, forward phase work shift progression during the preceding LFPT. In contrast, five longer cycles were preceded by a work shift interrupted either by an irregular shift or a number of "off days." Urinary follicle-stimulating hormone levels were reduced in the LFPT preceding longer cycles compared with those in the LFPT preceding shorter cycles. There was greater bone resorption in the follicular phase of longer cycles than in that of shorter cycles, as measured by urinary deoxypyridinoline. These data confirm reports that changes in work shift can lead to irregularity in menstrual cycle length. In addition, these data indicate that there may be an association between accelerated bone resorption in menstrual cycles and changes of regularity in work schedule during the preceding LFPT. PMID:12676625

  6. 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.

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

    PubMed Central

    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. PMID:26155460

  8. Longitudinal in vivo imaging of bone formation and resorption using fluorescence molecular tomography.

    PubMed

    Lambers, F M; Stuker, F; Weigt, C; Kuhn, G; Koch, K; Schulte, F A; Ripoll, J; Rudin, M; Müller, R

    2013-02-01

    Bone research often focuses on anatomical imaging of the bone microstructure, but in order to gain better understanding in how bone remodeling is modulated through interventions also bone formation and resorption processes should be investigated. With this in mind, the purpose of this study was to establish a longitudinal in vivo imaging approach of bone formation and resorption using fluorescence molecular tomography (FMT). In this study the reproducibility, accuracy and sensitivity of FMT for bone imaging were assessed by performing longitudinal measurements with FMT and comparing it to in vivo micro-computed tomography on a set of control mice, and mice in which load-adaptation was induced in the sixth caudal vertebra. The precision error for FMT measurements, expressed as coefficient of variation, was smaller than 16%, indicating acceptable reproducibility. A correlation was found between bone resorption measured with FMT and bone resorption rate measured with in vivo micro-computed tomography only over the first 14days (R=0.81, p<0.01), but not between bone formation measured with FMT and bone formation rate measured with in vivo micro-CT. Bone formation measured by FMT was 89-109% greater (p<0.05) for mice subjected to mechanical loading than control mice. Bone resorption was 5-8% lower, but did not reach a significant difference between groups, indicating moderate sensitivity for FMT. In conclusion, in vivo FMT in mouse tail bones is feasible but needs to be optimized for monitoring load adaptation in living mice.

  9. Effect of Kiwifruit on Bone Resorption in Ovariectomized Mice.

    PubMed

    Katsumata, Shinichi; Wolber, Frances M; Tadaishi, Miki; Tousen, Yuko; Ishimi, Yoshiko; Kruger, Marlena C

    2015-01-01

    Kiwifruit is a good source of dietary components and has beneficial effects for health. In this study, we investigated the effects of two types of kiwifruit, green kiwifruit (GRK) and gold kiwifruit (GOK), on bone metabolism in ovariectomized (OVX) mice. Seven-week-old female Balb/c-strain mice were divided into four groups: sham-operated (sham) group, OVX group, and OVX mice that were fed a GRK-supplemented diet or GOK-supplemented diet. Freeze-dried GRK and GOK were prepared and added in the diet at a concentration of 3 g/100 g. After 9 wk, the mice were sacrificed, and the serum, uterus, and femurs were obtained. Final body weight did not differ significantly among the four groups. Compared to the sham group, uterine weight was significantly lower and serum C-terminal telopeptide of type I collagen (CTx) levels and receptor activator of NF-κB ligand (RANKL) mRNA expression of the whole femur were significantly higher in the OVX group. Compared to the OVX group, GRK, but not GOK, reduced serum CTx concentrations and RANKL mRNA expression of the whole femur without changes in uterine weight. These results suggest that the GRK inhibited bone resorption, which might be due to a decrease in RANKL mRNA expression in OVX mice.

  10. Effect of Kiwifruit on Bone Resorption in Ovariectomized Mice.

    PubMed

    Katsumata, Shinichi; Wolber, Frances M; Tadaishi, Miki; Tousen, Yuko; Ishimi, Yoshiko; Kruger, Marlena C

    2015-01-01

    Kiwifruit is a good source of dietary components and has beneficial effects for health. In this study, we investigated the effects of two types of kiwifruit, green kiwifruit (GRK) and gold kiwifruit (GOK), on bone metabolism in ovariectomized (OVX) mice. Seven-week-old female Balb/c-strain mice were divided into four groups: sham-operated (sham) group, OVX group, and OVX mice that were fed a GRK-supplemented diet or GOK-supplemented diet. Freeze-dried GRK and GOK were prepared and added in the diet at a concentration of 3 g/100 g. After 9 wk, the mice were sacrificed, and the serum, uterus, and femurs were obtained. Final body weight did not differ significantly among the four groups. Compared to the sham group, uterine weight was significantly lower and serum C-terminal telopeptide of type I collagen (CTx) levels and receptor activator of NF-κB ligand (RANKL) mRNA expression of the whole femur were significantly higher in the OVX group. Compared to the OVX group, GRK, but not GOK, reduced serum CTx concentrations and RANKL mRNA expression of the whole femur without changes in uterine weight. These results suggest that the GRK inhibited bone resorption, which might be due to a decrease in RANKL mRNA expression in OVX mice. PMID:26440641

  11. 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. PMID:15724149

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  13. 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.

  14. Evidence for multiple bone resorption-stimulating factors produced by normal human keratinocytes in culture.

    PubMed

    Fried, R M; Voelkel, E F; Rice, R H; Levine, L; Tashjian, A H

    1988-06-01

    Conditioned medium from cultured normal human foreskin keratinocytes enhanced the release of calcium from neonatal mouse calvaria in organ culture. Unfractionated keratinocyte-conditioned medium (KCM) stimulated bone resorption in a dose-dependent manner, but it did not increase the concentration of prostaglandin E2 (PGE2) in the bone culture medium until a maximal dose of KCM for resorption was used. Furthermore, inhibitors of PGE2 synthesis, indomethacin, ibuprofen, and piroxicam, did not inhibit KCM-induced calcium release. High concentrations of KCM increased cAMP production by calvaria in the presence of isobutylmethylxanthine, but the increase was small compared with that produced by a dose of bovine PTH that caused a similar level of bone resorption. The bone resorption-stimulating activity of KCM was not lost after incubation at 56 C for 60 min, but it was lost after heating at 100 C for 10 min. Fractionation of KCM by gel filtration chromatography revealed two distinct peaks of bone resorption-stimulating activity. One peak, KCMI, caused a significant increase in bone resorption at 2 micrograms protein/ml. KCMI did not increase medium PGE2, and inhibition of PGE2 synthesis in bone had no effect on KCMI-induced bone resorption. KCMI failed to increase cAMP production by human osteosarcoma SaOS-2 cells. Another peak, KCMII, caused a dose-dependent increase in bone resorption, and a significant increase in medium calcium was noted at a 20-fold lower concentration (0.1 microgram protein/ml) than with KCMI. In contrast to KCMI, the increase in bone resorption stimulated by KCMII was accompanied by a parallel increase in the production of PGE2, and inhibition of PGE2 synthesis completely inhibited the bone resorption-stimulating activity of KCMII. KCMII also caused an increase in cAMP production by SaOS-2 cells. We conclude that KCM contains at least two distinct bone resorption-stimulating factors, one of which acts via a PG-mediated mechanism and the other by

  15. Response of Bone Resorption Markers to Aristolochia longa Intake by Algerian Breast Cancer Postmenopausal Women

    PubMed Central

    Benarba, Bachir; Meddah, Boumedienne; Tir Touil, Aicha

    2014-01-01

    Aristolochia longa is widely used in traditional medicine in Algeria to treat breast cancer. The aim of the present study was to investigate the response of bone resorption markers to A. longa intake by Algerian breast cancer postmenopausal women. According to the A. longa intake, breast cancer patients were grouped into A. longa group (Al) (n = 54) and non-A. longa group (non-Al) (n = 24). 32 women constituted the control group. Bone resorption markers (from urine) pyridinoline (PYD) and deoxypyridinoline (DPD) were determined by HPLC. Serum and urinary creatinine, uric acid, and urea were measured. 1 g of A. longa intake resulted in significant rise of renal serum markers and a pronounced increase of bone resorption markers. The intake of A. longa roots is detrimental for kidney function and resulted in high bone resorption, maybe due to the reduction in renal function caused by the aristolochic acids contained in the roots. PMID:24876833

  16. 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

  17. Bone resorption in incompletely impacted mandibular third molars and acute pericoronitis.

    PubMed

    Yamaoka, Minoru; Ono, Yusuke; Takahashi, Masahiro; Doto, Ryosuke; Yasuda, Kouichi; Uematsu, Takashi; Furusawa, Kiyofumi

    2009-01-01

    Acute pericoronitis (AP) arises frequently in incompletely impacted mandibular third molars, but it remains unknown whether bone resorption in aging is associated with acute inflammation of the third molar. We conducted an experiment to compare the ratio of bone resorption to root length in the distal surface of the second molar (A), the proximal surface (B), and distal surface (C) in mesio-angular, incompletely impacted third molars in 27 young and 58 older adults with AP and 77 young and 79 older adults without a history of AP. Bone resorption in A, B, and C in older adults with AP demonstrated a significantly higher ratio when compared to those without AP, whereas there was no difference between those with and without AP in young adults except for B in women. However, there were no differences between bone resorption in B with AP in young and older women, and between bone resorption in C with AP in young and older adults. These indicate that AP and bone resorption are associated with incompletely impacted mandibular third molars in older adults.

  18. Congenital adrenal hyperplasia: a case report with premature teeth exfoliation and bone resorption.

    PubMed

    Angelopoulou, Matina V; Kontogiorgos, Elias; Emmanouil, Dimitris

    2015-06-01

    Congenital adrenal hyperplasia (CAH) is an inherited autosomal recessive disorder characterized by insufficient production of cortisol. The aim of this case report was to present a child with CAH, premature exfoliation of primary teeth and accelerated eruption of his permanent teeth related to bone resorption. A 4.5-year-old Caucasian boy with CAH and long-term administration of glucocorticoids was referred for dental restoration. Clinical examination revealed primary molars with worn stainless steel crowns, severe attrition of the upper canines, and absence of the upper incisors. Before the completion of treatment, abnormal mobility of the first upper primary molars and the lower incisors was detected, and a few days later the teeth exfoliated prematurely. Histologic examination revealed normal tooth structure. Alkaline phosphatase and blood cells values were normal. Eruption of the permanent dentition was also accelerated. Tooth mobility was noticed in the permanent teeth as soon as they erupted, along with bone destruction. Examination revealed an elevated level of receptor activator of nuclear factor-κB ligand and lower-than-normal osteoprotegerin and vitamin D levels. The patient was treated with vitamin D supplements, and his teeth have been stable ever since. CAH is a serious chronic disorder appearing in children with accelerated dental development and possibly premature loss of primary teeth.

  19. 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.

  20. In vitro bone resorption is dependent on physiological concentrations of zinc.

    PubMed

    Chen, D; Waite, L C; Pierce, W M

    1998-01-01

    The addition of physiological concentrations of zinc (25-200 (microg/dL) to Dulbecco's Modified Eagle's Medium containing tibiae from 19-d chick embryos resulted in a concentration-dependent increase in tibial content of tartrate-resistant acid phosphatase (TRAP) and an increase in bone resorption, as measured by tibial calcium release. This increase in bone resorption was additive to the resorptive effect resulting from the addition of 10(-9)-10(-7) M parathyroid hormone (PTH), but was not additive to similar effects produced by the addition of 10(-9)-10(-7) M prostaglandin E2 (PGE2). An inhibitor of prostaglandin synthesis, flurbiprofen (10[-6] M), did not influence the effect of zinc on bone resorption. However, the addition of 2,6-pyridinedicarboxylic acid (10[-3] M, 2,6-PDCA), a chelator of zinc, did attenuate the effects of zinc, as did the addition of an inhibitor of DNA replication (hydroxyurea, 10[-3] M). Hydroxyurea also attenuated the bone resorptive response to PGE2, but had no influence on the effects of PTH. These results indicate that physiological concentrations of zinc alter bone resorptive rates in vitro by a mechanism that is dependent on DNA replication.

  1. 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.

  2. Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption.

    PubMed Central

    Jilka, R L; Takahashi, K; Munshi, M; Williams, D C; Roberson, P K; Manolagas, S C

    1998-01-01

    Loss of sex steroids causes an increase in both the resorption and formation of bone, with the former exceeding the latter. Based on evidence that the increased bone resorption after estrogen loss is due to an increase in osteoclastogenesis, we hypothesized that estrogen loss also stimulates osteoblastogenesis. We report that the number of mesenchymal osteoblast progenitors in the murine bone marrow was increased two- to threefold between 2 and 8 wk after ovariectomy and returned to control levels by 16 wk. Circulating osteocalcin, as well as osteoclastogenesis and the rate of bone loss, followed a very similar temporal pattern. Inhibition of bone resorption by administration of the bisphosphonate alendronate led to a decrease of the absolute number of osteoblast progenitors; however, it did not influence the stimulating effect of ovariectomy on osteoblastogenesis or osteoclastogenesis. These observations indicate that the increased bone formation that follows loss of estrogen can be explained, at least in part, by an increase in osteoblastogenesis. Moreover, they strongly suggest that unlike normal bone remodeling, whereby osteoblast development is stimulated by factors released from the bone matrix during osteoclastic resorption, estrogen deficiency unleashes signals that can stimulate the differentiation of osteoblast progenitors in a fashion that is autonomous from the need created by bone resorption, and therefore, inappropriate. PMID:9576759

  3. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

    PubMed Central

    Xiong, Lei; Jung, Ji-Ung; Wu, Haitao; Xia, Wen-Fang; Pan, Jin-Xiu; Shen, Chengyong; Mei, Lin; Xiong, Wen-Cheng

    2015-01-01

    Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high–bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis. PMID:25733894

  4. Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase.

    PubMed Central

    Kasten, T P; Collin-Osdoby, P; Patel, N; Osdoby, P; Krukowski, M; Misko, T P; Settle, S L; Currie, M G; Nickols, G A

    1994-01-01

    We have examined the effects of modulating nitric oxide (NO) levels on osteoclast-mediated bone resorption in vitro and the effects of nitric oxide synthase (NOS) inhibitors on bone mineral density in vivo. Diaphorase-based histochemical staining for NOS activity of bone sections or highly enriched osteoclast cultures suggested that osteoclasts exhibit substantial NOS activity that may account for basal NO production. Chicken osteoclasts were cultured for 36 hr on bovine bone slices in the presence or absence of the NO-generating agent sodium nitroprusside or the NOS inhibitors N-nitro-L-arginine methyl ester and aminoguanidine. Nitroprusside markedly decreased the number of bone pits and the average pit area in comparison with control cultures. On the other hand, NOS inhibition by N-nitro-L-arginine methyl ester or aminoguanidine dramatically increased the number of bone pits and the average resorption area per pit. In a model of osteoporosis, aminoguanidine potentiated the loss of bone mineral density in ovariectomized rats. Aminoguanidine also caused a loss of bone mineral density in the sham-operated rats. Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity. These findings suggest that endogenous NO production in osteoclast cultures may regulate resorption activity. The modulation of NOS and NO levels by cells within the bone microenvironment may be a sensitive mechanism for local control of osteoclast bone resorption. Images PMID:7513424

  5. Neural crest-mediated bone resorption is a determinant of species-specific jaw length

    PubMed Central

    Ealba, Erin L.; Jheon, Andrew H.; Hall, Jane; Curantz, Camille; Butcher, Kristin D.; Schneider, Richard A.

    2015-01-01

    Precise control of jaw length during development is crucial for proper form and function. Previously we have shown that in birds, neural crest mesenchyme (NCM) confers species-specific size and shape to the beak by regulating molecular and histological programs for the induction and deposition of cartilage and bone. Here we reveal that a hitherto unrecognized but similarly essential mechanism for establishing jaw length is the ability of NCM to mediate bone resorption. Osteoclasts are considered the predominant cells that resorb bone, although osteocytes have also been shown to participate in this process. In adults, bone resorption is tightly coupled to bone deposition as a means to maintain skeletal homeostasis. Yet, the role and regulation of bone resorption during growth of the embryonic skeleton have remained relatively unexplored. We compare jaw development in short-beaked quail versus long-billed duck and find that quail have substantially higher levels of enzymes expressed by bone-resorbing cells including tartrate-resistant acid phosphatase (TRAP), Matrix metalloproteinase 13 (Mmp13), and Mmp9. Then, we transplant NCM destined to form the jaw skeleton from quail to duck and generate chimeras in which osteocytes arise from quail donor NCM and osteoclasts come exclusively from the duck host. Chimeras develop quail-like jaw skeletons coincident with dramatically elevated expression of TRAP, Mmp13, and Mmp9. To test for a link between bone resorption and jaw length, we block resorption using a bisphosphonate, osteoprotegerin protein, or an MMP13 inhibitor, and this significantly lengthens the jaw. Conversely, activating resorption with RANKL protein shortens the jaw. Finally, we find that higher resorption in quail presages their relatively lower adult jaw bone mineral density (BMD) and that BMD is also NCM-mediated. Thus, our experiments suggest that NCM not only controls bone resorption by its own derivatives but also modulates the activity of mesoderm

  6. Bone resorption by isolated human osteoclasts in vitro: effects of calcitonin.

    PubMed

    Murrills, R J; Shane, E; Lindsay, R; Dempster, D W

    1989-04-01

    Human osteoclasts were isolated from 12- to 17-week-old fetal tissue and from transiliac crest bone biopsies for an in vitro study of their biology. A hypodermic needle was used to flush either the fetal long bones or the trabeculae of the iliac crest bone biopsy with tissue culture medium and the resulting cell suspension sedimented briefly either onto the surface of plastic tissue culture dishes, for time-lapse microcinematography, or onto slices of devitalized bovine cortical bone for quantitative assay of bone resorption. The osteoclasts were motile, tartrate-resistant acid phosphatase positive and capable of excavating pits in slices of devitalized bovine cortical bone. Human calcitonin, at doses of 1 ng/ml and 1 microgram/ml, caused a 70% inhibition of bone resorption by human fetal osteoclasts over a 24 h period but had no apparent effect on the morphology or motility of either fetal or adult osteoclasts. PMID:2728929

  7. Resorption of monetite calcium phosphate cement by mouse bone marrow derived osteoclasts.

    PubMed

    Montazerolghaem, M; Karlsson Ott, M; Engqvist, H; Melhus, H; Rasmusson, A J

    2015-01-01

    Recently the interest for monetite based biomaterials as bone grafts has increased; since in vivo studies have demonstrated that they are degradable, osteoconductive and improve bone healing. So far osteoclastic resorption of monetite has received little attention. The current study focuses on the osteoclastic resorption of monetite cement using primary mouse bone marrow macrophages, which have the potential to differentiate into resorbing osteoclasts when treated with receptor activator NF-κB ligand (RANKL). The osteoclast viability and differentiation were analysed on monetite cement and compared to cortical bovine bone discs. After seven days live/dead stain results showed no significant difference in viability between the two materials. However, the differentiation was significantly higher on the bone discs, as shown by tartrate resistant acid phosphatase (TRAP) activity and Cathepsin K gene expression. Moreover monetite samples with differentiated osteoclasts had a 1.4 fold elevated calcium ion concentration in their culture media compared to monetite samples with undifferentiated cells. This indicates active resorption of monetite in the presence of osteoclasts. In conclusion, this study suggests that osteoclasts have a crucial role in the resorption of monetite based biomaterials. It also provides a useful model for studying in vitro resorption of acidic calcium phosphate cements by primary murine cells. PMID:25953560

  8. Assessment of global morphological and topological changes in trabecular structure under the bone resorption process

    NASA Astrophysics Data System (ADS)

    Sidorenko, Irina N.; Bauer, Jan; Monetti, Roberto; Baum, Thomas; Rummeny, Ernst J.; Eckstein, Felix; Matsuura, Maiko; Lochmueller, Eva-Maria; Zysset, Philippe K.; Raeth, Christoph W.

    2012-03-01

    Osteoporosis is a frequent skeletal disease characterised both by loss of bone mineral mass and deterioration of cancellous bone micro-architecture. It can be caused by mechanical disuse, estrogen deficiency or natural age-related resorption process. Numerical analysis of high-resolution images of the trabecular network is recognised as a powerful tool for assessment of structural characteristics. Using μCT images of 73 thoracic and 78 lumbar human vertebral specimens in vitro with isotropic resolution of 26μm we simulate bone atrophy as random resorption of bone surface voxels. Global morphological and topological characteristics provided by four Minkowski Functionals (MF) are calculated for two numerical resorption models with and without conservation of global topological connectivity of the trabecular network, which simulates different types of bone loss in osteoporosis, as it has been described in males and females. Diagnostic performance of morphological and topological characteristics as a function of relative bone loss is evaluated by a correlation analysis with respect to experimentally measured Maximum Compressive Strength (MCS). In both resorption models the second MF, which coincides with bone surface fraction BS/TV, demonstrates almost constant value of Pearson's correlation coefficient with respect to the relative bone loss ▵BV/TV. This morphological characteristic does not vary considerably under age-related random resorption and can be used for predicting bone strength in the elderly. The third and fourth MF demonstrate an increasing correlation coefficients with MCS after applying random bone surface thinning without preserving topological connectivity, what can be used for improvement of evaluation of the current state of the structure.

  9. Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone.

    PubMed

    Asou, Y; Rittling, S R; Yoshitake, H; Tsuji, K; Shinomiya, K; Nifuji, A; Denhardt, D T; Noda, M

    2001-03-01

    Osteoclastic bone resorption requires a number of complex steps that are under the control of local regulatory molecules. Osteopontin is expressed in osteoclasts and is also present in bone matrix; however, its biological function has not been fully understood. To elucidate the role of osteopontin in the process of osteoclastic bone resorption, we conducted ectopic bone implantation experiments using wild-type and osteopontin knockout mouse. In the wild-type group, bone discs from calvariae implanted ectopically in muscle were resorbed, and their mass was reduced by 25% within 4 weeks. In contrast, the mass of the bone discs from calvariae of osteopontin knockout mice was reduced by only 5% when implanted in osteopontin knockout mice. Histological analyses indicated that the number of osteoclasts associated with the implanted bones was reduced in the osteopontin knockout mice. As osteopontin deficiency does not suppress osteoclastogenesis per se, we further examined vascularization immunohistologically and found that the number of vessels containing CD31-positive endothelial cells around the bone discs implanted in muscle was reduced in the osteopontin knockout mice. Furthermore, sc implantation assays indicated that the length and branching points of the newly formed vasculatures associated with the bone discs were also reduced in the absence of osteopontin. In this assay, tartrate-resistant acid phosphatase-positive area of the bone discs was also reduced in the osteopontin knockout mice, indicating further the link between the osteopontin-dependent vascularization and osteoclast accumulation. The bone resorption defect could be rescued by topical administration of recombinant osteopontin to the bones implanted in muscle. These observations indicate that osteopontin is required for efficient vascularization by the hemangiogenic endothelial cells and subsequent osteoclastic resorption of bones. PMID:11181551

  10. 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.

  11. Osteoclast TGF-β Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation.

    PubMed

    Weivoda, Megan M; Ruan, Ming; Pederson, Larry; Hachfeld, Christine; Davey, Rachel A; Zajac, Jeffrey D; Westendorf, Jennifer J; Khosla, Sundeep; Oursler, Merry Jo

    2016-01-01

    Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption. These processes become uncoupled with age, leading to increased risk for debilitating fractures. Therefore, understanding how osteoblasts are recruited to sites of resorption is vital to treating age-related bone loss. Osteoclasts release and activate TGF-β from the bone matrix. Here we show that osteoclast-specific inhibition of TGF-β receptor signaling in mice results in osteopenia due to reduced osteoblast numbers with no significant impact on osteoclast numbers or activity. TGF-β induced osteoclast expression of Wnt1, a protein crucial to normal bone formation, and this response was blocked by impaired TGF-β receptor signaling. Osteoclasts in aged murine bones had lower TGF-β signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGF-β-induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGF-β availability with age. Therefore, osteoclast responses to TGF-β are essential for coupling bone resorption to bone formation, and modulating this pathway may provide opportunities to treat age-related bone loss.

  12. Fresh-frozen human bone allograft in vertical ridge augmentation: clinical and tomographic evaluation of bone formation and resorption.

    PubMed

    Macedo, Luis Guilherme Scavone; Mazzucchelli-Cosmo, Luiz Antonio; Macedo, Nelson Luiz; Monteiro, Adriana Socorro Ferreira; Sendyk, Wilson Roberto

    2012-12-01

    The aim of the current study is to evaluate fresh-frozen human bone allografts (FHBAs) used in vertical ridge augmentation clinically and by computed tomography, and to analyze the resulting bone formation and graft resorption. Sixteen FHBAs were grafted in the maxillae and mandibles of 9 patients. The FHBAs, which were provided by the Musculoskeletal Tissue Bank of Marilia Hospital (Unioss), were frozen at -80°C. After 7 months, dental implants were placed and bone parameters were evaluated. Vertical bone formation was measured by computerized tomography before (T0) and at 7 months (T1) after the surgical procedure. Bone graft resorption was measured clinically from a landmark screw head using a periodontal probe. The results were analyzed by Student's t-test. Significant differences existed in the bone formation values at T0 and T1, with an average change of 4.03 ± 1.69 mm. Bone graft resorption values were 1.0 ± 0.82 mm (20%). Implants were placed with varying insertion torque values (35-45 Ncm), and achieved primary stability. This study demonstrates that FHBAs promote satisfactory vertical bone formation with a low resorption rates, good density, and primary implant stability. PMID:21811779

  13. Nobiletin, a polymethoxy flavonoid, suppresses bone resorption by inhibiting NFκB-dependent prostaglandin E synthesis in osteoblasts and prevents bone loss due to estrogen deficiency.

    PubMed

    Harada, Suguru; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Takita, Morichika; Inada, Masaki; Miyaura, Chisato

    2011-01-01

    Nobiletin, a polymethoxy flavonoid, prevents cancer and inflammation, but the roles of nobiletin in bone are unclear. We examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice in vivo. In vitro, nobiletin suppressed osteoclast formation and bone resorption induced by interleukin (IL)-1. Nobiletin suppressed the expression of cyclooxygenase-2, NFκB-dependent transcription, and prostaglandin E (PGE) production induced by IL-1 in osteoblasts. OVX mice showed severe bone loss in the femur by increased bone resorption due to estrogen deficiency, and nobiletin significantly restored the bone mass. Nobiletin could be beneficial to bone health in postmenopausal women.

  14. Bis-Enoxacin Blocks Rat Alveolar Bone Resorption from Experimental Periodontitis

    PubMed Central

    Lee, Ju-Youn; Bhattacharyya, Indraneel; Dolce, Calogero; Toro, Edgardo J.; Holliday, L. Shannon; Kesavalu, Lakshmyya

    2014-01-01

    Periodontal diseases are multifactorial, caused by polymicrobial subgingival pathogens, including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Chronic periodontal infection results in inflammation, destruction of connective tissues, periodontal ligament, and alveolar bone resorption, and ultimately tooth loss. Enoxacin and a bisphosphonate derivative of enoxacin (bis-enoxacin) inhibit osteoclast formation and bone resorption and also contain antibiotic properties. Our study proposes that enoxacin and/or bis-enoxacin may be useful in reducing alveolar bone resorption and possibly bacterial colonization. Rats were infected with 109 cells of polymicrobial inoculum consisting of P. gingivalis, T. denticola, and T. forsythia, as an oral lavage every other week for twelve weeks. Daily subcutaneous injections of enoxacin (5 mg/kg/day), bis-enoxacin (5, 25 mg/kg/day), alendronate (1, 10 mg/kg/day), or doxycycline (5 mg/day) were administered after 6 weeks of polymicrobial infection. Periodontal disease parameters, including bacterial colonization/infection, immune response, inflammation, alveolar bone resorption, and systemic spread, were assessed post-euthanasia. All three periodontal pathogens colonized the rat oral cavity during polymicrobial infection. Polymicrobial infection induced an increase in total alveolar bone resorption, intrabony defects, and gingival inflammation. Treatment with bis-enoxacin significantly decreased alveolar bone resorption more effectively than either alendronate or doxycycline. Histologic examination revealed that treatment with bis-enoxacin and enoxacin reduced gingival inflammation and decreased apical migration of junctional epithelium. These data support the hypothesis that bis-enoxacin and enoxacin may be useful for the treatment of periodontal disease. PMID:24638087

  15. Bis-enoxacin blocks rat alveolar bone resorption from experimental periodontitis.

    PubMed

    Rivera, Mercedes F; Chukkapalli, Sasanka S; Velsko, Irina M; Lee, Ju-Youn; Bhattacharyya, Indraneel; Dolce, Calogero; Toro, Edgardo J; Holliday, L Shannon; Kesavalu, Lakshmyya

    2014-01-01

    Periodontal diseases are multifactorial, caused by polymicrobial subgingival pathogens, including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Chronic periodontal infection results in inflammation, destruction of connective tissues, periodontal ligament, and alveolar bone resorption, and ultimately tooth loss. Enoxacin and a bisphosphonate derivative of enoxacin (bis-enoxacin) inhibit osteoclast formation and bone resorption and also contain antibiotic properties. Our study proposes that enoxacin and/or bis-enoxacin may be useful in reducing alveolar bone resorption and possibly bacterial colonization. Rats were infected with 10(9) cells of polymicrobial inoculum consisting of P. gingivalis, T. denticola, and T. forsythia, as an oral lavage every other week for twelve weeks. Daily subcutaneous injections of enoxacin (5 mg/kg/day), bis-enoxacin (5, 25 mg/kg/day), alendronate (1, 10 mg/kg/day), or doxycycline (5 mg/day) were administered after 6 weeks of polymicrobial infection. Periodontal disease parameters, including bacterial colonization/infection, immune response, inflammation, alveolar bone resorption, and systemic spread, were assessed post-euthanasia. All three periodontal pathogens colonized the rat oral cavity during polymicrobial infection. Polymicrobial infection induced an increase in total alveolar bone resorption, intrabony defects, and gingival inflammation. Treatment with bis-enoxacin significantly decreased alveolar bone resorption more effectively than either alendronate or doxycycline. Histologic examination revealed that treatment with bis-enoxacin and enoxacin reduced gingival inflammation and decreased apical migration of junctional epithelium. These data support the hypothesis that bis-enoxacin and enoxacin may be useful for the treatment of periodontal disease.

  16. 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

  17. 1,25-Dihydroxyvitamin D3 stimulates rat osteoblastic cells to release a soluble factor that increases osteoclastic bone resorption.

    PubMed Central

    McSheehy, P M; Chambers, T J

    1987-01-01

    Although 1,25-dihydroxyvitamin D3 stimulates osteoclastic bone resorption in vivo and in organ culture, the mechanism by which it effects this stimulation is unknown. We have recently found that the agent does not stimulate resorption by osteoclasts mechanically disaggregated from bone and incubated on slices of cortical bone. This suggests that the osteoclasts were removed by disaggregation from the influence of some cell type, present in intact bone, that mediates hormone responsiveness. We therefore tested the ability of osteoblastic cells derived from neonatal rat calvariae and of cloned, hormone-responsive osteosarcoma cells (UMR106) to restore hormone responsiveness to unresponsive populations of osteoclasts. We found that osteoblastic cells from both sources induced a two- to fourfold stimulation of osteoclastic bone resorption in the presence of 1,25-dihydroxyvitamin D3. Stimulation was observed at concentrations of 10(-10) M and above. Actinomycin D and cycloheximide did not affect bone resorption by osteoclasts incubated alone, but abolished the capacity of osteoblastic cells to stimulate osteoclastic resorption in the presence of 1,25-dihydroxyvitamin D3. When calvarial cells or osteoblastlike UMR cells were incubated with the hormone, they produced a factor in cell-free supernatants that stimulated bone resorption by disaggregated osteoclasts. These experiments suggest that 1,25-dihydroxyvitamin D3 stimulates bone resorption through a primary action on osteoblastic cells, that are induced by the hormone to produce a factor that stimulates osteoclastic bone resorption. PMID:3611354

  18. The relevance of leukotrienes for bone resorption induced by mechanical loading.

    PubMed

    Moura, A P; Taddei, S R A; Queiroz-Junior, C M; Madeira, M F M; Rodrigues, L F D; Garlet, G P; Souza, D G; Machado, F S; Andrade, I; Teixeira, M M; Silva, T A

    2014-12-01

    5-Lipoxygenase (5-LO) metabolites are important pro-inflammatory lipid mediators. However, much still remains to be understood about the role of such mediators in bone remodeling. This study aimed to investigate the effect of 5-LO metabolites, LTB4 and CysLTs, in a model of mechanical loading-induced bone remodeling. Strain-induced tooth movement and consequently alveolar bone resorption/apposition was achieved by using a coil spring placed on molar and attached to incisors of C57BL6 (wild-type-WT), 5-LO deficient mice (5-LO(-/-)) and mice treated with 5-LO inhibitor (zileuton-ZN) or with antagonist of CysLTs receptor (montelukast-MT). The amount of bone resorption and the number of osteoclasts were determined morphometrically. The expression of inflammatory and bone remodeling markers in periodontium was analyzed by qPCR. Osteoclast differentiation and TNF-α production were evaluated in vitro using RAW 264.7 cells treated with LTB4 or LTD4. Bone resorption, TRAP(+) cells and expression of Tnfa, Il10 and Runx2 were significantly diminished in 5-LO(-/-), ZN- and MT-treated mice. The expression of Rank was also reduced in 5-LO(-/-) and MT-treated mice. Accordingly, LTB4 and LTD4 in association with RANKL promoted osteoclast differentiation and increased TNF-α release in vitro. These data demonstrate that the absence of 5-LO metabolites, LTB4 and CysLTs reduces osteoclast recruitment and differentiation, consequently diminishing bone resorption induced by mechanical loading. Thus, 5-LO might be a potential target for controlling bone resorption in physiological and pathological conditions. PMID:25270168

  19. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo.

    PubMed Central

    Garrett, I R; Boyce, B F; Oreffo, R O; Bonewald, L; Poser, J; Mundy, G R

    1990-01-01

    The mechanisms by which bone resorbing osteoclasts form and are activated by hormones are poorly understood. We show here that the generation of oxygen-derived free radicals in cultured bone is associated with the formation of new osteoclasts and enhanced bone resorption, identical to the effects seen when bones are treated with hormones such as parathyroid hormone (PTH) and interleukin 1 (IL-1). When free oxygen radicals were generated adjacent to bone surfaces in vivo, osteoclasts were also formed. PTH and IL-1-stimulated bone resorption was inhibited by both natural and recombinant superoxide dismutase, an enzyme that depletes tissues of superoxide anions. We used the marker nitroblue tetrazolium (NBT) to identify the cells that were responsible for free radical production in resorbing bones. NBT staining was detected only in osteoclasts in cultures of resorbing bones. NBT staining in osteoclasts was decreased in bones coincubated with calcitonin, an inhibitor of bone resorption. We also found that isolated avian osteoclasts stained positively for NBT. NBT staining in isolated osteoclasts was increased when the cells were incubated with bone particles, to which they attach. We confirmed the formation of superoxide anion in isolated avian osteoclasts using ferricytochrome c reduction as a method of detection. The reduction of ferricytochrome c in isolated osteoclasts was inhibited by superoxide dismutase. Our results suggest that oxygen-derived free radicals, and particularly the superoxide anion, are intermediaries in the formation and activation of osteoclasts. Images PMID:2312718

  20. Aging Leads to a Dysregulation in Mechanically Driven Bone Formation and Resorption.

    PubMed

    Razi, Hajar; Birkhold, Annette I; Weinkamer, Richard; Duda, Georg N; Willie, Bettina M; Checa, Sara

    2015-10-01

    Physical activity is essential to maintain skeletal mass and structure, but its effect seems to diminish with age. To test the hypothesis that bone becomes less sensitive to mechanical strain with age, we used a combined in vivo/in silico approach. We investigated how maturation and aging influence the mechanical regulation of bone formation and resorption to 2 weeks of noninvasive in vivo controlled loading in mice. Using 3D in vivo morphometrical assessment of longitudinal microcomputed tomography images, we quantified sites in the mouse tibia where bone was deposited or resorbed in response to controlled in vivo loading. We compared the (re)modeling events (formation/resorption/quiescent) to the mechanical strains induced at these sites (predicted using finite element analysis). Mice of all age groups (young, adult, and elderly) responded to loading with increased formation and decreased resorption, preferentially at high strains. Low strains were associated with no anabolic response in adult and elderly mice, whereas young animals showed a strong response. Adult animals showed a clear separation between strain ranges where formation and resorption occurred but without an intermediate quiescent "lazy zone". This strain threshold disappeared in elderly mice, as mechanically induced (re)modeling became dysregulated, apparent in an inability to inhibit resorption or initiate formation. Contrary to what is generally believed until now, aging does not shift the mechanical threshold required to initiate formation or resorption, but rather blurs its specificity. These data suggest that pharmaceutical strategies augmenting physical exercise should consider this dysfunction in the mechanical regulation of bone (re)modeling to more effectively combat age-related bone loss.

  1. 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

    2015-01-01

    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. PMID:26782444

  2. 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.

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

    SciTech Connect

    Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang; Li, Haowei; Ouyang, Zhengxiao; Wu, Chuanlong; Liu, Guangwang; Fan, Qiming; Tang, Tingting; Qin, An; Dai, Kerong

    2014-01-10

    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 differentiation 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.

  4. Changes in Bone Resorption Across the Menopause Transition: Effects of Reproductive Hormones, Body Size, and Ethnicity

    PubMed Central

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

    2013-01-01

    Objective: 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. Methods: 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. Results: 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. Summary: 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. PMID:23666961

  5. Histomorphometric evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism.

    PubMed

    Masarachia, P; Yamamoto, M; Leu, C T; Rodan, G; Duong, L

    1998-03-01

    Echistatin, an RGD-containing peptide, was shown to inhibit the acute calcemic response to exogenous PTH or PTH-related protein (PTH-rP) in thyroparathyroidectomized rats, suggesting that echistatin inhibits bone resorption. In this study: 1) we present histological evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism, and show that 2) echistatin binds to osteoclasts in vivo, 3) increases osteoclast number, and 4) does not detectably alter osteoclast morphology. Infusion of echistatin (30 microg/kg x min) for 3 days prevented the 2.6-fold increase in tibial cancellous bone turnover and the 36% loss in bone volume, produced by a low calcium diet. At the light microscopy level, echistatin immunolocalized to osteoclasts and megakaryocytes. Echistatin treatment increased osteoclast-covered bone surface by about 50%. At the ultrastructural level, these osteoclasts appeared normal, and the fraction of cells containing ruffled borders and clear zones was similar to controls. Echistatin was found on the basolateral membrane and in intracellular vesicles of actively resorbing osteoclasts. Weak labeling was found in the ruffled border, and no immunoreactivity was detected at the clear zone/bone surface interface. These findings provide histological evidence for echistatin binding to osteoclasts and for inhibition of bone resorption in vivo, through reduced osteoclast efficacy, without apparent changes in osteoclast morphology.

  6. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation.

    PubMed

    Takeshita, Sunao; Fumoto, Toshio; Matsuoka, Kazuhiko; Park, Kyoung-ae; Aburatani, Hiroyuki; Kato, Shigeaki; Ito, Masako; Ikeda, Kyoji

    2013-09-01

    Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule serves as a coupling factor for bone resorption to formation. We found that CTHRC1, a protein secreted by mature bone-resorbing osteoclasts, targets stromal cells to stimulate osteogenesis. Cthrc1 expression was robustly induced when mature osteoclasts were placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increased in a high-turnover state (such as that induced by RANKL injections in vivo), but decreased in conditions associated with suppressed bone turnover (such as with aging and after alendronate treatment). Targeted deletion of Cthrc1 in mice eliminated Cthrc1 expression in bone, whereas its deficiency in osteoblasts did not exert any significant effect. Osteoclast-specific deletion of Cthrc1 resulted in osteopenia due to reduced bone formation and impaired the coupling process after resorption induced by RANKL injections, impairing bone mass recovery. These data demonstrate that CTHRC1 is an osteoclast-secreted coupling factor that regulates bone remodeling.

  7. Short-term effects of fluoride and strontium on bone formation and resorption in the mouse.

    PubMed

    Marie, P J; Hott, M

    1986-06-01

    The early effects of sodium fluoride (0.80 mg/kg/d) and strontium chloride (0.27%) given alone, or in combination in drinking water, on bone metabolism were examined in the mouse using dynamic histomorphometric methods. Four weeks of oral strontium supplementation increased the osteoid surface and reduced the number of acid phosphatase-stained osteoclasts. However the trabecular calcified bone volume was not augmented. By contrast, short-term treatment with fluoride produced a rapid stimulatory effect on bone formation at a dose that did not affect the bone mineralization rate. Four weeks of fluoride supplementation induced a rapid 21.1% increase in the osteoblastic surface and a 26.3% stimulation of the bone matrix apposition rate evaluated by the double tritiated proline labelling method, which resulted in a 29% increase in the amount of osteoid. This rapid stimulation of the bone formation rate without detectable change in osteoclastic bone resorption led to a 12% increase in the trabecular calcified bone density. This study shows that fluoride and strontium produce distinct early effects on bone formation and resorption in the mouse and that fluoride exerts a rapid stimulatory effect on the bone matrix synthesis rate through an augmentation of the number of bone-forming cells. PMID:3713515

  8. Dimensional analysis of osteoclastic bone resorption and the measurement of biologically active calcitonin.

    PubMed

    Zaidi, M; Bax, B E; Shankar, V S; Moonga, B S; Simon, B; Alam, A S; Gaines Das, R E; Pazianas, M; Huang, C L

    1994-05-01

    Calcitonin inhibits bone resorption through a direct action on the osteoclast. We report a quantitative analysis of bone resorption by disaggregated rat osteoclasts. We then used our findings to develop a formal bioassay for calcitonin. Osteoclasts were mechanically disaggregated from neonatal rat long bones and dispersed at low densities on slices of devitalized bovine cortical bone. The resulting areas of bone excavation were quantified to micrometric precision by scanning electron microscopy together with computer-assisted image analysis. These findings were correlated with the volumes of bone resorption in the same slices measured by confocal scanning microscopy for the first time. The total planar areas of bone resorption per slice correlated linearly (r = 0.78) with the confocal microscopic measurements of total volume resorbed, provided that volume was expressed to its two-thirds power. The latter transformation resulted in representations of the determined areas ([length]2) and volumes ([length]3) which were dimensionally consistent. These findings thus demonstrate that osteoclastic bone excavations show a consistent relationship between area and volume and that assessments of the area of excavations accordingly provide an empirical representation of the volume of bone resorbed. Furthermore, in view of the skewed nature of the distributions of area measurements, we assessed the effect of transforming the response variable to derive a metameter, (planar area of resorption)1/2. Such transformed data points, which expressed the data in the dimensions of [length], were more normally distributed than the raw data points and had more stable variances over a wider concentration range. We accordingly determined relative potencies using parallel line analyses on the transformed data. The latter offered a consistent correlation to the volume measurements when these were also converted to dimensions of [length] (r = 0.805). It was confirmed that the inhibition of bone

  9. 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

  10. Parathyroid hormone stimulates bone formation and resorption in organ culture: evidence for a coupling mechanism.

    PubMed Central

    Howard, G A; Bottemiller, B L; Turner, R T; Rader, J I; Baylink, D J

    1981-01-01

    We have developed an in vitro system, using embryonic chicken tibiae grown in a serum-free medium, which exhibits simultaneous bone formation and resorption. Tibiae from 8-day embryos increased in mean (+/- SD) length (4.0 +/- 0.4 to 11.0 +/- 0.3 mm) and dry weight (0.30 +/- 0.04 to 0.84 +/- 0.04 mg) during 12 days in vitro. There was increased incorporation of [3H]proline into hydroxyproline (120 +/- 20 to 340 +/- 20 cpm/mg of bone per 24 hr) as a measure of collagen synthesis, as well as a 62 +/- 5% increase in total calcium and 45Ca taken up as an indication of active mineralization. A physiologic concentration (1 pM) of parathyroid hormone was found to stimulate bone resorption over control levels in this system. Parathyroid hormone stimulated the release of [3H]hydroxyproline from the bone shafts but not from the cartilage ends, indicating the specificity of the response. With 1 pM parathyroid hormone we observed an acute inhibition of bone formation, followed (after 12-16 hr) by a chronic stimulation of bone formation during the 12-day incubation. Both mineral uptake and matrix formation were enhanced at approximately the same rate during the 12-day incubation. The chronic enhancement of formation required parathyroid hormone only for the initial 8-10 hr of incubation. These results could be explained by the production or release of a factor from bone to stimulate formation in response to the acute increase in resorption--a "coupling factor." Indeed, dialyzed culture medium conditioned by actively resorbing bones stimulated bone formation over controls when added to organ cultures at a 1:20 dilution. The factor is larger than 12,000 daltons as determined by dialysis. The factor is specific for the bone shaft and did not affect the cartilage ends. PMID:6942425

  11. Is the fasting calcium/creatinine a bone resorption marker in patients with calcium renal stones?

    PubMed

    Arrabal-Polo, Miguel Angel; Arrabal-Martin, Miguel; Poyatos-Andujar, Antonio; Cardenas-Grande, Encarnacion; Merino-Salas, Sergio; Zuluaga-Gomez, Armando

    2012-06-01

    Osteoporosis and osteopenia are an important endocrine-metabolic disease that affect women and men from a certain age and it has a high risk and health cost. The aim of this short communication is to show that fasting calcium/creatinine ratio in patients with calcium stones is a marker of bone resorption.We studied 180 patients with renal stones with calcium composition and the relationship of them between the calcium/creatinine in urine after 8 h of fasting with bone densitometry (T-score) and values of bone resorption marker β-crosslaps (ng/ml). The Pearson correlation test was applied for the analysis of linear correlations between quantitative variables.We have observed a statistically significant positive linear correlation between the fasting calcium/creatinine and serum and β-crosslaps (R = 0.534, p < 0.0001) and a statistically significant negative linear correlation between fasting calcium/creatinine and T-score of bone densitometry in hip (R = -0.237, p = 0.002), femoral neck (R = -0.217, p = 0.009) and lumbar spine (R = 0.292, p = 0.001).The fasting ratio calcium/creatinine in urine is associated with increased levels of β-crosslaps marker and therefore may be useful as a marker of bone resorption in these patients.

  12. siRNA Knock-Down of RANK Signaling to Control Osteoclast-Mediated Bone Resorption

    PubMed Central

    Wang, Yuwei; Grainger, David W.

    2010-01-01

    Purpose To demonstrate the ability of small interfering (si)RNA targeting the cell receptor, RANK, to control osteoclast function in cultures of both primary and secondary osteoclasts and their precursor cells. Methods siRNA targeting RANK was transfected into both RAW264.7 and primary bone marrow cell cultures. RANK knock-down by siRNA and functional inhibition were assessed in both mature osteoclast and their precursor cell cultures. RANK mRNA message and protein expression after the transfections were analyzed by PCR and Western blot, respectively. Off-target effects were assessed. The inhibition of osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) assay, and subsequent bone resorption was determined by resorption pit assay. Results Both osteoclasts and osteoclast precursors can be targeted by siRNA in serum-containing media. Delivery of siRNA targeting RANK to both RAW 264.7 and primary bone marrow cell cultures produces short term repression of RANK expression without off-targeting effects, and significantly inhibits both osteoclast formation and bone resorption. Moreover, data support successful RANK knock-down by siRNA specifically in mature osteoclast cultures. Conclusions RANK is demonstrated to be an attractive target for siRNA control of osteoclast activity, with utility for development of new therapeutics for low bone mass pathologies or osteoporosis. PMID:20333451

  13. Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R

    PubMed Central

    LIU, SHUANGXIN; ZHU, WEIPING; LI, SIJIA; MA, JIANCHAO; ZHANG, HUITAO; LI, ZHONGHE; ZHANG, LI; ZHANG, BIN; LI, ZHUO; LIANG, XINLING; SHI, WEI

    2016-01-01

    The vacuolar-type H+ adenosine triphosphatase (V-ATPase) plays an important role in cellular acidification and bone resorption by osteoclasts. However, the direct effect of bovine parathyroid hormone (bPTH) on V-ATPase has not yet been elucidated. The aim of the present study was to assess the effects of bPTH on V-ATPase and osteoclasts. Osteoclasts from bone marrow (BM)-derived monocytes of C57BL/6 mice were cultured with or without bPTH. The mRNA and protein expression levels of the V-ATPase a3-subunit and d2-subunit (by RT-qPCR and western blot analysis), V-ATPase activity (using the V type ATPase Activity Assay kit) and the bone resorption function of osteoclasts (by bone resorption assay) were examined following treatment with various concentrations of bPTH (0.1, 1.0, 10 and 100 ng/ml) alone or with bPTH and its inhibitor, bafilomycin A1. Furthermore, the expression of parathyroid hormone (PTH) receptors in osteoclasts was also detected. The results revealed that the mRNA and protein expression levels of V-ATPase a3-subunit and d2-subunit increased in a dose-dependent manner, paralleling the level of bPTH present. In addition, an increase in the concentration of bPTH was accompanied by the increased resorption capability of osteoclasts, whereas bone resorption was inhibited in the presence of bafilomycin A1. In addition, we confirmed the existence of parathyroid hormone 1 receptor (PTH1R) in osteoclasts using three different methods (RT-qPCR, western blot analysis and immunofluorescence staining). We found that bPTH enhanced the bone resorption capability of osteoclasts by modulating the expression of V-ATPase subunits, intracellular acidification and V-ATPase activity. Thus, we propose that PTH has a direct effect on osteoblasts and osteoclasts, and that this effect is mediated through PTH1R, thus contributing to bone remodeling. PMID:26647715

  14. In-vivo effect of andrographolide on alveolar bone resorption induced by Porphyromonas gingivalis and its relation with antioxidant enzymes.

    PubMed

    Al Batran, Rami; Al-Bayaty, Fouad H; Al-Obaidi, Mazen M Jamil

    2013-01-01

    Alveolar bone resorption is one of the most important facts in denture construction. Porphyromonas gingivalis (Pg) causes alveolar bone resorption, and morphologic measurements are the most frequent methods to identify bone resorption in periodontal studies. This study has aimed at evaluating the effect of Andrographolide (AND) on alveolar bone resorption in rats induced by Pg. 24 healthy male Sprague Dawley rats were divided into four groups as follows: normal control group and three experimental groups challenged orally with Pg ATCC 33277 five times a week supplemented with 20 mg/kg and 10 mg/kg of AND for twelve weeks. Alveolar bones of the left and right sides of the mandible were assessed by a morphometric method. The bone level, that is, the distance from the alveolar bone crest to cementumenamel junction (CEJ), was measured using 6.1 : 1 zoom stereomicroscope and software. AND reduced the effect of Pg on alveolar bone resorption and decreased the serum levels of Hexanoyl-Lysine (HEL); furthermore the reduced glutathione/oxidised glutathione (GSH/GSSG) ratio in AND treated groups (10 and 20 mg/kg) significantly increased when compared with the Pg group (P < 0.05). We can conclude that AND suppresses alveolar bone resorption caused by Pg in rats.

  15. Quercetin inhibits inflammatory bone resorption in a mouse periodontitis model.

    PubMed

    Napimoga, Marcelo H; Clemente-Napimoga, Juliana T; Macedo, Cristina G; Freitas, Fabiana F; Stipp, Rafael N; Pinho-Ribeiro, Felipe A; Casagrande, Rubia; Verri, Waldiceu A

    2013-12-27

    Periodontitis is a disease that leads to bone destruction and represents the main cause of tooth loss in adults. The development of aggressive periodontitis has been associated with increased inflammatory response that is induced by the presence of a subgingival biofilm containing Aggregatibacter actinomycetemcomitans. The flavonoid quercetin (1) is widespread in vegetables and fruits and exhibits many biological properties for possible medical and clinical applications such as its anti-inflamatory and antioxidant effects. Thus, in the present study, the properties of 1 have been evaluated in bone loss and inflammation using a mouse periodontitis model induced by A. actinomycetemcomitans infection. Subcutaneous treatment with 1 reduced A. actinomycetemcomitans-induced bone loss and IL-1β, TNF-α, IL-17, RANKL, and ICAM-1 production in the gingival tissue without affecting bacterial counts. These results demonstrated that quercetin exhibits protective effects in A. actinomycetemcomitans-induced periodontitis in mice by modulating cytokine and ICAM-1 production.

  16. The role of interleukin-1 in bone resorption in rheumatoid arthritis.

    PubMed

    Strand, V; Kavanaugh, A F

    2004-06-01

    Bone loss in RA includes juxta-articular osteopenia, erosions and systemic osteoporosis. In each case, synthesis of new bone matrix is unable to balance osteoclast-mediated bone resorption, resulting in net bone loss. IL-1, TNF and other proinflammatory cytokines stimulate osteoclast differentiation and activation, resulting in bone loss. In addition, these proinflammatory cytokines stimulate synovial fibroblasts and chondrocytes to produce proteinases that degrade cartilage. In animal arthritis models, blocking IL-1 significantly reduces bone erosions and cartilage degradation, whereas blocking TNF decreases synovitis. In patients with active RA, treatment with the TNF blockers etanercept and infliximab, as well as with anakinra, a recombinant human IL-1 receptor antagonist, significantly reduced erosions and joint space narrowing. It remains to be determined, however, whether slowing radiographic progression with these biological therapies will significantly improve long-term outcomes in RA.

  17. MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption

    PubMed Central

    He, Zhimin; He, Jin; Liu, Zhiqiang; Xu, Jingda; Yi, Sofia F.; Liu, Huan; Yang, Jing

    2014-01-01

    Breast cancer cells frequently metastasize to bone and induce osteolytic bone destruction in patients. These metastases cause severe bone pain, high risk of fractures and hypercalcemia, and are essentially incurable and fatal. Recent studies show that breast cancer cells in bone activate osteoclastogenesis and bone resorption. However the underlying mechanism is poorly understood. This study shows that the p38 MAPK (p38) isoform MAPK11 (p38β) is expressed in breast cancer cells. By using specific small hairpin RNAs for MAPK11, we demonstrated that p38β-mediated p38 activity in breast cancer cells is responsible for breast cancer-induced osteolytic bone destruction. The addition of conditioned media from breast cancer cell lines MDA-MB-231 and MDA-MB-468, which have high expression of p38β, induced osteoclast differentiation and bone resorption. In contrast, knockdown of p38β in breast cancer cells reduced osteoclast differentiation in vitro and reduced bone destruction in severe combined immunodeficiency (SCID) mouse models. The knockdown of p38β did not affect tumor growth or survival or the ability of cancer cells to home to bone. Furthermore, our results showed that p38β upregulated the expression and secretion of monocyte chemotactic protein-1 (MCP-1) in breast cancer cells, and upregulated MCP-1 activates osteoclast differentiation and activity. This study elucidates a novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction. This study also indicates that targeting breast cancer cell p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer. PMID:25066918

  18. Resorption of bone implants. The effect of in vivo incorporation of a diphosphonate and fluoride on resorption.

    PubMed

    Rosenquist, J B; Baylink, D J

    1978-02-01

    Weanling isogenously related rats were divided into one control group, one group given a fluoride supplement of 100 parts/10(6) of F- in the drinking water, and a third group given 0.5 mg per kg body weight of phosphorus as dichloromethylene diphosphanic acid (Cl2MDP). The rats were labeled with 1 muCi per g body weight of 3H proline and 40 muCi of 45Ca. Four weeks after labeling, the animals were sacrificed and one scapula was implanted subcutaneously in the back of an isogenously related rat of the same age. The other scapula was stored in a freezer pending analysis. After another 4 weeks the implants were recovered and the radioactivity of each isotope was compared with that of the initially stored scapulae. A 30-40% loss of activity was found, reflecting a considerable loss of bone. However, this loss was significantly lower (P less than 0.01) when Cl2MDP was given to the donor animals, whereas fluoride treatment did not affect the resorption.

  19. Influence of bone resorption on the mobilization of lead from bone among middle-aged and elderly men: the Normative Aging Study.

    PubMed Central

    Tsaih, S W; Korrick, S; Schwartz, J; Lee, M L; Amarasiriwardena, C; Aro, A; Sparrow, D; Hu, H

    2001-01-01

    Bone stores of lead accrued from environmental exposures and found in most of the general population have recently been linked to the development of hypertension, cognitive decrements, and adverse reproductive outcomes. The skeleton is the major endogenous source of lead in circulating blood, particularly under conditions of accelerated bone turnover and mineral loss, such as during pregnancy and in postmenopausal osteoporosis. We studied the influence of bone resorption rate on the release of lead from bone in 333 men, predominantly white, middle-aged and elderly (mostly retired) from the Boston area. We evaluated bone resorption by measuring cross-linked N-telopeptides of type I collagen (NTx) in 24-hr urine samples with an enzyme-linked immunosorbent assay. We used K-X-ray fluorescence to measure lead content in cortical (tibia) and trabecular (patella) bone; we used graphite furnace atomic absorption spectroscopy and inductively coupled plasma mass spectroscopy to measure lead in blood and urine, respectively. After adjustment for age and creatinine clearance, the positive relation of patella lead to urinary lead was stronger among subjects in the upper two NTx tertiles (beta for patella lead > or =0.015) than in the lowest NTx tertile (beta for patella lead = 0.008; overall p-value for interactions = 0.06). In contrast, we found no statistically significant influence of NTx tertile on the relationship of blood lead to urinary lead. As expected, the magnitude of the relationship of bone lead to urinary lead diminished after adjustment for blood lead. Nevertheless, the pattern of the relationships of bone lead to urinary lead across NTx tertiles remained unchanged. Furthermore, after adjustment for age, the relation of patella lead to blood lead was significantly stronger in the upper two NTx tertiles (beta for patella lead > or =0.125) than in the lowest NTx tertile (beta for patella lead = 0.072). The results provide evidence that bone resorption influences

  20. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles?

    PubMed

    Sapir-Koren, R; Livshits, G

    2014-12-01

    Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-β-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical

  1. Interleukin 6 production in fetal rat long bone cultures is correlated with PGE2 release and does not correlate with the extent of bone resorption.

    PubMed

    Bertolini, D R; Votta, B; Hoffman, S; Strassmann, G

    1994-07-01

    Reports from several laboratories have suggested that interleukin 6 (IL-6) may play a role in the process of bone resorption. We have extended these studies by examining the role of IL-6 in fetal rat long bone (FRLB) resorption stimulated by a variety of agents, including parathyroid hormone (PTH); 1,25 dihydroxyvitamin D3 (1,25(OH)2D3); interleukin 1 (IL-1); tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS). This model of bone resorption does not require the generation of osteoclasts in order to elicit a resorptive response and allowed us to assess whether IL-6 can directly affect osteoclastic bone resorption. We confirmed previous studies which showed that exogenous recombinant murine or human IL-6 does not stimulate bone resorption and demonstrated that IL-6, when added prior to the addition of parathyroid hormone, caused a significant but somewhat variable inhibition at 120 hours. Exogenous PGE2 stimulated both IL-6 production and resorption in FRLB cultures in a concentration-dependent manner. Endogenous production of IL-6 in fetal rat long bone (FRLB) cultures was stimulus dependent and generally correlated with prostaglandin E2 (PGE2) levels in the same cultures. However, endogenous IL-6 production did not correlate with the extent of bone resorption, except when IL-1 and PGE2 were used as stimuli. Addition of indomethacin and diclofenac to IL-1 stimulated cultures demonstrated that both the IL-6 production and bone resorption were largely PGE-2 dependent. Neutralizing anti-IL-6 antibodies inhibited IL-6 activity in FRLB cultures but did not affect bone resorption, even in the IL-1 stimulated cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. 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

  3. 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

  4. Isotopic evidence for resorption of soft tissues and bone in immobilized dogs

    SciTech Connect

    Klein, L.; Player, J.S.; Heiple, K.G.; Bahniuk, E.; Goldberg, V.M.

    1982-02-01

    Various experimental methods for producing bone and ligament atrophy have yielded contradictory results. These methods include denervation, immobilization (both internal and external), and disarticulation. We studied a model of internal skeletal fixation for twelve weeks in dogs that were chronically prelabeled with 3H-tetracycline, 45Ca, and 3H-proline. Bone resorption was analyzed by the loss of 3H-tetracycline, and bone and soft-tissue mass were analyzed by the radiochemical and chemical analysis of calcium and collagen. The strength of the anterior cruciate ligament was studied in tension to failure when a fast rate of deformation was applied. Failure of the femur-ligament-tibia complex occurred through the insertion of the ligament into the tibia for both the experimental and the control limbs. Loss of collagen was greater in the tibia and femur than in the lateral meniscus and anterior cruciate ligament, and correlated with a mechanical failure via bone. No evidence for collagen replacement in atrophied tissues was found, but one-half of the resorbed calcium was conserved. The marked loss of 3H-tetracycline indicated that bone atrophy was the result of increased resorption of bone rather than decreased bone formation. Clinical Relevance: We have demonstrated significant atrophy of the soft tissues (lateral meniscus and anterior cruciate ligament) as well as of bone in immobilized joints of dogs. It is likely that the decrease in strength of the bone-ligament-bone complex is related to this atrophy of soft tissues and bone around the joint.

  5. Role of carbonic anhydrase in bone resorption induced by 1,25 dihydroxyvitamin D3 in vitro

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

    The calvaria of 5-to-6-day-old mice treated with 1 x 10 to the -8th M of 1,25(OH)2D3 in vitro for 48 hours are examined in order to study the function of carbonic anhydrase in bone resorption. Calcium concentrations in the culture were measured to assess bone resorption. It is observed that 1,25(OH)2D3 effectively stimulates bone resorption in vitro and the resorption is dose-dependent. The effects of azetazolamide on 1,25(OH)2D3-induced bone resorption are investigated. The data reveal that 1,25(OH)2D3-induced calcium release is associated with an increase in the carbonic anhydrase activity of bone, and bone alkaline phosphatase activity is decreased and acid phosphatase activity is increased in response to 1,25(OH)2D3. A two-fold mechanism for 1,25(OH)2D3-induced bone resorption is proposed; the first mechanism is an indirect activation of osteoclasts and the second involves an interaction between hormone and osteoclast precursors.

  6. Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops.

    PubMed

    Li, Jing; Zeng, Li; Xie, Juan; Yue, Zhiying; Deng, Huayun; Ma, Xueyun; Zheng, Chunbing; Wu, Xiushan; Luo, Jian; Liu, Mingyao

    2015-01-01

    Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca(2+)/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis. PMID:26620037

  7. Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops

    PubMed Central

    Li, Jing; Zeng, Li; Xie, Juan; Yue, Zhiying; Deng, Huayun; Ma, Xueyun; Zheng, Chunbing; Wu, Xiushan; Luo, Jian; Liu, Mingyao

    2015-01-01

    Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca2+/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis. PMID:26620037

  8. Simulation of the in vivo resorption rate of β-tricalcium phosphate bone graft substitutes implanted in a sheep model.

    PubMed

    Bashoor-Zadeh, Mahdieh; Baroud, Gamal; Bohner, Marc

    2011-09-01

    A few years ago, a model was proposed to predict the effect of the pore architecture of a bone graft substitute on its cell-mediated resorption rate. The aim of the present study was to compare the predictions of the model with the in vivo resorption rate of four β-tricalcium phosphate bone graft substitutes implanted in a sheep model. The simulation algorithm contained two main steps: (1) detection of the pores that could be accessed by blood vessels of 50 μm in diameter, and (2) removal of one solid layer at the surface of these pores. This process was repeated until full resorption occurred. Since the pore architecture was complex, μCT data and fuzzy imaging techniques were combined to reconstruct the precise bone graft substitute geometry and then image processing algorithms were developed to perform the resorption simulation steps. The proposed algorithm was verified by comparing its results with the analytical results of a simple geometry and experimental in-vivo data of β-TCP bone substitutes with more complex geometry. An excellent correlation (r(2)>0.9 for all 4 bone graft substitutes) was found between simulation results and in-vivo data, suggesting that this resorption model could be used to (i) better understand the in vivo behavior of bone graft substitutes resorbed by cell-mediation, and (ii) optimize the pore architecture of a bone graft substitute, for example to maximize its resorption rate.

  9. Epstein-Barr virus infection induces bone resorption in apical periodontitis via increased production of reactive oxygen species.

    PubMed

    Jakovljevic, Aleksandar; Andric, Miroslav; Miletic, Maja; Beljic-Ivanovic, Katarina; Knezevic, Aleksandra; Mojsilovic, Slavko; Milasin, Jelena

    2016-09-01

    Chronic inflammatory processes in periapical tissues caused by etiological agents of endodontic origin lead to apical periodontitis. Apart from bacteria, two herpesviruses, Epstein-Barr virus (EBV) and Human cytomegalovirus (HCMV) are recognized as putative pathogens in apical periodontitis. Although previous reports suggest the involvement of EBV in the pathogenesis of apical periodontitis, its exact role in periapical bone resorption has not yet been fully elucidated. We hypothesize that EBV infection in apical periodontitis is capable of inducing periapical bone resorption via stimulation of reactive oxygen species (ROS) overproduction. Increased levels of ROS induce expression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL). RANKL binding to receptor activator of nuclear factor κB (RANK) present on the surface of preosteoclasts induces their maturation and activation which consequently leads to bone resorption. The potential benefit of antiviral and antioxidant-based therapies in periapical bone resorption treatment remains to be assessed. PMID:27515196

  10. Bortezomib Inhibits Osteoclastogenesis and Porphyromonas gingivalis Lipopolysaccharide-induced Alveolar Bone Resorption.

    PubMed

    Kim, Y-G; Kang, J H; Kim, H J; Kim, H J; Kim, H-H; Kim, J-Y; Lee, Y

    2015-09-01

    Healthy bone is maintained by the coordinated activities of osteoblast-mediated bone formation and osteoclast-dependent bone resorption. Pathologic conditions such as hormonal imbalance and inflammation cause increased osteoclastogenesis resulting in osteoporosis, rheumatoid arthritis, and periodontitis. Bortezomib is novel antimyeloma agent that has a direct beneficial effect on bone formation. However, the role of bortezomib in osteoclastogenesis and underlying mechanisms remains to be fully comprehended. In the present study, we show that bortezomib directly inhibited the receptor activator of nuclear factor κB ligand (RANKL)- and lipopolysaccharide-dependent osteoclast differentiation. Interestingly, the bortezomib-mediated inhibition of osteoclastogenesis was transient, since the removal of bortezomib from culture completely restored osteoclast differentiation. Bortezomib impeded the induction and nuclear localization of nuclear factor of activated T cells, cytoplasmic 1 and reduced both macrophage colony-stimulating factor- and RANKL-induced extracellular-signal-regulated kinase (ERK) phosphorylation. In a mouse model of periodontitis, bortezomib prevented alveolar bone erosion induced by Porphyromonas gingivalis lipopolysaccharide. These data not only suggest a previously unappreciated mechanism by which bortezomib regulates bone resorption but also propose novel applications of bortezomib beyond its use as an antimyeloma agent.

  11. Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics.

    PubMed

    Zaidi, Mone; Blair, Harry C; Moonga, Baltit S; Abe, Etsuko; Huang, Christopher L H

    2003-04-01

    Over the past decade, advances in molecular tools, stem cell differentiation, osteoclast and osteoblast signaling mechanisms, and genetically manipulated mice models have resulted in major breakthroughs in understanding osteoclast biology. This review focuses on key advances in our understanding of molecular mechanisms underlying the formation, function, and survival of osteoclasts. These include key signals mediating osteoclast differentiation, including PU.1, RANK, CSF-1/c-fms, and src, and key specializations of the osteoclast including HCl secretion driven by H+-ATPase and the secretion of collagenolytic enzymes including cathepsin K and matrix metalloproteinases (MMPs). These pathways and highly expressed proteins provide targets for specific therapies to modify bone degradation. The main outstanding issues, basic and translational, will be considered in relation to the osteoclast as a target for antiresorptive therapies.

  12. Autogenous calvarium bone grafting as a treatment for severe bone resorption in the upper maxilla: a case report.

    PubMed

    Díaz-Romeral-Bautista, Migugel; Manchón-Miralles, Angel; Asenjo-Cabezón, Jorge; Cebrián-Carretero, José-Luis; Torres-García-Denche, Jesús; Linares-García-Valdecasas, Rafael

    2010-03-01

    Atrophic maxilla rehabilitation has been the subject of several studies for decades; despite this, there are still many different therapeutic choices for the best way to treat maxillary resorption in order to enable implant placement and integration. These possibilities include the optimal use of remaining bone structures, such as the pterygoid processes or zygomatic arch, which involves using zygomaticus and pterygoid implants in combination with standard implants placed in the residual bone; alternatively, regenerative techniques, alveolar bone expansion/distraction or bone grafting techniques may be used. Severe maxillary atrophy has a multifactorial aetiology; the most important factors being long evolution edentulism, hyperpneumatization of the maxillary sinus, post-traumatic deficit, bone loss after surgery (tumours, cysts) and periodontal problems or infection. In this report, we present a clinical case of onlay block reconstruction in an atrophic maxilla with harvested cranial calvarium bone grafts for successful future implant-supported oral rehabilitation.

  13. 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.

  14. Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma.

    PubMed

    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

    2016-08-24

    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 up-regulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP up-regulated the methylation of IRF8 and thereby enhanced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1 protein), leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2-deoxy-d-ribose (2DDR). Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K (phosphoinositide 3-kinase)/Akt signaling, and increased DNMT3A (DNA methyltransferase 3A) 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. Because TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications. PMID:27559096

  15. Biocompatibility, resorption and biofunctionality of a new synthetic biodegradable membrane for guided bone regeneration.

    PubMed

    Hoornaert, Alain; d'Arros, Cyril; Heymann, Marie-Francoise; Layrolle, Pierre

    2016-01-01

    Membranes for guided bone regeneration (GBR) were prepared from the synthetic biodegradable polymer poly-D,L-lactic/glycolic acid (PLGA). This GBR membrane has a bi-layered structure with a dense film to prevent gingival fibroblast ingrowth and ensure mechanical function, and a micro-fibrous layer to support colonization by osteogenic cells and promote bone regeneration. Hydrolysis and biodegradation were both studied in vitro through soaking in phosphate buffered saline (PBS) and in vivo by implantation in the subcutis of rats for 4, 8, 16, 26, 48 and 52 weeks. Histology revealed an excellent colonization of the micro-fibrous layer by cells with a minimal inflammatory reaction during resorption. GBR using the synthetic PLGA membrane was evaluated on critical-size calvaria defects in rats for 4 and 8 weeks. Radiographs, micro-computed tomography and histology showed bone regeneration with the PLGA membrane, while the defects covered with a collagen membrane showed a limited amount of mineralized bone, similar to that of the defect left empty. The biofunctionality of the PLGA membranes was also compared to collagen membranes in mandible defects in rabbits, associated or not with beta-tricalcium phosphate granules. This study revealed that the bi-layered synthetic membrane made of PLGA was safer, more biocompatible, and had a greater controlled resorption rate and bone regeneration capacity than collagen membranes. This new PLGA membrane could be used in pre-implantology and peri-odontology surgery. PMID:27509180

  16. Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis

    PubMed Central

    Marriott, Ian

    2013-01-01

    The mechanisms underlying the destruction of bone tissue in osteomyelitis are only now being elucidated. While some of the tissue damage associated with osteomyelitis likely results from the direct actions of bacteria and infiltrating leukocytes, perhaps exacerbated by bacterial manipulation of leukocyte survival pathways, infection-induced bone loss predominantly results from an uncoupling of the activities of osteoblasts and osteoclasts. Bacteria or their products can directly increase osteoclast formation and activity, and the inflammatory milieu at sites of infection can further promote bone resorption. In addition, osteoclast activity is critically regulated by osteoblasts that can respond to bacterial pathogens and foster both inflammation and osteoclastogenesis. Importantly, bone loss during osteomyelitis is also brought about by a decline in new bone deposition due to decreased bone matrix synthesis and by increased rates of osteoblast apoptosis. Extracellular bacterial components may be sufficient to reduce osteoblast viability, but the causative agents of osteomyelitis are also capable of inducing continuous apoptosis of these cells by activating intrinsic and extrinsic cell death pathways to further uncouple bone formation and resorption. Interestingly, bacterial internalization appears to be required for maximal osteoblast apoptosis, and cytosolic inflammasome activation may act in concert with autocrine/paracrine death receptor-ligand signaling to induce cell death. The manipulation of apoptotic pathways in infected bone cells could be an attractive new means to limit inflammatory damage in osteomyelitis. However, the mechanism that is the most important in bacterium-induced bone loss has not yet been identified. Furthermore, it remains to be determined whether the host would be best served by preventing osteoblast cell death or by promoting apoptosis in infected cells. PMID:24392356

  17. Dasatinib as a Bone-Modifying Agent: Anabolic and Anti-Resorptive Effects

    PubMed Central

    Garcia-Gomez, Antonio; Ocio, Enrique M.; Crusoe, Edvan; Santamaria, Carlos; Hernández-Campo, Pilar; Blanco, Juan F.; Sanchez-Guijo, Fermin M.; Hernández-Iglesias, Teresa; Briñón, Jesús G.; Fisac-Herrero, Rosa M.; Lee, Francis Y.; Pandiella, Atanasio; San Miguel, Jesús F.; Garayoa, Mercedes

    2012-01-01

    Background Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. Methods For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. Results Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2–5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1–2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression. Conclusions Low dasatinib concentrations show convergent bone anabolic and reduced bone

  18. 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.

  19. Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption.

    PubMed Central

    Greenfield, E M; Shaw, S M; Gornik, S A; Banks, M A

    1995-01-01

    Parathyroid hormone and other bone resorptive agents function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previously identified two potentially important cytokines by demonstrating that parathyroid hormone induces expression by osteoblasts of IL-6 and leukemia inhibitory factor without affecting levels of 14 other cytokines. Although parathyroid hormone activates multiple signal transduction pathways, induction of IL-6 and leukemia inhibitory factor is dependent on activation of adenyl cyclase. This study demonstrates that adenyl cyclase is also required for stimulation of osteoclast activity in cultures containing osteoclasts from rat long bones and UMR106-01 rat osteoblast-like osteosarcoma cells. Since the stimulation by parathyroid hormone of both cytokine production and bone resorption depends on the same signal transduction pathway, we hypothesized that IL-6 might be a downstream effector of parathyroid hormone. We found that addition of exogenous IL-6 mimics the ability of parathyroid hormone to stimulate bone resorption. More importantly, an antibody directed against the IL-6 receptor blocks moderate stimulation of osteoclast activity induced by the hormone. Interestingly, strong stimulation of resorption overcomes this dependence on IL-6. Thus, parathyroid hormone likely induces multiple, redundant cytokines that can overcome the IL-6 requirement associated with moderate stimulation. Taken together with studies showing that many other bone resorptive agents also stimulate IL-6 production, our results suggest that IL-6 may be a downstream effector of these agents as well as of parathyroid hormone. Images PMID:7657797

  20. Role of serum FSH measurement on bone resorption in postmenopausal women.

    PubMed

    García-Martín, Antonia; Reyes-García, Rebeca; García-Castro, José Miguel; Rozas-Moreno, Pedro; Escobar-Jiménez, Fernando; Muñoz-Torres, Manuel

    2012-04-01

    In vitro and animals models have shown follicle-stimulating hormone (FSH) effects on osteoclastic function, and FSH levels seem to influence bone loss independently of estrogen concentrations in humans. Our aim was to evaluate the role of serum FSH measurement in the assessment of bone resorption in postmenopausal women. We conducted a cross-sectional study including 92 postmenopausal healthy women aged 56.2 (3.6) and 7.2 (4) years since menopause. Serum FSH, luteinizing hormone (LH), estradiol (E2) and bone turnover markers as osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTX) were measured. We analyzed the relationship between serum levels of gonadotropins, E2, and bone turnover markers. Serum levels of OC and CTX were positively related to FSH (r = 0.234, P = 0.047 and r = 0.384, P = 0.003) and LH (r = 0.319, P = 0.012 and r = 0.273, P = 0.038). There was no relationship with E2 levels. When gonadotropins levels were divided into quartiles, we found significant differences in bone turnover markers between the first and the fourth quartile. OC levels were higher in the highest quartile of FSH (P = 0.024) and LH (P = 0.001). Serum CTX was also higher in the highest quartile of FSH (P = 0.004) and LH (P = 0.039). FSH levels could explain approximately 14.7% of the chances in CTX. In summary, gonadotropins were related to bone turnover in postmenopausal healthy women. Moreover, the rise in FSH appears to contribute to higher bone resorption. Our results suggest that the measurement of FSH could be usefulness to perform a more comprehensive assessment of bone loss in these women.

  1. 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

  2. Targeted overexpression of osteoactivin in cells of osteoclastic lineage promotes osteoclastic resorption and bone loss in mice.

    PubMed

    Sheng, Matilda H-C; Wergedal, Jon E; Mohan, Subburaman; Amoui, Mehran; Baylink, David J; Lau, K-H William

    2012-01-01

    This study sought to test whether targeted overexpression of osteoactivin (OA) in cells of osteoclastic lineage, using the tartrate-resistant acid phosphase (TRAP) exon 1B/C promoter to drive OA expression, would increase bone resorption and bone loss in vivo. OA transgenic osteoclasts showed ∼2-fold increases in OA mRNA and proteins compared wild-type (WT) osteoclasts. However, the OA expression in transgenic osteoblasts was not different. At 4, 8, and 15.3 week-old, transgenic mice showed significant bone loss determined by pQCT and confirmed by μ-CT. In vitro, transgenic osteoclasts were twice as large, had twice as much TRAP activity, resorbed twice as much bone matrix, and expressed twice as much osteoclastic genes (MMP9, calciton receptor, and ADAM12), as WT osteoclasts. The siRNA-mediated suppression of OA expression in RAW264.7-derived osteoclasts reduced cell size and osteoclastic gene expression. Bone histomorphometry revealed that transgenic mice had more osteoclasts and osteoclast surface. Plasma c-telopeptide (a resorption biomarker) measurements confirmed an increase in bone resorption in transgenic mice in vivo. In contrast, histomorphometric bone formation parameters and plasma levels of bone formation biomarkers (osteocalcin and pro-collagen type I N-terminal peptide) were not different between transgenic mice and WT littermates, indicating the lack of bone formation effects. In conclusion, this study provides compelling in vivo evidence that osteoclast-derived OA is a novel stimulator of osteoclast activity and bone resorption.

  3. Influences of Fucoxanthin on Alveolar Bone Resorption in Induced Periodontitis in Rat Molars

    PubMed Central

    Kose, Oguz; Arabaci, Taner; Yemenoglu, Hatice; Kara, Adem; Ozkanlar, Seckin; Kayis, Sevki; Duymus, Zeynep Yesil

    2016-01-01

    The aim of this study was to evaluate the effects of systemic fucoxanthin treatment on alveolar bone resorption in rats with periodontitis. Thirty rats were divided into control, experimental periodontitis (EP), and experimental periodontitis-fucoxanthin (EP-FUCO) groups. Periodontitis was induced by ligature for four weeks. After removal of the ligature, the rats in the EP-FUCO group were treated with a single dose of fucoxanthin (200 mg/kg bw) per day for 28 consecutive days. At the end of the study, all of the rats were euthanized and intracardiac blood and mandible tissue samples were obtained for biochemical, immunohistochemical, and histometric analyses. Fucoxanthin treatment resulted in a slight decrease in tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels and a significant decrease in oxidative stress index. It was observed that fucoxanthin caused a significant reduction in receptor activator of nuclear factor kappa-β ligand (RANKL) levels and a statistically non-significant elevation in osteoprotegerin and bone-alkaline phosphatase levels. There were no significant differences in alveolar bone loss levels between the EP and EP-FUCO groups. This experimental study revealed that fucoxanthin provides a limited reduction in alveolar bone resorption in rats with periodontitis. One of the mechanisms underlying the mentioned limited effect might be related to the ability of fucoxanthin to inhibit oxidative stress-related RANKL-mediated osteoclastogenesis. PMID:27043583

  4. 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.

  5. Follicle-stimulating hormone enhances alveolar bone resorption via upregulation of cyclooxygenase-2

    PubMed Central

    Zhu, Chunxia; Ji, Yaoting; Liu, Shengbo; Bian, Zhuan

    2016-01-01

    This study aimed to investigate whether follicle-stimulating hormone (FSH)-induced alveolar bone resorption was mediated by a cyclooxygenase 2 (COX-2) enzyme related mechanism. Experimental periodontitis was induced in bilateral ovariectomized (OVX) rats, some of which were injected with triptorelin, an FSH inhibitor. After mandibles were collected, we performed micro-computed tomography to evaluate alveolar bone loss and immunohistochemical staining to assess COX-2 expression. As well, human periodontal ligament cells (PDLCs) were treated with FSH (30 ng/ml), and the COX-2 mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qPCR) and Western blotting, respectively; prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay (ELISA). The results indicated that FSH significantly increased alveolar bone resorption and the expression of COX-2 in the bilateral OVX + Ligatured rats compared with the other treatment groups. FSH also increased the mRNA and protein expression of COX-2 and PGE2 (P < 0.01) in human PDLCs. Further, the analysis of signaling pathways revealed the activation of COX-2-mediated pathways including Erk, p38, and Akt. These data suggest that FSH aggravates alveolar bone loss via a COX-2-upregulation mechanism and that the Erk, p38, and Akt pathways are involved in this pathological process. PMID:27725865

  6. Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis.

    PubMed

    Wisłowska, Margaret; Jakubicz, Danuta; Stepień, Krystyna; Cicha, Małgorzata

    2009-10-01

    Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-alpha, IL-1, IL-6) osteoclasts' activation, osteoprotegerin and its ligand's (RANKL) function disorders, patients' immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation--serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler-Rose's test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers' concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers' concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers' concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale's than at

  7. 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

  8. Treatment with the combination of ibandronate plus eldecalcitol has a synergistic effect on inhibition of bone resorption without suppressing bone formation in ovariectomized rats.

    PubMed

    Sakai, Sadaoki; Takeda, Satoshi; Sugimoto, Masanori; Shimizu, Masaru; Shimonaka, Yasushi; Yogo, Kenji; Hashimoto, Junko; Bauss, Frieder; Endo, Koichi

    2015-12-01

    Bisphosphonates are widely used in the treatment of osteoporosis and contribute to the reduction of bone fractures. Ibandronate (IBN) is a highly potent, nitrogen-containing bisphosphonate, which is administered orally or intravenously at extended dosing intervals. Vitamin D or active vitamin D3 derivatives are also used in the treatment of osteoporosis, and are often used in combination with other drugs. In this study, we investigated the effect of treatment with the combination of once-monthly s.c. dosing of IBN plus once-daily oral eldecalcitol (ELD), an active vitamin D3 derivative, using aged ovariectomized (OVX) rats. Treatment was started the day after OVX, and analyses were performed 4, 8, and 12 weeks thereafter by determination of bone markers, bone mineral density, biomechanical properties, and histomorphometry. The combination treatment showed a synergistic effect in increasing both lumbar and femoral BMD, and resulted in a significant increase in bone ultimate load. The combination of IBN plus ELD acted synergistically to reduce bone resorption, whereas bone formation did not decrease any more than with monotherapy with either IBN or ELD. Bone formation independent of bone resorption (a process known as 'minimodeling') was not changed in vehicle treated OVX rats despite the increase in bone turnover. ELD upregulated minimodeling, which was however not diminished in the combination treatment. In conclusion, treatment with the combination of IBN plus ELD was beneficial in the treatment of osteoporosis in aged OVX rats. It exhibited a synergistic inhibitory effect on bone resorption and keeps bone formation at the level of sham controls. This uncoupling of bone resorption/bone formation was affected, to some extent, by minimodeling-based bone formation which is independent of bone resorption. This combination regimen which showed synergistic effect on BMD and bone ultimate load without inhibition of bone formation may be beneficial in long

  9. From histology to micro-CT: Measuring and modeling resorption cavities and their relation to bone competence

    PubMed Central

    Vanderoost, Jef; van Lenthe, G Harry

    2014-01-01

    The process of bone remodelling plays an essential role in the emergence and maintenance of bone geometry and its internal structure. Osteoclasts are one of the three main bone cell types that play a crucial role in the bone remodelling cycle. At the microstructural level, osteoclasts create bone deficits by eroding resorption cavities. Understanding how these cavities impair the mechanical quality of the bone is not only relevant in quantifying the impact of resorption cavities in healthy bone and normal aging, but maybe even more so in quantifying their role in metabolic bone diseases. Metabolic bone diseases and their treatment are both known to affect the bone remodelling cycle; hence, the bone mechanical competence can and will be affected. However, the current knowledge of the precise dimensions of these cavities and their effect on bone competence is rather limited. This is not surprising considering the difficulties in deriving three-dimensional (3D) properties from two-dimensional (2D) histological sections. The measurement difficulties are reflected in the evaluation of how resorption cavities affect bone competence. Although detailed 3D models are generally being used to quantify the mechanical impact of the cavities, the representation of the cavities themselves has basically been limited to simplified shapes and averaged cavity properties. Qualitatively, these models indicate that cavity size and location are important, and that the effect of cavities is larger than can be expected from simple bone loss. In summary, the dimensions of osteoclast resorption cavities were until recently estimated from 2D measures; hence, a careful interpretation of resorption cavity dimensions is necessary. More effort needs to go into correctly quantifying resorption cavities using modern 3D imaging techniques like micro-computed tomography (micro-CT) and synchrotron radiation CT. Osteoclast resorption cavities affect bone competence. The structure-function relationships

  10. Doxycycline inhibits bone resorption by human interface membrane cells from aseptically loose hip replacements.

    PubMed

    Ong, S M; Taylor, G J S

    2003-04-01

    Matrix metalloproteinases (MMPs) may have a role in the process of aseptic loosening. Doxycycline has been shown to inhibit MMPs. Our aim was to investigate the potential pharmacological effect of doxycycline on aseptic loosening. We used radiolabelled mouse calvariae cultured with human interface membrane cells from aseptically loosened hips. Bone resorption was confirmed in this model. The effect of doxycycline was assessed by culturing dead radiolabelled bone discs with cells from the interface membrane with doxycycline. The control group consisted of the same culture system without doxycycline. Supernatant 45calcium and the total 45calcium remaining in the bone discs at the completion of the culture were used to measure osteolysis. We found that doxycycline can inhibit osteolysis at the interface membrane of aseptically loosened hips. This may have therapeutic implications for the treatment of patients with aseptic loosening of total joint replacements. PMID:12729128

  11. 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

  12. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.

    PubMed

    Park-Min, Kyung-Hyun; Lim, Elisha; Lee, Min Joon; Park, Sung Ho; Giannopoulou, Eugenia; Yarilina, Anna; van der Meulen, Marjolein; Zhao, Baohong; Smithers, Nicholas; Witherington, Jason; Lee, Kevin; Tak, Paul P; Prinjha, Rab K; Ivashkiv, Lionel B

    2014-11-13

    Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption.

  13. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.

    PubMed

    Park-Min, Kyung-Hyun; Lim, Elisha; Lee, Min Joon; Park, Sung Ho; Giannopoulou, Eugenia; Yarilina, Anna; van der Meulen, Marjolein; Zhao, Baohong; Smithers, Nicholas; Witherington, Jason; Lee, Kevin; Tak, Paul P; Prinjha, Rab K; Ivashkiv, Lionel B

    2014-01-01

    Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption. PMID:25391636

  14. Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation

    PubMed Central

    Park-Min, Kyung-Hyun; Lim, Elisha; Lee, Min Joon; Park, Sung Ho; Giannopoulos, Eugenia; Yarilina, Anna; van der Meulen, Marjolein; Zhao, Baohong; Smithers, Nicholas; Witherington, Jason; Lee, Kevin; Tak, Paul P.; Prinjha, Rab K.; Ivashkiv, Lionel B.

    2014-01-01

    Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that “read” chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis, and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and estrogen deficiency-mediated pathologic bone resorption. PMID:25391636

  15. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis.

    PubMed

    Ritchlin, Christopher T; Haas-Smith, Sally A; Li, Ping; Hicks, David G; Schwarz, Edward M

    2003-03-01

    Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-kappaB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-alpha than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-alpha-activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-alpha. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone.

  16. Inhibited osteoblastogenesis, enhanced bone resorption and disrupted vitamin d3 homeostasis in female c57bl/6 mice fed alcohol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alcohol abuse is a well-known factor for increased risk of osteoporosis. Previous studies have shown that molecular mechanisms underlying alcohol-induced bone loss are complex, involving direct effects on both bone formation and resorption and additional indirect actions via endocrine disruption. Wh...

  17. Interleukin-1 and tumor necrosis factor-alpha induce collagenolysis and bone resorption by regulation of matrix metalloproteinase-2 in mouse calvarial bone cells.

    PubMed

    Kang, Bong-Seok; Park, Young-Guk; Cho, Jin-Young; Kim, June-Ki; Lee, Tae-Kyun; Kim, Dong-Wook; Gu, Yeun-Hwa; Suzuki, Ikukatsu; Chang, Young-Chae; Kim, Cheorl-Ho

    2003-08-01

    Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) greatly induces osteoclast formation and stimulates bone resorption of mouse calvaria in culture. We examined the effects of the two cytokines on the collagenolysis and bone resorption by induction of matrix metalloproteinases (MMPs). The cells were analyzed using zymographic analysis. It was shown that the mouse calvarial osteoblasts constitutively synthesize progelatinase-A (MMP-2). Interleukin-1beta markedly enhanced the messenger RNAs (mRNAs) expression of MMP-2 (gelatinase A), but slightly MMP-9 (gelatinase B), which associated with increases in bone matrix degradation. Both pro- and active-forms of MMP-2 were detected in the conditioned medium collected from calvarial cultures, and IL-1beta markedly stimulated both pro- and active-forms of the MMP-2. The expression of MMP-2 mRNAs could be detected, and they were markedly enhanced by IL-1beta on days 1 and 2. These results demonstrate that the potency of induction of MMP-2 by IL-1beta and TNF-alpha is closely linked to the respective bone-resorbing activity, suggesting that MMP-2-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines. On the other hand, when the mouse osteoblasts were stimulated with parathyroid hormone, 1,25(OH)2D3, mononuclear cell conditioned medium (MCM) and IL-1 as bone resorption agents, collagenolysis was increased by producing the active gelatinase. Interleukin-1 in stimulating bone resorption was examined using fetal mouse long bone organ culture. Interleukin-1 stimulated bone resorption and produced marked resorption when present simultaneously. Furthermore, treatment of indomethacin and dexamethasone clearly abolished the responses of IL-1alpha and IL-1beta.

  18. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice.

    PubMed Central

    Kitazawa, R; Kimble, R B; Vannice, J L; Kung, V T; Pacifici, R

    1994-01-01

    To investigate the contribution of IL-1, IL-6, and TNF to the increased osteoclastogenesis induced by estrogen deficiency, ovariectomized (ovx) mice were treated with either IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1, TNF binding protein (TNFbp), an inhibitor of TNF, or the anti-IL-6 antibody (Ab) 20F3 for the first 2 wk after surgery. ovx increased the bone marrow cells secretion of IL-1 and TNF, but not IL-6, and the formation of TRAP-positive osteoclast-like multinucleated cells (MNCs) in bone marrow cultures treated with 1,25(OH)2D3. The increase in MNC formation induced by ovx was prevented by in vivo treatment with either 17 beta estradiol, IL-1ra, TNFbp, or anti-IL-6 Ab. However, the percent change in MNC formation induced by the anti-IL-6 Ab was similar in ovx and sham-operated animals, whereas IL-1ra and TNFbp were effective only in ovx mice. MNC formation was also decreased by in vitro treatment of bone marrow cultures with IL-1ra and TNFbp, but not with anti-IL-6 Ab. Ovx also increased bone resorption in vivo and in vitro, as assessed by the urinary excretion of pyridinoline cross links and the formation of resorption pits, respectively. IL-1ra, TNFbp and estrogen decreased bone resorption in vivo and in vitro whereas the anti-IL-6 Ab inhibited bone resorption in vitro but not in vivo. In conclusion, these data indicate that IL-1 and TNF play a direct role in mediating the effects of ovx on osteoclastogenesis and bone resorption. The data also suggest that IL-6 is not essential for increasing bone resorption in the early postovariectomy period. Images PMID:7989596

  19. Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats.

    PubMed

    Turner, R T; Wakley, G K; Hannon, K S; Bell, N H

    1988-03-01

    The effects of the nonsteroidal antiestrogen tamoxifen were determined on trabecular bone mass in the proximal tibial metaphysis of intact and ovariectomized rats. Rats were ovariectomized at the beginning of the study. On day 7 of the study, 5-mg slow release pellets of tamoxifen or placebo were implanted sc. All of the rats were killed on day 28 of the experiment. Sections of the proximal tibial metaphysis were stained for acid phosphatase and evaluated histomorphometrically. Ovariectomy resulted in marked loss of bone. Compared to the values in sham-operated animals, the trabecular bone at a sampling site in the secondary spongiosa of ovariectomized rats was reduced by more than 60%, the length of trabecular bone surface covered by osteoclasts was increased by 563%, the percentage of trabecular bone surface covered by osteoclasts was increased by 567%, the mean osteoclast size was increased by 84%, and the number of nuclei per osteoclast was increased by 38%. In contrast, treatment of ovariectomized rats for 3 weeks with tamoxifen restored the histomorphometric measurements to values comparable to those in sham-operated animals. 17 beta-Estradiol increased trabecular bone fractional area in ovariectomized and sham-operated rats, and administration of tamoxifen to estrogen-treated, ovariectomized, and sham-operated animals produced a further increase in trabecular bone. In summary, 1) ovariectomy resulted in large increases in both the number and activity of osteoclasts, 2) the increased bone resorption associated with ovariectomy produced a net loss of trabecular bone, and 3) treatment of ovariectomized rats with tamoxifen prevented these skeletal changes. The results indicate that in the rat, tamoxifen mimics the effects of estrogen on trabecular bone at concentrations that are not uterotropic.

  20. 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.

  1. 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.

  2. Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment

    PubMed Central

    Buttigliero, Consuelo; Fioramonti, Marco; Bertaglia, Valentina; Vincenzi, Bruno; Zoccoli, Alice; Ribelli, Giulia; Tucci, Marcello; Vignani, Francesca; Berruti, Alfredo; Scagliotti, Giorgio Vittorio; Tonini, Giuseppe; Santini, Daniele

    2015-01-01

    Abiraterone acetate (ABI) is associated not only with a significant survival advantage in both chemotherapy-naive and -treated patients with metastatic castration-resistant prostate cancer (mCRPC), but also with a delay in time to development of Skeletal Related Events and in radiological skeletal progression. These bone benefits may be related to a direct effect on prostate cancer cells in bone or to a specific mechanism directed to bone microenvironment. To test this hypothesis we designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI. Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients. These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity. PMID:25904051

  3. Response of three murine macrophage populations to particulate debris: bone resorption in organ cultures.

    PubMed

    Glant, T T; Jacobs, J J

    1994-09-01

    Particulate wear debris from bone cement or prosthetic components can stimulate macrophages to cause bone resorption. We compared the effect of particle composition (titanium and polymethylmethacrylate as inherent components of prosthetic materials or bone cement and polystyrene as a reference material) on the secretion of interleukin-1 and prostaglandin E2 by peritoneal macrophages and monocyte/macrophage cell lines (P388D1 and IC-21) and on the bone-resorbing activity of conditioned medium harvested from these particle-challenged macrophages. Titanium particles (1-3 microns) in peritoneal macrophage cultures exhibited significantly enhanced bone-resorbing activity measured as 45Ca release, whereas polymethylmethacrylate and polystyrene exhibited this effect to a greater extent in the P388D1 and IC-21 monocyte/macrophage cultures. Although exogenous prostaglandin E2 and recombinant human interleukin-1 could significantly increase the 45Ca release and indomethacin significantly reduced both the spontaneous calcium efflux and active 45Ca release from calvarial bones labeled in vivo, the levels of interleukin-1 and prostaglandin E2, alone or together, did not always correlate with the bone-resorbing activity of conditioned media. Thus, the actual levels of potent bone-resorbing agents (prostaglandin E2 and interleukin-1) measured in conditioned tissue culture media did not necessarily reflect the bone-resorbing capability. An important result of this study is that different macrophage populations may respond differently to the same microenvironmental signal, which in our investigation was particulate wear debris of differing composition and size. PMID:7931789

  4. Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.

    PubMed

    Ostrov, David A; Magis, Andrew T; Wronski, Thomas J; Chan, Edward K L; Toro, Edgardo J; Donatelli, Richard E; Sajek, Kristen; Haroun, Ireni N; Nagib, Michael I; Piedrahita, Ana; Harris, Ashley; Holliday, L Shannon

    2009-08-27

    An interaction between the B2 subunit of vacuolar H(+)-ATPase (V-ATPase) and microfilaments is required for osteoclast bone resorption. An atomic homology model of the actin binding site on B2 was generated and molecular docking simulations were performed. Enoxacin, a fluoroquinolone antibiotic, was identified and in vitro testing demonstrated that enoxacin blocked binding between purified B2 and microfilaments. Enoxacin dose dependently reduced the number of osteoclasts differentiating in mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D(3), as well as markers of osteoclast activity, and the number of resorption lacunae formed on bone slices. Enoxacin inhibited osteoclast formation at concentrations where osteoblast formation was not altered. In summary, enoxacin is a novel small molecule inhibitor of osteoclast bone resorption that acts by an unique mechanism and is therefore an attractive lead molecule for the development of a new class of antiosteoclastic agents.

  5. 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.

  6. 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. PMID:18037367

  7. Nondigestible oligosaccharides increase calcium absorption and suppress bone resorption in ovariectomized rats.

    PubMed

    Zafar, Tasleem A; Weaver, Connie M; Zhao, Yongdong; Martin, Berdine R; Wastney, Meryl E

    2004-02-01

    Nondigestible oligosaccharides (NDO) including inulin and fructooligosaccharides (FOS) have been reported to stimulate calcium absorption. Here we report the effect of a mixture of inulin and FOS (Raftilose Synergy 1, Orafti) on calcium and bone metabolism in ovariectomized (OVX) rats. OVX rats (6 mo old) were fed a semipurified diet for 3 mo in our animal care laboratory for stabilization after ovariectomy. They were then divided into two groups (n = 13/group) and fed either a control or a NDO-supplemented diet (55 g/kg) for 21 d. Catheters were placed in their jugular veins. After 2 d, a tracer ((45)Ca) was administered by gavage or i.v. and blood was sampled for up to 300 min. Urine and fecal samples were collected for 4 d after (45)Ca administration. Femurs were measured for bone mineral density (BMD), breaking strength, and total calcium. Calcium absorption, femoral calcium content, BMD, and bone balance (V(bal)) were significantly increased (P < 0.05) by NDO, whereas the bone resorption rate relative to the bone formation rate was significantly depressed by NDO. We conclude that feeding NDO at 5.5 g/100 g for 21 d has a positive effect on calcium absorption and retention in ovariectomized rats.

  8. Prevention of bone resorption by intake of phytoestrogens in postmenopausal women: a meta-analysis.

    PubMed

    Salari Sharif, Pooneh; Nikfar, Shekoufeh; Abdollahi, Mohammad

    2011-09-01

    Phytoestrogens as selective estrogen receptor modulators like compounds may consider as a therapeutic option in osteoporosis. In this regard, the effect of phytoestrogens on bone biomarkers was examined in several trials which their results are controversial. We aimed this meta-analysis to evaluate the net effect of phytoestrogens on bone markers. A thorough search was conducted from 2000 to 2010 in English articles. All randomized clinical trials were reviewed, and finally, 11 eligible randomized clinical trials were selected for meta-analysis. Totally 1,252 postmenopausal women were enrolled in the study by considering the changes of pyridinoline (Pyd), desoxypyridinoline (Dpyd), bone alkaline phosphatase, and osteocalcin concentrations in urine and serum after phytoestrogens consumption. The urine Pyd and Dpyd levels decreased significantly in phytoestrogens consumers. Effect size and effect size for weighted mean difference of urine Pyd levels showed -1.229171 (95% confidence interval (CI) = -1.927639 to -0.530703) and -9.780623 (95% CI = -14.240401 to -5.320845), respectively, a significant results in comparison to control group and significant results for Dpyd -0.520132 (95% CI = -0.871988 to -0.168275) and -0.818582 (95% CI = -1.247758 to -0.389407), respectively. Meta-analysis indicates that phytoestrogens intake can prevent bone resorption, but its benefits on bone formation are not significant. This favorable effect was observed in low doses and in at least 3 weeks of phytoestrogens intake.

  9. 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.

  10. Erythrina variegata extract exerts osteoprotective effects by suppression of the process of bone resorption.

    PubMed

    Zhang, Yan; Li, Qi; Li, Xiaoli; Wan, Hoi-Ying; Wong, Man-Sau

    2010-10-01

    Our previous study showed that Erythrina variegata L. (EV) inhibited bone loss and improved bone properties in ovariectomised rats. The purpose of the present study is to investigate the potential mechanism involved in mediating the osteoprotective actions of EV. Female Sprague-Dawley rats were fed a phyto-oestrogen-free diet and subjected to either ovariectomy or a sham operation. Ovariectomised rats were treated with genistein (40 mg/kg) as well as low (200 mg/kg), medium (500 mg/kg) or high (1000 mg/kg) doses of EV extract. Bone properties and mRNA expressions were evaluated by micro-computed tomography and quantitative RT-PCR, respectively. Osteoclast differentiation in RAW 264.7 cells was studied by tartrate-resistant acid phosphatase (TRAP) staining. High doses of EV could decrease urinary Ca and P excretion, maintain serum Ca and P level, and exert beneficial effects on the micro-structure and morphology of trabecular bone and cortical bone in ovariectomised rats. EV suppressed the up-regulation of cathepsin K mRNA and the down-regulation of osteoprotegrin mRNA in the tibia of ovariectomised rats. TRAP-positive cell numbers were significantly decreased in receptor activator of nuclear factor-κB ligand (RANKL)-induced RAW 264.7 cells when co-cultured with EV extracts. The present study indicated that the protective effects of EV on bone properties in ovariectomised rats are likely to be mediated by its inhibitory actions on the process of bone resorption via the suppression of osteoclast differentiation and maturation. PMID:20487580

  11. Effect of placement of occlusive membranes on root resorption and bone regeneration during healing of circumferential periodontal defects in dogs.

    PubMed

    Claffey, N; Hahn, R; Egelberg, J

    1989-07-01

    Previous studies indicate that root resorption is a frequent sequela to significant amounts of periodontal repair in animal models. A model was developed in labrador dogs to study periodontal wound healing in large circumferential defects in the absence of influence from the oral environment. A polytetrafluorethylene membrane of 1 micron pore size (GORE-TEX) was used to occlude cells from specific tissues from populating the healing dentin-connective tissue wound. 3 modalities were studied: (1) control, in which no membrane and therefore no cell occlusion was used, (2) flap occlusion, in which the internal surface of the flap was lined with the membrane preventing contribution of cells from the flap, (3) bone occlusion, in which the reduced alveolar bone was lined with the membrane preventing contribution from bone cells. Wound closure included total submergence of teeth and membranes. The membranes remained incorporated and no exposure of membranes or teeth occurred during the 3 months healing period. Histology revealed bone regrowth in all 3 treatment modalities. It is suggested that inductive elements in the connective tissue or dentin, or bone cells from periosteum were responsible for bone regrowth in the bone membrane treatment modality. No significant difference was seen for root resorption between the 3 treatment modalities. This study found that physical occlusion of cells from the inside of the surgical flap, or from the pre-existing bone, is not sufficient to prevent root resorption in periodontal wound healing.

  12. Investigation of the relationship between low environmental exposure to metals and bone mineral density, bone resorption and renal function.

    PubMed

    Callan, A C; Devine, A; Qi, L; Ng, J C; Hinwood, A L

    2015-07-01

    Environmental exposure to metals has been linked to adverse health outcomes. Exposure to cadmium has been associated with decreased bone density, an increased risk of osteoporotic fracture and possible renal dysfunction. Older women are a group at risk of renal and bone density impacts and exposure to metals may be an important risk factor for these health outcomes. This study was a cross sectional study of 77 women aged 50 years and above examining the relationship between metals exposure and renal and bone health. Urinary and blood metals concentrations, plasma creatinine, iron, ferritin and transferrin were measured in these subjects. Bone biomarkers assessed included the pyridinium crosslinks, pyridinoline and deoxypyridinoline measured by ELISA. Renal function was assessed using eGFR and KIM-1. Whole body, hip and lumbar spine bone mineral density was assessed using DEXA. Blood and urinary metals concentrations were generally low in the subjects, with a median urinary cadmium concentration of 0.26 μg/g creatinine (range <0.065-1.03 μg/g). Urinary cadmium was found to be a significant predictor of bone mineral density at whole body, lumber spine, total hip and femoral neck, with increasing urinary Cd concentrations associated with decreased bone density. Urinary cadmium and aluminium concentrations were positively correlated with bone resorption whilst blood zinc and mercury concentrations were negatively correlated. Urinary aluminium was positively correlated with KIM-1 concentrations, a marker of early kidney damage, however blood zinc concentrations were significantly negatively correlated with this biomarker. This study provides additional support for low cadmium exposure being of concern for the health of older women. Further investigation into the role of exposure to other metals on bone and renal health is warranted.

  13. Skeletal lead release during bone resorption: effect of bisphosphonate treatment in a pilot study.

    PubMed Central

    Gulson, Brian; Mizon, Karen; Smith, Howard; Eisman, John; Palmer, Jacqueline; Korsch, Michael; Donnelly, John; Waite, Kay

    2002-01-01

    There has been renewed interest in impacts on physiologic systems in the middle and older age groups, especially from fractures and hypertension. Increased blood lead (BPb) levels in postmenopausal females, which are thought to arise from bone demineralization, may also relate to other health effects including hypertension. Taking advantage of natural differences in lead isotope signature between Australian sources of lead and those from other countries, a 2-year pilot study was performed in premenopausal and postmenopausal females and male partners in which the subjects were administered a bisphosphonate, alendronate, for 6 months. The aim of the study was to determine how lead isotopes and lead concentrations changed in relation to bone remodeling processes. Premenopausal subjects were a woman (and male partner) from Bosnia and two women from Colombia. The postmenopausal subject was a woman from Russia. Her male partner and one man from Sri Lanka were included. Multigenerational Australian subjects were 2 perimenopausal women and 1 postmenopausal woman. Each subject had blood and urine samples collected for markers of bone turnover and for lead isotope studies monthly for 7-9 months before, for 3 months during, and for up to 6 months after treatment with alendronate to inhibit bone resorption. Each subject thus acted as his or her own control. As predicted, there were significant decreases in the lead isotope ratio, (206)Pb/(204)Pb, for the migrant subjects during treatment compared with the pretreatment period (p < 0.01). After cessation of treatment, an increasing isotope ratio for the postmenopausal subject (and older male partner) occurred later than for premenopausal subjects, indicative of prolonged efficacy of the alendronate for the older subjects. The average BPb concentrations in migrant subjects decreased by about 20% during the treatment compared with the pretreatment period (p < 0.01). To our knowledge, these are the first BPb concentrations reported

  14. Low-Level Mechanical Vibrations can Reduce Bone Resorption and Enhance Bone Formation in the Growing Skeleton

    SciTech Connect

    Xie,L.; Jacobsen, J.; Busa, B.; Donahue, L.; Miller, L.; Rubin, C.; Judex, S.

    2006-01-01

    Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day{sup -1} (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P < 0.05) than in age-matched controls. Bone formation rates (BFR{center_dot}BS{sup -1}) on the endocortical surface of the metaphysis were 30% greater (P < 0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately

  15. Characterization of Bone Resorption in Novel In Vitro and In Vivo Models of Oral Squamous Cell Carcinoma

    PubMed Central

    Martin, Chelsea K.; Dirksen, Wessel P.; Shu, Sherry T.; Werbeck, Jillian L.; Thudi, Nanda K.; Yamaguchi, Mamoru; Wolfe, Tobie D.; Heller, Kristin N.; Rosol, Thomas J.

    2012-01-01

    Objectives Oral squamous cell carcinoma (OSCC) is the most commonly diagnosed oral malignancy in humans and cats and frequently invades bone. The objective of this study was to determine if feline OSCC serves as a relevant model of human OSCC in terms of osteolytic behavior and expression of bone resorption agonists. Materials and Methods Novel feline OSCC cell lines (SCCF2 and SCCF3) were derived from spontaneous carcinomas. Gene expression and osteolytic behavior were compared to an established feline OSCC cell line (SCCF1) and three human OSCC cell lines (UMSCC-12, A253 and SCC25). Interaction of OSCC with bone and murine pre-osteoblasts (MC3T3) was investigated using in vitro co-culture techniques. In vivo bioluminescent imaging, faxitron radiography and microscopy were used to measure xenograft growth and bone invasion in nude mice. Results Human and feline OSCC expressing the highest levels of parathyroid hormone-related protein (PTHrP) were associated with in vitro and in vivo bone resorption and osteoclastogenesis. MC3T3 cells had increased receptor activator of nuclear factor κB ligand (RANKL) expression and reduced osteoprotegerin (OPG) expression in conditioned medium from bone-invasive SCCF2 cells compared to minimally bone invasive SCCF3 cells, which was partially reversed with a neutralizing anti-PTHrP antibody. Human and feline OSCC cells cultured in bone-conditioned medium had increased PTHrP secretion and proliferation. Conclusion Feline OSCC-induced bone resorption was associated with tumor cell secretion of PTHrP and with increased RANKL : OPG expression ratio in mouse preosteoblasts. Bone-CM increased OSCC proliferation and secretion of PTHrP. The preclinical models of feline OSCC recapitulated the bone-invasive phenotype characteristic of spontaneous OSCC and will be useful to future preclinical and mechanistic studies of bone invasive behavior. PMID:22265717

  16. Fisetin antagonizes cell fusion, cytoskeletal organization and bone resorption in RANKL-differentiated murine macrophages.

    PubMed

    Kim, Yun-Ho; Kim, Jung-Lye; Lee, Eun-Jung; Park, Sin-Hye; Han, Seon-Young; Kang, Soon Ah; Kang, Young-Hee

    2014-03-01

    Osteoclastogenesis is comprised of several stage s including progenitor survival, differentiation to mononuclear preosteoclasts, cell fusion to multinuclear mature osteoclasts, and activation to osteoclasts with bone resorbing activity. Botanical antioxidants are now being increasingly investigated for their health-promoting effects on bone. This study investigated that fisetin, a flavonol found naturally in many fruits and vegetables, suppressed osteoclastogenesis by disturbing receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated signaling pathway and demoting osteoclastogenic protein induction. Nontoxic fisetin at ≤10 μM inhibited the induction of RANK, tumor necrosis factor receptor associated factor 6 (TRAF6) and the activation of NF-κB in RANKL-stimulated RAW 264.7 macrophages. In RANKL-differentiated osteoclasts cell fusion protein of E-cadherin was induced, which was dampened by fisetin. The formation of tartrate-resistance acid phosphatase-positive multinucleated osteoclasts was suppressed by adding fisetin to RANKL-exposed macrophages. It was also found that fisetin reduced actin ring formation and gelsolin induction of osteclasts enhanced by RANKL through disturbing c-Src-proline-rich tyrosine kinase 2 signaling. Fisetin deterred preosteoclasts from the cell-cell fusion and the organization of the cytoskeleton to seal the resorbing area and to secret protons for bone resorption. Consistently, the 5 day-treatment of fisetin diminished RANKL-induced cellular expression of carbonic anhydrase II and integrin β3 concurrently with a reduction of osteoclast bone-resorbing activity. Therefore, fisetin was a natural therapeutic agent retarding osteoclast fusion and cytoskeletal organization such as actin rings and ruffled boarder, which is a property of mature osteoclasts and is required for osteoclasts to resorb bone.

  17. Disruption of the dynein-dynactin complex unveils motor-specific functions in osteoclast formation and bone resorption.

    PubMed

    Ng, Pei Ying; Cheng, Tak Sum; Zhao, Haibo; Ye, Shiqiao; Sm Ang, Estabelle; Khor, Ee Cheng; Feng, Hao-Tian; Xu, Jiake; Zheng, Ming H; Pavlos, Nathan J

    2013-01-01

    Osteoclastic bone resorption requires strict interplay between acidified carrier vesicles, motor proteins, and the underlying cytoskeleton in order to sustain the specialized structural and functional polarization of the ruffled border. Cytoplasmic dynein, a large processive mechanochemical motor comprising heavy, intermediate, and light chains coupled to the dynactin cofactor complex, powers unilateral motility of diverse cargos to microtubule minus-ends. We have recently shown that regulators of the dynein motor complex constitute critical components of the osteoclastic bone resorptive machinery. Here, by selectively modulating endogenous dynein activity, we show that the integrity of the dynein-dynactin motor complex is an essential requirement for both osteoclast formation and function. Systematic dissection of the osteoclast dynein-dynactin complex revealed that it is differentially localized throughout RANKL-induced osteoclast formation and activation, undergoing microtubule-coupled reorganization upon the establishment of cellular polarization. In osteoclasts actively resorbing bone, dynein-dynactin intimately co-localizes with the CAP-Gly domain-containing microtubule plus-end protein CLIP-170 at the resorptive front, thus orientating the ruffled border as a microtubule plus-end domain. Unexpectedly, disruption of the dynein-dynactin complex by exogenous p50/dynamitin expression retards osteoclast formation in vitro, owing largely to prolonged mitotic stasis of osteoclast progenitor cells. More importantly, loss of osteoclastic dynein activity results in a drastic redistribution of key intracellular organelles, including the Golgi and lysosomes, an effect that coincides with impaired cathepsin K secretion and diminished bone resorptive function. Collectively, these data unveil a previously unrecognized role for the dynein-dynactin motor complex in osteoclast formation and function, serving not only to regulate their timely maturation but also the delivery

  18. 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

  19. Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice.

    PubMed

    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

    2010-02-01

    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.

  20. Inhibitory effects of French pine bark extract, Pycnogenol®, on alveolar bone resorption and on the osteoclast differentiation.

    PubMed

    Sugimoto, Hideki; Watanabe, Kiyoko; Toyama, Toshizo; Takahashi, Shun-suke; Sugiyama, Shuta; Lee, Masaichi-Chang-il; Hamada, Nobushiro

    2015-02-01

    Pycnogenol(®) (PYC) is a standardized bark extract from French maritime pine (Pinus pinaster Aiton). We examined the inhibitory effects of PYC on alveolar bone resorption, which is a characteristic feature of periodontitis, induced by Porphyromonas gingivalis (P. gingivalis) and osteoclast differentiation. In rat periodontitis model, rats were divided into four groups: group A served as the non-infected control, group B was infected orally with P. gingivalis ATCC 33277, group C was administered PYC in the diet (0.025%: w/w), and group D was infected with P. gingivalis and administered PYC. Administration of PYC along with P. gingivalis infection significantly reduced alveolar bone resorption. Treatment of P. gingivalis with 1 µg/ml PYC reduced the number of viable bacterial cells. Addition of PYC to epithelial cells inhibited adhesion and invasion by P. gingivalis. The effect of PYC on osteoclast formation was confirmed by tartrate-resistant acid phosphatase staining. PYC treatment significantly inhibited osteoclast formation. Addition of PYC (1-100 µg/ml) to purified osteoclasts culture induced cell apoptosis. These results suggest that PYC may prevent alveolar bone resorption through its antibacterial activity against P. gingivalis and by suppressing osteoclastogenesis. Therefore, PYC may be useful as a therapeutic and preventative agent for bone diseases such as periodontitis.

  1. PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.

    PubMed

    Stechschulte, L A; Czernik, P J; Rotter, Z C; Tausif, F N; Corzo, C A; Marciano, D P; Asteian, A; Zheng, J; Bruning, J B; Kamenecka, T M; Rosen, C J; Griffin, P R; Lecka-Czernik, B

    2016-08-01

    The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease. PMID:27422345

  2. Does collagen trigger the recruitment of osteoblasts into vacated bone resorption lacunae during bone remodeling?

    PubMed

    Abdelgawad, Mohamed Essameldin; Søe, Kent; Andersen, Thomas Levin; Merrild, Ditte M H; Christiansen, Peer; Kjærsgaard-Andersen, Per; Delaisse, Jean-Marie

    2014-10-01

    Osteoblast recruitment during bone remodeling is obligatory to re-construct the bone resorbed by the osteoclast. This recruitment is believed to be triggered by osteoclast products and is therefore likely to start early during the remodeling cycle. Several osteoclast products with osteoblast recruitment potential are already known. Here we draw the attention on the osteoblast recruitment potential of the collagen that is freshly demineralized by the osteoclast. Our evidence is based on observations on adult human cancellous bone, combined with in vitro assays. First, freshly eroded surfaces where osteoblasts have to be recruited show the presence of non-degraded demineralized collagen and close cell-collagen interactions, as revealed by electron microscopy, while surface-bound collagen strongly attracts osteoblast lineage cells in a transmembrane migration assay. Compared with other extracellular matrix molecules, collagen's potency was superior and only equaled by fibronectin. Next, the majority of the newly recruited osteoblast lineage cells positioned immediately next to the osteoclasts exhibit uPARAP/Endo180, an endocytic collagen receptor reported to be involved in collagen internalization and cell migration in various cell types, and whose inactivation is reported to lead to lack of bone formation and skeletal deformities. In the present study, an antibody directed against this receptor inhibits collagen internalization in osteoblast lineage cells and decreases to some extent their migration to surface-bound collagen in the transmembrane migration assay. These complementary observations lead to a model where collagen demineralized by osteoclasts attracts surrounding osteoprogenitors onto eroded surfaces, and where the endocytic collagen receptor uPARAP/Endo180 contributes to this migration, probably together with other collagen receptors. This model fits recent knowledge on the position of osteoprogenitor cells immediately next to remodeling sites in adult

  3. Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption.

    PubMed

    Kim, Mi-Hyun; Bae, Yun-Jung; Choi, Mi-Kyeong; Chung, Yoon-Sok

    2009-06-01

    The purpose of this study was to investigate the effect of silicon (Si) supplementation on bone mineral density (BMD) and bone metabolism parameters relative to calcium (Ca) intake levels in ovariectomized rats. A total of 72 female Wistar rats (6 weeks) were ovariectomized (OVX) and divided into six groups, and Si (500 mg of Si per kilogram of feed) was or was not administered with diets containing various levels of Ca (0.1%, 0.5%, and 1.5%) for 10 weeks. The groups were as follows: (1) Ca-deficient group (0.1% Ca), (2) Ca-deficient with Si supplementation group, (3) adequate Ca group (0.5% Ca), (4) adequate Ca with Si supplementation group, (5) high Ca group (1.5% Ca), and (6) high Ca with Si supplementation group. Si supplementation significantly increased the BMD of the femur and tibia in Ca-deficient OVX rats, while no change was observed with Si supplementation in the BMD of the spine, femur, and tibia in the adequate and high Ca groups. Serum alkaline phosphatase and osteocalcin levels were not affected by Si supplementation or Ca intake levels. C-telopeptide type I collagen levels were significantly decreased as a result of Si supplementation in Ca-deficient OVX rats. In summary, Si supplementation produced positive effects on bone mineral density in Ca-deficient OVX rats by reducing bone resorption. Therefore, Si supplementation may also prove to be helpful in preventing osteoporosis in postmenopausal women whose calcium intake is insufficient.

  4. Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption.

    PubMed

    Chabbi-Achengli, Yasmine; Coman, Tereza; Collet, Corinne; Callebert, Jacques; Corcelli, Michelangelo; Lin, Hilène; Rignault, Rachel; Dy, Michel; de Vernejoul, Marie-Christine; Côté, Francine

    2016-04-01

    Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonin's involvement during collagen-induced arthritis in wild-type and Tph1(-/-) mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1(-/-) mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1(-/-) mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1(-/-) mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis.

  5. Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.

    PubMed

    Homer, Bruce L; Morton, Daniel; Bagi, Cedo M; Warneke, James A; Andresen, Catharine J; Whiteley, Laurence O; Morris, Dale L; Tones, Michael A

    2015-04-01

    Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.

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

    SciTech Connect

    Shagina, N. B.; Tolstykh, E. I.; Degteva, M. O.; Anspaugh, L. R.; Napier, Bruce A.

    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 on 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.

  7. Stimulation of a Gs-like G protein in the osteoclast inhibits bone resorption but enhances tartrate-resistant acid phosphatase secretion.

    PubMed

    Moonga, B S; Pazianas, M; Alam, A S; Shankar, V S; Huang, C L; Zaidi, M

    1993-01-29

    Previous studies have demonstrated that G-protein agonists induce quiescence (Q effect) or retraction (R effect) in isolated osteoclasts. We now report the functional effects of such agonists on osteoclastic bone resorption and enzyme release. Exposure of osteoclasts to tetrafluoro-aluminate anions (AlF4-), a universal G protein stimulator, resulted in a marked concentration-dependent inhibition of bone resorption. This was associated with a dramatic increase in the secretion of the osteoclast-specific enzyme, tartrate-resistant acid phosphatase (TRAP). Cholera toxin, a Gs stimulator and a selective Q effect agonist, similarly abolished bone resorption and enhanced TRAP secretion. In contrast, pertussis toxin, a Gi inhibitor and a selective R effect agonist, inhibited bone resorption significantly, but slightly reduced enzyme release. The results suggest an involvement of a Gs-like G protein in TRAP secretion from the osteoclast, possibly through a cyclic AMP-dependent mechanism.

  8. Anti-inflammatory and Anti-resorptive Effects of Atorvastatin on Alveolar Bone Loss in Wistar Rats.

    PubMed

    Goes, Paula; Lima, Neiberg Alcântara; Rodrigues, José Ariévilo Gurgel; Benevides, Norma Maria Barros; Brito, Gerly Anne Castro; Lima, Vilma

    2016-01-01

    The aim of this study was to evaluate the anti-inflammatory and anti-resorptive effect of atorvastatin (ATV) in an experimental alveolar bone loss (ABL) model. Wistar rats were subjected to ligature placement around the maxillary second molar for 11 days. The animals received 0.9% saline (2 mL/kg) or ATV (0.3, 3 or 27 mg/kg) daily by gavage. ABL was evaluated by resorption area and histopathological analysis. Serum bone-specific alkaline phosphatase (BALP) activity was also evaluated. Leukogram was performed at 0 h, 6th h, 2nd, 7th and 11th days. Kidney and liver conditions and the body mass variation were analyzed. ATV (3 and 27 mg/kg) inhibited ABL by 39% and 56%, respectively. Histopathological analysis showed that ATV 27 mg/kg prevented ABL and cemental resorption, and inflammatory cell infiltration induced by ligature. ATV (27 mg/kg) prevented serum BALP levels reduction. ATV (27 mg/kg) prevented leukocytosis and did not affect either kidney or liver function nor body mass weight. ATV showed a protecting effect in the ligature-induced periodontitis, without affecting system parameters, by inhibition of inflammatory process and by its anabolic activity on the alveolar bone. PMID:27224558

  9. Mouse tail vertebrae adapt to cyclic mechanical loading by increasing bone formation rate and decreasing bone resorption rate as shown by time-lapsed in vivo imaging of dynamic bone morphometry.

    PubMed

    Lambers, Floor M; Schulte, Friederike A; Kuhn, Gisela; Webster, Duncan J; Müller, Ralph

    2011-12-01

    It is known that mechanical loading leads to an increase in bone mass through a positive shift in the balance between bone formation and bone resorption. How the remodeling sites change over time as an effect of loading remains, however, to be clarified. The purpose of this paper was to investigate how bone formation and resorption sites are modulated by mechanical loading over time by using a new imaging technique that extracts three dimensional formation and resorption parameters from time-lapsed in vivo micro-computed tomography images. To induce load adaptation, the sixth caudal vertebra of C57BL/6 mice was cyclically loaded through pins in the adjacent vertebrae at either 8 N or 0 N (control) three times a week for 5 min (3000 cycles) over a total of 4 weeks. The results showed that mechanical loading significantly increased trabecular bone volume fraction by 20% (p<0.001) and cortical area fraction by 6% (p<0.001). The bone formation rate was on average 23% greater (p<0.001) and the bone resorption rate was on average 25% smaller (p<0.001) for the 8 N group than for the 0 N group. The increase in bone formation rate for the 8 N group was mostly an effect of a significantly increased surface of bone formation sites (on average 16%, p<0.001), while the thickness of bone formation packages was less affected (on average 5% greater, p<0.05). At the same time the surface of bone resorption sites was significantly reduced (on average 15%, p<0.001), while the depth of resorption pits remained the same. For the 8 N group, the strength of the whole bone increased significantly by 24% (p<0.001) over the loading period, while the strain energy density in the trabecular bone decreased significantly by 24% (p<0.001). In conclusion, mouse tail vertebrae adapt to mechanical loading by increasing the surface of formation sites and decreasing the surface of resorption sites, leading to an overall increase in bone strength. This new imaging technique will provide opportunities

  10. 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

  11. Caffeic acid phenethyl ester abrogates bone resorption in a murine calvarial model of polyethylene particle-induced osteolysis.

    PubMed

    Zawawi, M S F; Perilli, E; Stansborough, R L; Marino, V; Cantley, M D; Xu, J; Dharmapatni, A A S S K; Haynes, D R; Gibson, R J; Crotti, T N

    2015-06-01

    Particle-induced bone loss by osteoclasts is a common cause of aseptic loosening around implants. This study investigates whether caffeic acid phenethyl ester (CAPE), a potent and specific inhibitor of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 and nuclear factor kappa B, at a low dose reduces bone resorption in a murine calvarial model of polyethylene (PE) particle-induced osteolysis. The effects of particles and CAPE treatment on gastrointestinal tract (GIT) histopathology were also evaluated. Mice were scanned using in vivo animal micro-computed tomography (μCT) as a baseline measurement. PE particles (2.82 × 10(9) particles/mL) were implanted over the calvariae on day 0. CAPE was administered subcutaneously (1 mg/kg/day) at days 0, 4, 7 and 10. Mice were killed at day 14 and serum was analysed for Type-1 carboxyterminal collagen crosslinks (CTX)-1 and osteoclast-associated receptor (OSCAR) levels. Ex vivo μCT scans were conducted to assess bone volume (BV) change and percentage area of calvarial surface resorbed. Calvarial and GIT tissue was processed for histopathology. By day 14, PE particles significantly induced calvarial bone loss compared with control animals as evidenced by resorption areas adjacent to the implanted PE in three-dimensional μCT images, an increase in percentage of resorbed area (p = 0.0022), reduction in BV (p = 0.0012) and increased Tartrate-resistant acid phosphatase positive cells. Serum CTX-1 (p = 0.0495) and OSCAR levels (p = 0.0006) significantly increased in the PE implant group. CAPE significantly inhibited PE particle-induced calvarial osteolysis, as evidenced by a significant reduction in surface bone resorption (p = 0.0012) and volumetric change (p = 0.0154) compared with PE only, but had no effect on systemic CTX-1. Neither particles nor CAPE had an effect on GIT histopathology. PMID:25804981

  12. Role of interleukin 6 in epithelial hyperproliferation and bone resorption in middle ear cholesteatomas.

    PubMed

    Bujía, J; Kim, C; Ostos, P; Kastenbauer, E; Hültner, L

    1996-01-01

    Locally produced pro-inflammatory cytokines are considered to play an important role in the initiation and/or maintenance of inflammatory diseases. In cholesteatomatous lesions there are increased levels of some cytokines and inflammatory mediators like interleukin 1, tumor necrosis factor and colony-stimulating factor, etc. Interleukin 6 (IL-6) can be produced by different cells present in cholesteatoma (e.g. keratinocytes, lymphocytes, fibroblasts and macrophages). Until now, no data have been available on the role of IL-6 in cholesteatoma. In this study we used immunohistochemistry to investigate the presence and distribution of IL-6 in tissue samples from cholesteatoma patients. Levels of the cytokine were quantified in tissue extracts using an enzyme-linked immunosorbent assay. Finally, the presence of biologically active IL-6 was analyzed in the murine cell line 7TD1. Human skin samples obtained from the external ear canal were used as controls. Using the anti-IL-6 antibody in an alkaline phosphatase anti alkaline phosphatase technique, a moderate diffuse staining of the whole epidermis was observed in sections of normal skin. In cryostat sections of cholesteatoma samples, a stronger staining of the whole epithelium was observed. Many of the cells infiltrating the cholesteatoma stroma also showed positive immunostainings. The concentration of IL-6 in relation to the total protein concentration in cholesteatoma (119.33 +/- 30) were higher than in human skin (9.16 +/- 13). While IL-6 activity was not detected in skin samples, two of the ten cholesteatoma samples studied showed a stimulatory effect when incubated with the cell line 7TD1. The overexpression of IL-6 in middle ear cholesteatoma suggests a participation of this cytokine in some of the clinical features seen: epithelial hyperproliferation and bone resorption. The absence of biological activity in the majority of the cholesteatoma samples points to the presence of natural inhibitors for IL-6.

  13. 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

  14. Human calcium metabolism including bone resorption measured with {sup 41}Ca tracer

    SciTech Connect

    Freeman, S.P.H.T.; King, J.C.; Vieira, N.E.; Woodhouse, L.R.; Yergey, A.L.

    1996-08-01

    Accelerator mass spectrometry is so sensitive to small quantities of {sup 41}Ca that it might be used as a tracer in the study of human calcium kinetics to generate unique kinds of data. In contrast with the use of other Ca isotopic tracers, {sup 41}Ca tracer can be so administered that the tracer movements between the various body pools achieve a quasi steady state. Resorbing bone may thus be directly measured. We have tested such a protocol against a conventional stable isotope experiment with good agreement.

  15. 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

  16. Analysis of correlation between initial alveolar bone density and apical root resorption after 12 months of orthodontic treatment without extraction

    PubMed Central

    Scheibel, Paula Cabrini; Ramos, Adilson Luiz; Iwaki, Lilian Cristina Vessoni; Micheletti, Kelly Regina

    2014-01-01

    OBJECTIVE: The aim of the present study was to investigate the correlation between initial alveolar bone density of upper central incisors (ABD-UI) and external apical root resorption (EARR) after 12 months of orthodontic movement in cases without extraction. METHODS: A total of 47 orthodontic patients 11 years old or older were submitted to periapical radiography of upper incisors prior to treatment (T1) and after 12 months of treatment (T2). ABD-UI and EARR were measured by means of densitometry. RESULTS: No statistically significant correlation was found between initial ABD-UI and EARR at T2 (r = 0.149; p = 0.157). CONCLUSION: Based on the present findings, alveolar density assessed through periapical radiography is not predictive of root resorption after 12 months of orthodontic treatment in cases without extraction. PMID:25715722

  17. Tooth loss early in life accelerates age-related bone deterioration in mice.

    PubMed

    Kurahashi, Minori; Kondo, Hiroko; Iinuma, Mitsuo; Tamura, Yasuo; Chen, Huayue; Kubo, Kin-ya

    2015-01-01

    Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis.

  18. Fin Spine Bone Resorption in Atlantic Bluefin Tuna, Thunnus thynnus, and Comparison between Wild and Captive-Reared Specimens

    PubMed Central

    Santamaria, Nicoletta; Bello, Giambattista; Pousis, Chrysovalentinos; Vassallo-Agius, Robert; de la Gándara, Fernando; Corriero, Aldo

    2015-01-01

    Bone resorption in the first spine of the first dorsal fin of Atlantic bluefin tuna (ABFT) has long been considered for age estimation studies. In the present paper spine bone resorption was assessed in wild (aged 1 to 13 years) and captive-reared (aged 2 to 11 years) ABFT sampled from the Mediterranean Sea. Total surface (TS), solid surface (SS) and reabsorbed surface (RS) were measured in spine transverse sections in order to obtain proportions of SS and RS. The spine section surface was found to be isometrically correlated to the fish fork length by a power equation. The fraction of solid spine bone progressively decreased according to a logarithmic equation correlating SS/TS to both fish size and age. The values ranged from 57% in the smallest examined individuals to 37% in the largest specimens. This phenomenon was further enhanced in captive-reared ABFT where SS/TS was 22% in the largest measured specimen. The difference between the fraction of SS of wild and captive-reared ABFT was highly significant. In each year class from 1- to 7-year-old wild specimens, the fraction of spine reabsorbed surface was significantly higher in specimens collected from March to May than in those sampled during the rest of the year. In 4-year-old fish the normal SS increase during the summer did not occur, possibly coinciding with their first sexual maturity. According to the correlations between SS/TS and age, the rate of spine bone resorption was significantly higher, even almost double, in captive-reared specimens. This could be attributed to the wider context of systemic dysfunctions occurring in reared ABFT, and may be related to a number of factors, including nutritional deficiencies, alteration of endocrine profile, cortisol-induced stress, and loss of spine functions during locomotion in rearing conditions. PMID:25751271

  19. 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.

  20. Impaired Bone Resorption by Lipopolysaccharide In Vivo in Mice Deficient in the Prostaglandin E Receptor EP4 Subtype

    PubMed Central

    Sakuma, Yoko; Tanaka, Kiyoshi; Suda, Michio; Komatsu, Yasato; Yasoda, Akihiro; Miura, Masako; Ozasa, Ami; Narumiya, Shuh; Sugimoto, Yukihiko; Ichikawa, Atsushi; Ushikubi, Fumitaka; Nakao, Kazuwa

    2000-01-01

    In a previous study we showed that the involvement of EP4 subtype of the prostaglandin E (PGE) receptor is crucial for lipopolysaccharide (LPS)-induced osteoclast formation in vitro. The present study was undertaken to test whether EP4 is actually associated with LPS-induced bone resorption in vivo. In wild-type (WT) mice, osteoclast formation in vertebrae and tibiae increased 5 days after systemic LPS injection, and urinary excretion of deoxypyridinoline, a sensitive marker for bone resorption, statistically increased 10 days after injection. In EP4 knockout (KO) mice, however, LPS injection caused no significant changes in these parameters throughout the experiment. LPS exposure for 4 h strongly induced osteoclast differentiation factor (ODF) mRNA expression in primary osteoblastic cells (POB) both from WT and EP4 KO mice, and this expression was not inhibited by indomethacin, suggesting prostaglandin (PG) independence. LPS exposure for 24 h further induced ODF expression in WT POB, but not in EP4 KO POB. Indomethacin partially inhibited ODF expression in WT POB, but not in EP4 KO POB. These data suggest that ODF is induced both PG dependently and PG independently. LPS exposure for 24 h induced slightly greater osteoclastgenesis inhibitory factor (OCIF) mRNA expression in EP4 KO than in WT POB. These findings suggest that the reduced ODF expression and apparently increased OCIF expression also are responsible for the markedly reduced LPS-induced osteoclast formation in EP4 KO mice. Our results show that the EP4 subtype of the PGE receptor is involved in LPS-induced bone resorption in vivo also. Since LPS is considered to be largely involved in bacterially induced bone loss, such as in periodontitis and osteomyelitis, our study is expected to help broaden our understanding of the pathophysiology of these conditions. PMID:11083800

  1. Tumor necrosis factor alpha and interleukin-1 stimulate bone resorption in vivo as measured by urinary ( sup 3 H)tetracycline excretion from prelabeled mice

    SciTech Connect

    Koenig, A.M.; Muehlbauer, R.C.F.; Fleisch, H. )

    1988-12-01

    Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) have been shown to stimulate bone resorption in vitro. We have now investigated whether these cytokines also cause a similar action when administered in vivo. This was made possible by the adaptation of a newly developed technique that enables the continual assessment of bone resorption in vivo in mice by measuring urinary excretion of {sup 3}H from ({sup 3}H)tetracycline-prelabeled animals. Experiments using maneuvers known to influence bone resorption, such as a change in dietary calcium or administration of parathyroid hormone or dichloromethylenebisphosphonate, indicate that the technique is reliable and sensitive in mice. Daily intravenous administration of either recombinant human or recombinant murine TNF-alpha, as well as subcutaneous administration of recombinant human IL-1 alpha, were found to stimulate bone resorption in a dose-dependent manner. The effect was maximal within 2 days. Thus, exogenous TNF-alpha and IL-1 alpha can stimulate bone resorption in vivo, suggesting that these cytokines may also exert a systemic effect on bone.

  2. Short-Term Hypoxia Accelerates Bone Loss in Ovariectomized Rats by Suppressing Osteoblastogenesis but Enhancing Osteoclastogenesis

    PubMed Central

    Wang, Guixin; Wang, Jia; Sun, Dawei; Xin, Jingyi; Wang, Liping; Huang, Dong; Wu, Weichi; Xian, Cory J.

    2016-01-01

    Background Although it has been reported that hypoxic exposure can attenuate hypertension, heart disease, diabetes, and some other diseases, effects of hypoxia on osteoporosis are still unknown. Material/Methods The current study investigated whether short-term hypoxic exposure (in comparison with normoxic conditions) affects bone metabolism in normal or ovariectomized (OVX) adult female rats in an vivo study. Micro-computed tomography bone volume/structural analyses, histological examination, and serum bone turnover biochemical assays were used. In addition, the expressions of some associated major regulatory molecules were measured in osteoblastic cultures. Results While the 14-day hypoxic exposure did not change the bone-remodeling process in normal adult female rats, it decreased bone volume, osteoclast density, and serum bone formation marker (alkaline phosphatase) level, but increased osteoclast density and serum bone resorption marker (C-telopeptide of collagen) level in OVX rats. The bone marrow adipocyte number and serum fatty acid binding protein-4 level were increased in OVX-hypoxic rats compared with OVX-normoxic rats. Consistently, in human MG-63 osteoblastic cultures, the hypoxic condition suppressed protein expression of osteogenic transcriptional factors Runx2 and osterix, elevated protein expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand, but reduced that of osteoclastogenic inhibitor osteoprotegerin. Conclusions Our results suggest that, although no change occurred in the bone-remodeling process in normal adult female rats after hypoxic exposure, under the estrogen-deficient osteoporotic condition, the hypoxic condition can alter the bone microenvironment so that it may further impair osteoblastic differentiation and enhance osteoclastic formation, and thus reduce bone formation, enhance bone resorption, and accelerate bone loss. PMID:27550548

  3. Short-Term Hypoxia Accelerates Bone Loss in Ovariectomized Rats by Suppressing Osteoblastogenesis but Enhancing Osteoclastogenesis.

    PubMed

    Wang, Guixin; Wang, Jia; Sun, Dawei; Xin, Jingyi; Wang, Liping; Huang, Dong; Wu, Weichi; Xian, Cory J

    2016-01-01

    BACKGROUND Although it has been reported that hypoxic exposure can attenuate hypertension, heart disease, diabetes, and some other diseases, effects of hypoxia on osteoporosis are still unknown. MATERIAL AND METHODS The current study investigated whether short-term hypoxic exposure (in comparison with normoxic conditions) affects bone metabolism in normal or ovariectomized (OVX) adult female rats in an vivo study. Micro-computed tomography bone volume/structural analyses, histological examination, and serum bone turnover biochemical assays were used. In addition, the expressions of some associated major regulatory molecules were measured in osteoblastic cultures. RESULTS While the 14-day hypoxic exposure did not change the bone-remodeling process in normal adult female rats, it decreased bone volume, osteoclast density, and serum bone formation marker (alkaline phosphatase) level, but increased osteoclast density and serum bone resorption marker (C-telopeptide of collagen) level in OVX rats. The bone marrow adipocyte number and serum fatty acid binding protein-4 level were increased in OVX-hypoxic rats compared with OVX-normoxic rats. Consistently, in human MG-63 osteoblastic cultures, the hypoxic condition suppressed protein expression of osteogenic transcriptional factors Runx2 and osterix, elevated protein expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand, but reduced that of osteoclastogenic inhibitor osteoprotegerin. CONCLUSIONS Our results suggest that, although no change occurred in the bone-remodeling process in normal adult female rats after hypoxic exposure, under the estrogen-deficient osteoporotic condition, the hypoxic condition can alter the bone microenvironment so that it may further impair osteoblastic differentiation and enhance osteoclastic formation, and thus reduce bone formation, enhance bone resorption, and accelerate bone loss. PMID:27550548

  4. Tctex-1, a Novel Interaction Partner of Rab3D, Is Required for Osteoclastic Bone Resorption

    PubMed Central

    Pavlos, Nathan J.; Cheng, Tak Sum; Qin, An; Ng, Pei Ying; Feng, Hao-Tian; Ang, Estabelle S. M.; Carrello, Amerigo; Sung, Ching-Hwa; Jahn, Reinhard; Zheng, Ming-Hao; Xu, Jiake

    2011-01-01

    Vesicular transport along microtubules must be strictly regulated to sustain the unique structural and functional polarization of bone-resorbing osteoclasts. However, the molecular mechanisms bridging these vesicle-microtubule interactions remain largely obscure. Rab3D, a member of the Rab3 subfamily (Rab3A/B/C/D) of small exocytotic GTPases, represents a core component of the osteoclastic vesicle transport machinery. Here, we identify a new Rab3D-interacting partner, Tctex-1, a light chain of the cytoplasmic dynein microtubule motor complex, by a yeast two-hybrid screen. We demonstrate that Tctex-1 binds specifically to Rab3D in a GTP-dependent manner and co-occupies Rab3D-bearing vesicles in bone-resorbing osteoclasts. Furthermore, we provide evidence that Tctex-1 and Rab3D intimately associate with the dynein motor complex and microtubules in osteoclasts. Finally, targeted disruption of Tctex-1 by RNA interference significantly impairs bone resorption capacity and mislocalizes Rab3D vesicles in osteoclasts, attesting to the notion that components of the Rab3D-trafficking pathway contribute to the maintenance of osteoclastic resorptive function. PMID:21262767

  5. Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

    PubMed

    Coelho, Rui Moura; Lemos, João Miranda; Alho, Irina; Valério, Duarte; Ferreira, Arlindo R; Costa, Luís; Vinga, Susana

    2016-02-21

    Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.

  6. Nanogel-crosslinked nanoparticles increase the inhibitory effects of W9 synthetic peptide on bone loss in a murine bone resorption model.

    PubMed

    Sato, Toshimi; Alles, Neil; Khan, Masud; Nagano, Kenichi; Takahashi, Mariko; Tamura, Yukihiko; Shimoda, Asako; Ohya, Keiichi; Akiyoshi, Kazunari; Aoki, Kazuhiro

    2015-01-01

    We investigated the biological activity of W9, a bone resorption inhibitor peptide, using NanoClik nanoparticles as an injectable carrier, where acryloyl group-modified cholesterol-bearing pullulan (CHPOA) nanogels were crosslinked by pentaerythritol tetra (mercaptoethyl) polyoxyethylene. Thirty 5-week-old male C57BL/6J mice were fed a low calcium diet and received once-daily subcutaneous injections of the carrier alone, W9 24 mg/kg/day alone, W9 24 mg/kg/day incorporated in cholesterol bearing pullulan (CHP) nanogels, or W9 (8 and 24 mg/kg/day) incorporated in NanoClik nanoparticles for 4 days (n=5). Mice that received a normal calcium diet with NanoClik nanoparticle injections without W9 were used as a control group. Radiological analyses showed that administration of W9 24 mg/kg/day significantly prevented low calcium-induced reduction of bone mineral density in the long bones and lumbar vertebrae, but only when the NanoClik nanoparticles were used as a carrier. Histomorphometric analyses of the proximal tibiae revealed that W9 24 mg/kg/day incorporated in NanoClik nanoparticles prevented the increase in bone resorption indices induced by a low calcium diet, which was confirmed by measurement of serum bone resorption markers. These data suggest that NanoClik nanoparticles could be a useful carrier for peptide therapeutics, and also demonstrate that daily subcutaneous injections of the W9 peptide with the nanoparticles were able to inhibit bone loss in vivo. An osteoclastogenesis inhibition assay performed in vitro confirmed a slower release profile of W9 from NanoClik nanoparticles compared with conventional CHP nanogels. PMID:25999711

  7. Nanogel-crosslinked nanoparticles increase the inhibitory effects of W9 synthetic peptide on bone loss in a murine bone resorption model

    PubMed Central

    Sato, Toshimi; Alles, Neil; Khan, Masud; Nagano, Kenichi; Takahashi, Mariko; Tamura, Yukihiko; Shimoda, Asako; Ohya, Keiichi; Akiyoshi, Kazunari; Aoki, Kazuhiro

    2015-01-01

    We investigated the biological activity of W9, a bone resorption inhibitor peptide, using NanoClik nanoparticles as an injectable carrier, where acryloyl group-modified cholesterol-bearing pullulan (CHPOA) nanogels were crosslinked by pentaerythritol tetra (mercaptoethyl) polyoxyethylene. Thirty 5-week-old male C57BL/6J mice were fed a low calcium diet and received once-daily subcutaneous injections of the carrier alone, W9 24 mg/kg/day alone, W9 24 mg/kg/day incorporated in cholesterol bearing pullulan (CHP) nanogels, or W9 (8 and 24 mg/kg/day) incorporated in NanoClik nanoparticles for 4 days (n=5). Mice that received a normal calcium diet with NanoClik nanoparticle injections without W9 were used as a control group. Radiological analyses showed that administration of W9 24 mg/kg/day significantly prevented low calcium-induced reduction of bone mineral density in the long bones and lumbar vertebrae, but only when the NanoClik nanoparticles were used as a carrier. Histomorphometric analyses of the proximal tibiae revealed that W9 24 mg/kg/day incorporated in NanoClik nanoparticles prevented the increase in bone resorption indices induced by a low calcium diet, which was confirmed by measurement of serum bone resorption markers. These data suggest that NanoClik nanoparticles could be a useful carrier for peptide therapeutics, and also demonstrate that daily subcutaneous injections of the W9 peptide with the nanoparticles were able to inhibit bone loss in vivo. An osteoclastogenesis inhibition assay performed in vitro confirmed a slower release profile of W9 from NanoClik nanoparticles compared with conventional CHP nanogels. PMID:25999711

  8. Nanogel-crosslinked nanoparticles increase the inhibitory effects of W9 synthetic peptide on bone loss in a murine bone resorption model.

    PubMed

    Sato, Toshimi; Alles, Neil; Khan, Masud; Nagano, Kenichi; Takahashi, Mariko; Tamura, Yukihiko; Shimoda, Asako; Ohya, Keiichi; Akiyoshi, Kazunari; Aoki, Kazuhiro

    2015-01-01

    We investigated the biological activity of W9, a bone resorption inhibitor peptide, using NanoClik nanoparticles as an injectable carrier, where acryloyl group-modified cholesterol-bearing pullulan (CHPOA) nanogels were crosslinked by pentaerythritol tetra (mercaptoethyl) polyoxyethylene. Thirty 5-week-old male C57BL/6J mice were fed a low calcium diet and received once-daily subcutaneous injections of the carrier alone, W9 24 mg/kg/day alone, W9 24 mg/kg/day incorporated in cholesterol bearing pullulan (CHP) nanogels, or W9 (8 and 24 mg/kg/day) incorporated in NanoClik nanoparticles for 4 days (n=5). Mice that received a normal calcium diet with NanoClik nanoparticle injections without W9 were used as a control group. Radiological analyses showed that administration of W9 24 mg/kg/day significantly prevented low calcium-induced reduction of bone mineral density in the long bones and lumbar vertebrae, but only when the NanoClik nanoparticles were used as a carrier. Histomorphometric analyses of the proximal tibiae revealed that W9 24 mg/kg/day incorporated in NanoClik nanoparticles prevented the increase in bone resorption indices induced by a low calcium diet, which was confirmed by measurement of serum bone resorption markers. These data suggest that NanoClik nanoparticles could be a useful carrier for peptide therapeutics, and also demonstrate that daily subcutaneous injections of the W9 peptide with the nanoparticles were able to inhibit bone loss in vivo. An osteoclastogenesis inhibition assay performed in vitro confirmed a slower release profile of W9 from NanoClik nanoparticles compared with conventional CHP nanogels.

  9. Lysophosphatidic Acid Receptor Type 1 (LPA1) Plays a Functional Role in Osteoclast Differentiation and Bone Resorption Activity*

    PubMed Central

    David, Marion; Machuca-Gayet, Irma; Kikuta, Junichi; Ottewell, Penelope; Mima, Fuka; Leblanc, Raphael; Bonnelye, Edith; Ribeiro, Johnny; Holen, Ingunn; Vales, Rùben Lopez; Jurdic, Pierre; Chun, Jerold; Clézardin, Philippe; Ishii, Masaru; Peyruchaud, Olivier

    2014-01-01

    Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1–6) with pleiotropic activities on multiple cell types. We have previously demonstrated that LPA is necessary for successful in vitro osteoclastogenesis of bone marrow cells. Bone cells controlling bone remodeling (i.e. osteoblasts, osteoclasts, and osteocytes) express LPA1, but delineating the role of this receptor in bone remodeling is still pending. Despite Lpar1−/− mice displaying a low bone mass phenotype, we demonstrated that bone marrow cell-induced osteoclastogenesis was reduced in Lpar1−/− mice but not in Lpar2−/− and Lpar3−/− animals. Expression of LPA1 was up-regulated during osteoclastogenesis, and LPA1 antagonists (Ki16425, Debio0719, and VPC12249) inhibited osteoclast differentiation. Blocking LPA1 activity with Ki16425 inhibited expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and dendritic cell-specific transmembrane protein and interfered with the fusion but not the proliferation of osteoclast precursors. Similar to wild type osteoclasts treated with Ki16425, mature Lpar1−/− osteoclasts had reduced podosome belt and sealing zone resulting in reduced mineralized matrix resorption. Additionally, LPA1 expression markedly increased in the bone of ovariectomized mice, which was blocked by bisphosphonate treatment. Conversely, systemic treatment with Debio0719 prevented ovariectomy-induced cancellous bone loss. Moreover, intravital multiphoton microscopy revealed that Debio0719 reduced the retention of CX3CR1-EGFP+ osteoclast precursors in bone by increasing their mobility in the bone marrow cavity. Overall, our results demonstrate that LPA1 is essential for in vitro and in vivo osteoclast activities. Therefore, LPA1 emerges as a new target for the treatment of diseases associated with excess bone loss. PMID:24429286

  10. Commercial Honeybush (Cyclopia spp.) Tea Extract Inhibits Osteoclast Formation and Bone Resorption in RAW264.7 Murine Macrophages-An in vitro Study.

    PubMed

    Visagie, Amcois; Kasonga, Abe; Deepak, Vishwa; Moosa, Shaakirah; Marais, Sumari; Kruger, Marlena C; Coetzee, Magdalena

    2015-10-28

    Honeybush tea, a sweet tasting caffeine-free tea that is indigenous to South Africa, is rich in bioactive compounds that may have beneficial health effects. Bone remodeling is a physiological process that involves the synthesis of bone matrix by osteoblasts and resorption of bone by osteoclasts. When resorption exceeds formation, bone remodeling can be disrupted resulting in bone diseases such as osteoporosis. Osteoclasts are multinucleated cells derived from hematopoietic precursors of monocytic lineage. These precursors fuse and differentiate into mature osteoclasts in the presence of receptor activator of NF-kB ligand (RANKL), produced by osteoblasts. In this study, the in vitro effects of an aqueous extract of fermented honeybush tea were examined on osteoclast formation and bone resorption in RAW264.7 murine macrophages. We found that commercial honeybush tea extract inhibited osteoclast formation and TRAP activity which was accompanied by reduced bone resorption and disruption of characteristic cytoskeletal elements of mature osteoclasts without cytotoxicity. Furthermore, honeybush tea extract decreased expression of key osteoclast specific genes, matrix metalloproteinase-9 (MMP-9), tartrate resistant acid phosphatase (TRAP) and cathepsin K. This study demonstrates for the first time that honeybush tea may have potential anti-osteoclastogenic effects and therefore should be further explored for its beneficial effects on bone.

  11. Commercial Honeybush (Cyclopia spp.) Tea Extract Inhibits Osteoclast Formation and Bone Resorption in RAW264.7 Murine Macrophages—An in vitro Study

    PubMed Central

    Visagie, Amcois; Kasonga, Abe; Deepak, Vishwa; Moosa, Shaakirah; Marais, Sumari; Kruger, Marlena C.; Coetzee, Magdalena

    2015-01-01

    Honeybush tea, a sweet tasting caffeine-free tea that is indigenous to South Africa, is rich in bioactive compounds that may have beneficial health effects. Bone remodeling is a physiological process that involves the synthesis of bone matrix by osteoblasts and resorption of bone by osteoclasts. When resorption exceeds formation, bone remodeling can be disrupted resulting in bone diseases such as osteoporosis. Osteoclasts are multinucleated cells derived from hematopoietic precursors of monocytic lineage. These precursors fuse and differentiate into mature osteoclasts in the presence of receptor activator of NF-kB ligand (RANKL), produced by osteoblasts. In this study, the in vitro effects of an aqueous extract of fermented honeybush tea were examined on osteoclast formation and bone resorption in RAW264.7 murine macrophages. We found that commercial honeybush tea extract inhibited osteoclast formation and TRAP activity which was accompanied by reduced bone resorption and disruption of characteristic cytoskeletal elements of mature osteoclasts without cytotoxicity. Furthermore, honeybush tea extract decreased expression of key osteoclast specific genes, matrix metalloproteinase-9 (MMP-9), tartrate resistant acid phosphatase (TRAP) and cathepsin K. This study demonstrates for the first time that honeybush tea may have potential anti-osteoclastogenic effects and therefore should be further explored for its beneficial effects on bone. PMID:26516894

  12. A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep.

    PubMed

    Andreasen, Christina M; Ding, Ming; Overgaard, Søren; Bollen, Peter; Andersen, Thomas L

    2015-06-01

    Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6 mg/kg/day, 5 times weekly) for 7 months. At 7 months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7 months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7 months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces. In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid

  13. Distribution of resorption processes in the compacta and spongiosa of bones from lactating rats fed a low-calcium diet.

    PubMed

    Lozupone, E; Favia, A

    1988-01-01

    An attempt has been made to determine if the structural renewal of bone tissue takes place to a greater extent in the spongiosa than in the compacta and how this is related to the more extensive free surface area in the former. To this purpose, on transverse sections of the femur and 2 degrees lumbar vertebral body of the female lactating rats fed a normal (L group) or a calcium free diet (H group) the area of compact and spongy bone, and the perimeter of the trabeculae were measured. Then TBV, MTPT, MTPD, MTPS, Sv and S/V, according to the Parfitt et al. (1983) method were calculated. In the femurs of rats maintained on a normal calcium diet bone loss takes place to a higher degree in the spongiosa than in the compacta. In the distal metaphysis, moreover, the bone loss is more elevated than in other femoral regions. In the second lumbar vertebral body the bone rarefaction appears to have a similar extent in the compacta and spongiosa and in the three levels inspected. In rats maintained on a restricted calcium intake the osteoporosis is enhanced but the bone is removed predominantly from the compacta in all the femoral regions except in the distal metaphysis and, to a similar degree, from the compacta and the spongiosa of the vertebral body. In the centrodiaphyseal compacta the bone is reabsorbed exclusively at the endosteal level, while in the spongiosa the frameworks subjected to a more extensive resorption occupy a topographic position specific for each single region, and are often formed of thin trabeculae. The dynamic of the trabecular resorption seems to be different in the various spongy frameworks: in each of these it would take place by the removal of the entire trabecula or the thinning of the single trabeculae or by both mechanisms. Lastly, significative correlation was found between trabecular bone loss and trabecular thickness, none with trabecular surfaces. This study shows that bone removal is not regulated by the extent of the trabecular free

  14. Systemic treatment with strontium ranelate accelerates the filling of a bone defect and improves the material level properties of the healing bone.

    PubMed

    Zacchetti, Giovanna; Dayer, Romain; Rizzoli, René; Ammann, Patrick

    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

  15. Evaluation of in vitro bone resorption: high-performance liquid chromatography measurement of the pyridinolines released in osteoclast cultures.

    PubMed

    Lorget, F; Mentaverri, R; Meddah, B; Cayrolle, G; Wattel, A; Morel, A; Schecroun, N; Maamer, M; de Vernejoul, M C; Kamel, S; Brazier, M

    2000-09-10

    None of the currently used methods to evaluate bone resorption by osteoclasts cultured on bone substrate measures directly the amounts of degraded bone collagen, which is a direct reflection of the osteoclast "work done." We therefore propose a reliable biochemical method to evaluate the in vitro collagenolysis process. Bone-resorbing activity was evaluated, after HPLC separation, by fluorimetric measurement of hydroxylysylpyridinoline (HP), a collagen cross-link molecule, released in culture supernatants. We first confirm previous data reporting that HP is released in the culture medium in a peptide-conjugated form. After acid hydrolysis, we show that HP is highly correlated with the lacunae area (r = 0.68, P<0.0001) and with the amounts of antigenic collagen fragments (Cross-laps for culture) released in culture medium (r = 0.77, P<0.0002). Using a cysteine protease inhibitor, we observed that lacunae areas are dramatically less inhibited (35% inhibition) than the release of bone-degraded products, including HP and antigenic collagen fragments (96 and 92% inhibition, respectively). Coupled to the resorbed area measurement, biochemical evaluations offer both quantitative and qualitative complementary measurements of the osteoclastic bone-resorbing process.

  16. Disturbed synthesis of type II collagen interferes with rate of bone formation and growth and increases bone resorption in transgenic mice.

    PubMed

    Nieminen, Jyrki; Sahlman, Janne; Hirvonen, Teemu; Lapveteläinen, Tuomo; Miettinen, Markku; Arnala, Ilkka; Malluche, Hartmut H; Helminen, Heikki J

    2008-03-01

    Transgenic mice carrying an internally deleted human type II collagen gene (COL2A1) were used to study bone growth and development. This mutation has previously been shown to disturb the development of collagen fibrils in articular cartilage, causing chondrodysplasia and osteoarthritis. Type II collagen expression in bones was investigated with immunohistochemistry. The development and mineralization of the skeleton and anthropometric measurements on bones were evaluated using X-rays and dynamic histomorphometry. Type II collagen was expressed in the cartilage of developing bones. The bones of transgenic mice were smaller compared with the controls. The bone mass remained almost unchanged in transgenic mice after 1 month of age, leading to differences of 47% in trabecular bone volume (P = 0.012) and 40% in trabecular thickness (P < 0.01) at the age of 3 months compared with controls. At the age of 3 months the eroded surface per bone volume was 31% greater in transgenic mice compared with controls (P < 0.05). Trabecular thickness correlated positively with body weight (R = 0.71, P < 0.001). Interestingly, body weight correlated with bone volume in control mice (R = 0.27, P < 0.01), but no correlation was observed in transgenic mice. The disturbed synthesis of cartilage-specific type II collagen in growing transgenic mice retarded bone development, increased bone resorption, and altered tissue properties. This led to a negative net bone balance and small bone size. The results support the idea that an altered synthesis of cartilage-specific molecule(s) can disturb postnatal bone development and growth.

  17. Photoelastic stress analysis of endodontically treated teeth restored with different post systems: normal and alveolar bone resorption cases.

    PubMed

    Ma, Jinbao; Miura, Hiroyuki; Okada, Daizo; Yusa, Koichiro

    2011-01-01

    The present study examined the influence of different post materials and their lengths on the mechanical stress of endodontically treated incisor roots in two alveolar bone conditions. Two-dimensional photoelastic models were fabricated to simulate the endodontically treated maxillary central incisors restored with three kinds of posts materials (low Young's modulus glass fiber post, high Young's modulus glass fiber post, and prefabricated stainless steel post) and two post lengths (8 and 4 mm). Completed models were placed in a transmission polariscope and loaded with a static force of 150 N at 45° to the tooth axis. Photoelastic photographs and the magnitudes of fringe order revealed stress distribution in the root, and suggest that the glass fiber post with a low Young's modulus and long length can reduce the stress concentration both in normal and alveolar bone resorption conditions.

  18. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL.

    PubMed

    Kostenuik, Paul J; Nguyen, Hung Q; McCabe, James; Warmington, Kelly S; Kurahara, Carol; Sun, Ning; Chen, Ching; Li, Luke; Cattley, Russ C; Van, Gwyneth; Scully, Shelia; Elliott, Robin; Grisanti, Mario; Morony, Sean; Tan, Hong Lin; Asuncion, Frank; Li, Xiaodong; Ominsky, Michael S; Stolina, Marina; Dwyer, Denise; Dougall, William C; Hawkins, Nessa; Boyle, William J; Simonet, William S; Sullivan, John K

    2009-02-01

    RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of RANKL are prevented by binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes RANKL from multiple species and reduced bone resorption and increased bone volume, density, and strength in a number of rodent models of bone disease. The clinical development of OPG-Fc was discontinued in favor of denosumab, a fully human monoclonal antibody that specifically inhibits primate RANKL. Direct binding assays showed that denosumab bound to human RANKL but not to murine RANKL, human TRAIL, or other human TNF family members. Denosumab did not suppress bone resorption in normal mice or rats but did prevent the resorptive response in mice challenged with a human RANKL fragment encoded primarily by the fifth exon of the RANKL gene. To create mice that were responsive to denosumab, knock-in technology was used to replace exon 5 from murine RANKL with its human ortholog. The resulting "huRANKL" mice exclusively express chimeric (human/murine) RANKL that was measurable with a human RANKL assay and that maintained bone resorption at slightly reduced levels versus wildtype controls. In young huRANKL mice, denosumab and OPG-Fc each reduced trabecular osteoclast surfaces by 95% and increased bone density and volume. In adult huRANKL mice, denosumab reduced bone resorption, increased cortical and cancellous bone mass, and improved trabecular microarchitecture. These huRANKL mice have potential utility for characterizing the activity of denosumab in a variety of murine bone disease models.

  19. Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis.

    PubMed

    Verdrengh, Margareta; Carlsten, Hans; Ohlsson, Claes; Tarkowski, Andrej

    2007-03-01

    Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus-induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction.

  20. Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2.

    PubMed

    Kwon, Jun-Oh; Jin, Won Jong; Kim, Bongjun; Kim, Hong-Hee; Lee, Zang Hee

    2015-12-01

    Cytoskeletal changes in osteoclasts such as formation of actin ring is required for bone-resorbing activity. The tyrosine kinase Src is a key player in massive cytoskeletal change of osteoclasts, thereby in bone destruction. In order for Src to be activated, trafficking to the inner plasma membrane via myristoylation is of importance. A previous study reported that myristoleic acid derived from myristic acid, inhibited N-myristoyl-transferase, an essential enzyme for myristoylation process. This prompted us to investigate whether myristoleic acid could affect osteoclastogenesis. Indeed, we observed that myristoleic acid inhibited RANKL-induced osteoclast formation in vitro, especially, at later stages of differentiation. Myristoleic acid attenuated the tyrosine phosphorylation of c-Src and Pyk2, which associates with Src, by RANKL. When myristoleic acid was co-administered with soluble RANKL into mice, RANKL-induced bone loss was substantially prevented. Bone dissection clearly revealed that the number of multinucleated osteoclasts was significantly diminished by myristoleic acid. On the other hand, myristoleic acid treatment had little or no influence on early osteoclast differentiation markers, such as c-Fos and NFATc1, and proteins related to cytoskeletal rearrangement, including DC-STAMP, integrin αv and integrin β3 in vitro. Taken together, our data suggest that myristoleic acid is capable of blocking the formation of large multinucleated osteoclasts and bone resorption likely through suppressing activation of Src and Pyk2.

  1. Markers of bone resorption and calcium metabolism are related to dietary intake patterns in male and female bed rest subjects

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Zwart, S. R.; Hargens, A. r.

    2006-01-01

    Dietary potassium and protein intakes predict net endogenous acid production in humans. Intracellular buffers, including exchangeable bone mineral, play a crucial role in balancing chronic acid-base perturbations in the body; subsequently, chronic acid loads can potentially contribute to bone loss. Bone is lost during space flight, and a dietary countermeasure would be desirable for many reasons. We studied the ability of diet protein and potassium to predict levels of bone resorption markers in males and females. Identical twin pairs (8 M, 7 F) were assigned to 2 groups: bed rest (sedentary, SED) or bed rest with supine treadmill exercise in a lower body negative pressure chamber (EX). Diet was controlled for 3 d before and 30 d of bed rest (BR). Urinary Ca, N-telopeptide (NTX), and pyridinium crosslinks (PYD) were measured before and on days 5, 12, 19, and 26 of BR. Data were analyzed by Pearson correlation (P<0.05). The ratio of dietary animal protein/potassium intake was not correlated with NTX before BR for males or females, but they were positively correlated in both groups of males during bed rest. Dietary animal protein/potassium and urine Ca were correlated before and during bed rest for the males, and only during bed rest for the females. Conversely, the ratio of dietary vegetable protein/potassium intake was negatively correlated with urinary calcium during bed rest for the females, but there was no relationship between vegetable protein/potassium intake and bone markers for the males. These data suggest that the ratio of animal protein/potassium intake may affect bone, particularly in bed rest subjects. These data show that the type of protein and gender may be additional factors that modulate the effect of diet on bone metabolism during bed rest. Altering this ratio may help prevent bone loss on Earth and during space flight.

  2. Leptin modulates both resorption and formation while preventing disuse-induced bone loss in tail-suspended female rats.

    PubMed

    Martin, Aline; de Vittoris, Raphaël; David, Valentin; Moraes, Ricardo; Bégeot, Martine; Lafage-Proust, Marie-Hélène; Alexandre, Christian; Vico, Laurence; Thomas, Thierry

    2005-08-01

    In vitro studies have demonstrated leptin-positive effects on the osteoblast lineage and negative effects on osteoclastogenesis. Therefore, we tested the hypothesis that leptin may prevent tail-suspension-induced bone loss characterized by an uncoupling pattern of bone remodeling, through both mechanisms. Female rats were randomly tail-suspended or not and treated either with ip administration of leptin or vehicle for 3, 7, and 14 d. As measured by dual energy x-ray absorptiometry, tail-suspension induced a progressive decrease in tibia-metaphysis bone mineral density, which was prevented by leptin. Histomorphometry showed that this was related to the prevention of the transient increase in osteoclast number observed with suspension at d 7. These effects could be mediated by the receptor activator of nuclear factor kappaB-ligand (RANKL)/osteoprotegerin (OPG) pathway since we observed using direct RT-PCR, a suspension-induced increase in RANKL gene expression in proximal tibia at d 3, which was counterbalanced by leptin administration with a similar 3-fold increase in OPG expression and a RANKL to OPG ratio close to nonsuspended conditions. In addition, leptin prevented the decrease in bone formation rate induced by tail-suspension at d 14. The latter could be related to the role of leptin in mediating the reciprocal differentiation between adipocytes and osteoblasts, because leptin concurrently blunted the disuse-induced increase in bone marrow adipogenesis. In summary, these data suggest that peripheral administration of leptin could prevent disuse-induced bone loss through, first, a major inhibitory effect on bone resorption and, second, a delayed effect preventing the decrease in bone formation.

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

    SciTech Connect

    Tolstykh, E I; Shagina, N B; Degteva, M O; Anspaugh, L R; Napier, Bruce A

    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 resorption 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.

  4. Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator of NF-κB Ligand) through Activation of Toll-like Receptor 2 in Osteoblasts*

    PubMed Central

    Kassem, Ali; Henning, Petra; Lundberg, Pernilla; Souza, Pedro P. C.; Lindholm, Catharina; Lerner, Ulf H.

    2015-01-01

    Periodontitis has been associated with rheumatoid arthritis. In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P. gingivalis stimulates bone resorption. The effects by LPS P. gingivalis and four other TLR2 ligands on bone resorption, osteoclast formation, and gene expression in wild type and Tlr2-deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected subcutaneously over the skull bones. LPS P. gingivalis stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL (receptor activator of NF-κB ligand). LPS P. gingivalis stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-κB-mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2, and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P. gingivalis and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P. gingivalis and Pam2 also up-regulated RANKL and osteoclastic genes in vivo, resulting in an increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2-deficient mice. These data demonstrate that LPS P. gingivalis stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in rheumatoid arthritis patients with concomitant periodontal disease. PMID:26085099

  5. Long-term bony integration and resorption kinetics of a xenogeneic bone substitute after sinus floor augmentation: histomorphometric analyses of human biopsy specimens.

    PubMed

    Klein, Marcus O; Kämmerer, Peer W; Götz, Hermann; Duschner, Heinz; Wagner, Wilfried

    2013-01-01

    In this case series, a systematic histomorphometric analysis of two human bone biopsy specimens was conducted 1 and 5 years after grafting with a xenogeneic bovine bone substitute material (BSM). While the 1-year specimen still showed extensive signs of an active desmal ossification, the specimen after 5 years mainly showed mature lamellar bone without bone turnover or remodeling. A completed bony integration without extensive resorption of the BSM particles could be detected. Altogether, a good integration in the bone with osteoconduction and a high biocompatibility was seen. PMID:23820714

  6. High-Frequency Acceleration: Therapeutic Tool to Preserve Bone following Tooth Extractions.

    PubMed

    Alikhani, M; Lopez, J A; Alabdullah, H; Vongthongleur, T; Sangsuwon, C; Alikhani, M; Alansari, S; Oliveira, S M; Nervina, J M; Teixeira, C C

    2016-03-01

    A common problem in clinical dentistry is the significant and rapid bone loss that occurs after tooth extraction. Currently there is no solution for the long-term preservation of alveolar bone. Previously, we showed that high-frequency acceleration (HFA) has an osteogenic effect on healthy alveolar bone. However, it is not known if HFA can preserve alveolar bone after extraction without negatively affecting wound healing. The purpose of this study was to evaluate the effect of HFA on alveolar bone loss and the rate of bone formation after tooth extraction. Eighty-five adult Sprague-Dawley rats were divided into 3 groups: control, static (static load), and HFA. In all groups, the maxillary right third molar was extracted. The HFA group received HFA for 5 min/d, applied through the second molar. The static group received the same magnitude of static load. The control group did not receive any stimulation. Some animals received fluorescent dyes at 26 and 54 d. Samples were collected on days 0, 7, 14, 28, and 56 for fluorescence microscopy, micro-computed tomography, histology, RNA, and protein analyses. We found that HFA increased bone volume in the extraction site and surrounding alveolar bone by 44% when compared with static, while fully preserving alveolar bone height and width long-term. These effects were accompanied by increased expression of osteogenic markers and intramembranous bone formation and by decreased expression of osteoclastic markers and bone resorption activity, as well as decreased expression of many inflammatory markers. HFA is a noninvasive safe treatment that can be used to prevent alveolar bone loss and/or accelerate bone healing after tooth extraction.

  7. Oestrogen regulates bone resorption and cytokine production in the maxillae of female mice.

    PubMed

    Macari, Soraia; Duffles, Letícia F; Queiroz-Junior, Celso M; Madeira, Mila F M; Dias, George J; Teixeira, Mauro M; Szawka, Raphael E; Silva, Tarcília A

    2015-02-01

    Oestrogen plays major role in bone metabolism/remodelling. Despite of well-established effect of oestrogen deficiency on long bones, it remains unclear whether alveolar bone is affected. We aimed to determine the effect of oestrogen-deficiency in the alveolar bone microarchitecture. C57BL6/J and Balb/c mice were ovariectomized and implanted with oil-(OVX) or 17β-estradiol (E2)-containing (OVX+E2) capsules. Ovary-intact mice were used as controls. The dose of E2 replacement was selected based on trophic effects on the uterus and femur bone loss. As determined by maxillary alveolar bone MicroCT analysis, both C57BL6/J and Balb/c OVX mice displayed decreased trabecular thickness, bone density and bone volume, and increased trabecular separation at 15 and 30 days after ovariectomy. These effects were associated with a reduction of trabecular bone percentage and cortical thickness in the femur. A significant loss of alveolar bone crest was also associated with ovariectomy in both mice strains. The E2 replacement fully prevented ovariectomy-induced alterations in the alveolar and femoral bones. Moreover, TNF-α (tumour necrosis factor-α) levels and RANKL/OPG (receptor activator of NF-κB ligand/osteoprotegerin) ratio were increased in the maxilla after OVX, and these responses were also reversed by E2. In conclusion, oestrogen deficiency causes maxillary alveolar bone loss, which is similar to the effects found in the femur. The release of inflammatory molecules like TNF-α, RANKL and OPG is the potential mechanism to the decrease of bone quality and alveolar bone crest.

  8. Loss of Protein Kinase C-δ Protects against LPS-Induced Osteolysis Owing to an Intrinsic Defect in Osteoclastic Bone Resorption

    PubMed Central

    Khor, Ee Cheng; Abel, Tamara; Tickner, Jennifer; Chim, Shek Man; Wang, Cathy; Cheng, Taksum; Ng, Benjamin; Ng, Pei Ying; Teguh, Dian Astari; Kenny, Jacob; Yang, Xiaohong; Chen, Honghui; Nakayama, Keiichi I.; Nakayama, Keiko; Pavlos, Nathan; Zheng, Ming H.; Xu, Jiake

    2013-01-01

    Bone remodeling is intrinsically regulated by cell signaling molecules. The Protein Kinase C (PKC) family of serine/threonine kinases is involved in multiple signaling pathways including cell proliferation, differentiation, apoptosis and osteoclast biology. However, the precise involvement of individual PKC isoforms in the regulation of osteoclast formation and bone homeostasis remains unclear. Here, we identify PKC-δ as the major PKC isoform expressed among all PKCs in osteoclasts; including classical PKCs (−α, −β and −γ), novel PKCs (−δ, −ε, −η and −θ) and atypical PKCs (−ι/λ and −ζ). Interestingly, pharmacological inhibition and genetic ablation of PKC-δ impairs osteoclastic bone resorption in vitro. Moreover, disruption of PKC-δ activity protects against LPS-induced osteolysis in mice, with osteoclasts accumulating on the bone surface failing to resorb bone. Treatment with the PKC-δ inhibitor Rottlerin, blocks LPS-induced bone resorption in mice. Consistently, PKC-δ deficient mice exhibit increased trabeculae bone containing residual cartilage matrix, indicative of an osteoclast-rich osteopetrosis phenotype. Cultured ex vivo osteoclasts derived from PKC-δ null mice exhibit decreased CTX-1 levels and MARKS phosphorylation, with enhanced formation rates. This is accompanied by elevated gene expression levels of cathepsin K and PKC −α, −γ and −ε, as well as altered signaling of pERK and pcSrc416/527 upon RANKL-induction, possibly to compensate for the defects in bone resorption. Collectively, our data indicate that PKC-δ is an intrinsic regulator of osteoclast formation and bone resorption and thus is a potential therapeutic target for pathological osteolysis. PMID:23951014

  9. Triptolide Inhibits Osteoclast Differentiation and Bone Resorption In Vitro via Enhancing the Production of IL-10 and TGF-β1 by Regulatory T Cells

    PubMed Central

    Xu, Huihui; Zhao, Hongyan; Wang, Gui; Huang, Jing; Guo, Minghui; Guo, Baosheng; Tan, Yong

    2016-01-01

    Triptolide, a purified component of Tripterygiumwilfordii Hook F, has been shown to have immunosuppressive and anti-inflammatory properties in rheumatoid arthritis (RA). Although triptolide has demonstrated that it could suppress bone destruction in collagen-induced mice, its therapeutic mechanism remains unclear. Many studies have investigated the effect of triptolide on Tregs and Tregs-related cytokine involved in RA. Additionally, previous studies have implied that Tregs inhibit osteoclast differentiation and bone resorption. Thus, in this study we aimed to explore the regulatory mechanism by which triptolide influences the Treg-mediated production of IL-10 and TGF-β1 to affect osteoclast differentiation and bone resorption. In cocultures system of Tregs and mouse bone marrow macrophages (BMMs), Tregs inhibited the differentiation of osteoclasts and reduced the resorbed areas significantly and the production of both IL-10 and TGF-β1 was upregulated. When the coculture systems were pretreated with triptolide, they produced higher levels of IL-10 and TGF-β1. Our data indicate that triptolide enhances the suppressive effects of Tregs on osteoclast differentiation and bone resorption by enhancing the secretion of IL-10 and TGF-β1. Tregs are most likely involved in the triptolide-mediated regulation of bone metabolism and may provide a potential therapeutic target for the treatment of inflammatory bone destruction. PMID:27413257

  10. Prevention of Wear Particle-Induced Osteolysis by a Novel V-ATPase Inhibitor Saliphenylhalamide through Inhibition of Osteoclast Bone Resorption

    PubMed Central

    Lin, Zhen; Cao, Lei; Chim, Shek M.; Pavlos, Nathan J.; Xu, Jiake; Zheng, Ming Hao; Dai, Ke Rong

    2012-01-01

    Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis. PMID:22509274

  11. Phosphorylated Peptides from Antarctic Krill (Euphausia superba) Prevent Estrogen Deficiency Induced Osteoporosis by Inhibiting Bone Resorption in Ovariectomized Rats.

    PubMed

    Xia, Guanghua; Zhao, Yanlei; Yu, Zhe; Tian, Yingying; Wang, Yiming; Wang, Shanshan; Wang, Jingfeng; Xue, Changhu

    2015-11-01

    In the current study, we investigated the improvement of phosphorylated peptides from Antarctic krill Euphausia superba (PP-AKP) on osteoporosis in ovariectomized rats. PP-AKP was supplemented to ovariectomized Sprague-Dawley rats for 90 days. The results showed that PP-AKP treatment remarkably prevented the reduction of bone mass and improved cancellous bone structure and biochemical properties. PP-AKP also significantly decreased serum contents of tartrate-resistant acid phosphatase (TRACP), cathepsin K (Cath-k), matrix metalloproteinases-9 (MMP-9), deoxypyridinoline (DPD), C-terminal telopeptide of collagen I (CTX-1), Ca, and P. Mechanism investigation revealed that PP-AKP significantly increased the osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio in mRNA expression, protein expression, and serum content. Further research suggested that NF-κB signaling pathways were inhibited by suppressing the mRNA and protein expressions of nuclear factor of activated T-cells (NFATc1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), diminishing the mRNA expression and phosphorylation of nuclear factor κB p65 (NF-κB p65), three key transcription factors in NF-κB pathways. These results suggest that PP-AKP can improve osteoporosis by inhibiting bone resorption via suppressing the activation of osteoclastogenesis related NF-κB pathways.

  12. Can medio-lateral baseplate position and load sharing induce asymptomatic local bone resorption of the proximal tibia? A finite element study

    PubMed Central

    Innocenti, Bernardo; Truyens, Evelyn; Labey, Luc; Wong, Pius; Victor, Jan; Bellemans, Johan

    2009-01-01

    Background Asymptomatic local bone resorption of the tibia under the baseplate can occasionally be observed after total knee arthroplasty (TKA). Its occurrence is not well documented, and so far no explanation is available. We report the incidence of this finding in our practice, and investigate whether it can be attributed to specific mechanical factors. Methods The postoperative radiographs of 500 consecutive TKA patients were analyzed to determine the occurrence of local medial bone resorption under the baseplate. Based on these cases, a 3D FE model was developed. Cemented and cementless technique, seven positions of the baseplate and eleven load sharing conditions were considered. The average VonMises stress was evaluated in the bone-baseplate interface, and the medial and lateral periprosthetic region. Results Sixteen cases with local bone resorption were identified. In each, bone loss became apparent at 3 months post-op and did not increase after one year. None of these cases were symptomatic and infection screening was negative for all. The FE analysis demonstrated an influence of baseplate positioning, and also of load sharing, on stresses. The average stress in the medial periprosthetic region showed a non linear decrease when the prosthetic baseplate was shifted laterally. Shifting the component medially increased the stress on the medial periprosthetic region, but did not significantly unload the lateral side. The presence of a cement layer decreases the stresses. Conclusion Local bone resorption of the proximal tibia can occur after TKA and might be attributed to a stress shielding effect. This FE study shows that the medial periprosthetic region of the tibia is more sensitive than the lateral region to mediolateral positioning of the baseplate. Medial cortical support of the tibial baseplate is important for normal stress transfer to the underlying bone. The absence of medial cortical support of the tibial baseplate may lead to local bone resorption at

  13. Feeding blueberry diets dose-dependently inhibits bone resorption in young rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nutritional status is a critical factor that influences bone development. We previously reported that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for only two weeks beginning on postnatal day 21 (PND21) significantly promoted bone formation. Howeve...

  14. 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

  15. Age-related bone resorption in the normal incus: a case of maladaptive remodelling?

    PubMed Central

    Lannigan, F J; O'Higgins, P; Oxnard, C E; McPhie, P

    1995-01-01

    The changes that occur in the normal human incus with age have been investigated. Evidence for age-related changes in this ossicle, especially in the region of the long process, has been accumulating over the last 30-40 years and yet they have neither been confirmed quantitatively nor explained satisfactorily. In this study the results of a morphometric study of the long processes of a series of normal incudes are presented. These demonstrate that the lenticular and long processes undergo progressive symmetric resorption with advancing age. We consider these findings in the light of previous considerations of incudal remodelling and propose that these remodelling changes may reflect a normal adaptive response to the biomechanical milieu of the human middle ear. PMID:7559138

  16. Whole-body vibration can reduce calciuria induced by high protein intakes and may counteract bone resorption: A preliminary study.

    PubMed

    Cardinale, M; Leiper, J; Farajian, P; Heer, M

    2007-01-01

    Excess protein intake can adversely affect the bone via an increase in calcium excretion, while suitable mechanical loading promotes osteogenesis. We therefore investigated whether vibration exposure could alleviate the bone mineral losses associated with a metabolic acidosis. Ten healthy individuals aged 22 - 29 years (median = 25) underwent three 5-day study periods while monitoring their dietary intake. The study consisted of recording the participants' usual dietary intake for 5 consecutive days. Participants were then randomly divided into two groups, one of which received a protein supplement (2 g x kg(-1) body mass x day(-1); n = 5) and the other whole-body low-magnitude (3.5 g), low-frequency (30 Hz) mechanical vibration (WBV) delivered through a specially designed vibrating plate for 10 min each day (n = 5). Finally, for the third treatment period, all participants consumed the protein supplement added to their normal diet and were exposed to WBV exercise for 10 min per day. Daily urine samples were collected throughout the experimental periods to determine the excretion of calcium, phosphate, titratable acid, urea, and C-telopeptide. As expected, when the participants underwent the high protein intake, there was an increase in urinary excretion rates of calcium (P < 0.001), phosphate (P < 0.003), urea (P < 0.001), titratable acid (P < 0.001), and C-telopeptide (P < 0.05) compared with baseline values. However, high protein intake coupled with vibration stimulation resulted in a significant reduction in urinary calcium (P = 0.006), phosphate excretion (P = 0.021), and C-telopeptide (P < 0.05) compared with protein intake alone, but did not affect titratable acid and urea output. The participants showed no effect of WBV exercise alone on urinary excretion of calcium, phosphate, urea, titratable acid, or C-telopeptide. The results indicate that vibration stimulation can moderate the increase in bone resorption and reduction in bone formation caused by a

  17. CX3CR1hi Monocyte/Macrophages Support Bacterial Survival and Experimental Infection-Driven Bone Resorption.

    PubMed

    Steinmetz, Orit; Hoch, Shifra; Avniel-Polak, Shani; Gavish, Keren; Eli-Berchoer, Luba; Wilensky, Asaf; Nussbaum, Gabriel

    2016-05-01

    Porphyromonas gingivalis,an anaerobic bacterium strongly linked to infection-driven inflammatory bone erosion, thrives within a highly inflamed milieu and disseminates to distant sites, such as atherosclerotic plaque. We examined the role of monocyte/macrophages in determining the outcome of infection with P. gingivalis. Surprisingly, transient monocyte/macrophage depletion led to greatly improved clearance of P. gingivalis. The chemokine receptors CCR2 and CX3CR1 play a major role in monocyte recruitment and differentiation to Ly6C(hi) vs CX3CR1(hi) subsets, respectively. To determine the contribution of particular monocyte/macrophage subsets to bacterial survival, we challenged chemokine receptor knockout mice and found that P. gingivalis clearance is significantly improved in the absence of CX3CR1. CX3CR1(hi) monocyte/macrophages promote P. gingivalis survival by downregulating neutrophil phagocytosis. Furthermore, CX3CR1 knockout mice resist bone resorption in the oral cavity following challenge with P. gingivalis Our findings provide an explanation for bacterial coexistence alongside an activate neutrophil infiltrate. PMID:26704610

  18. Inhibition of Osteoclast Differentiation and Bone Resorption by Bisphosphonate-conjugated Gold Nanoparticles

    PubMed Central

    Lee, Donghyun; Heo, Dong Nyoung; Kim, Han-Jun; Ko, Wan-Kyu; Lee, Sang Jin; Heo, Min; Bang, Jae Beum; Lee, Jung Bok; Hwang, Deok-Sang; Do, Sun Hee; Kwon, Il Keun

    2016-01-01

    In recent years, gold nanoparticles (GNPs) have been reported to affect the regeneration of bone tissue. The goal of this study was to improve bone tissue regeneration by using targeted GNPs. We fabricated a functionalized GNPs conjugated with alendronate (ALD), of the bisphosphonate group. Subsequently, the ALD, GNPs, and ALD conjugated GNPs (GNPs-ALD) were analyzed by ultraviolet-visible absorbance (UV-vis) spectrophotometer, Attenuated total reflectance Fourier transform infrared spectrometer (ATR-FTIR), and thermo gravimetric analysis (TGA). The prepared GNPs-ALD were used to investigate their inhibitory effects on the receptor activator of nuclear factor- κb ligand (RANKL)-induced osteoclastogenesis in bone marrow-derived macrophages (BMMs). Additionally, the GNPs-ALD were applied to ovariectomy (OVX)-induced osteoporotic mice and the experiments were evaluated. ALD was found to be successfully conjugated to the GNPs surface, and it displayed significant adhesion onto the bone surface. The in-vitro study indicated that the GNPs, ALD and GNPs-ALD suppressed osteoclast formation in a dose-dependent manner. Furthermore, in the OVX mouse model, the mice treated GNPs-ALD had higher bone density as compared to other OVX mice groups. The results from these tests indicated that GNPs-ALD can be useful agents for preventing and treating osteoporosis. PMID:27251863

  19. alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis.

    PubMed

    Ha, Hyunil; Lee, Jong-Ho; Kim, Ha-Neui; Kim, Hyun-Man; Kwak, Han Bok; Lee, Seungbok; Kim, Hong-Hee; Lee, Zang Hee

    2006-01-01

    alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several pathological conditions, including diabetic polyneuropathy. In the present study, we examined the effects of LA on osteoclastic bone loss associated with inflammation. LA significantly inhibited IL-1-induced osteoclast formation in cocultures of mouse osteoblasts and bone marrow cells, but LA had only a marginal effect on osteoclastogenesis from bone marrow macrophages induced by receptor activator of NF-kappaB ligand (RANKL). LA inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts. In addition, treatment with either prostaglandin E2 (PGE2) or RANKL rescued IL-1-induced osteoclast formation inhibited by LA or NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, in cocultures. LA blocked IL-1-induced PGE2 production even in the presence of arachidonic acid, without affecting the expression of COX-2 and membrane-bound PGE2 synthase. Dihydrolipoic acid (the reduced form of LA), but not LA, attenuated recombinant COX-2 activity in vitro. LA also inhibited osteoclast formation and bone loss induced by IL-1 and LPS in mice. Our results suggest that the reduced form of LA inhibits COX-2 activity, PGE2 production, and sustained RANKL expression, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.

  20. Methanol Extract of Euchelus asper Prevents Bone Resorption in Ovariectomised Mice Model

    PubMed Central

    Balakrishnan, Babita; Chiplunkar, Shubhada Vivek; Indap, Madhavi Manohar

    2014-01-01

    Marine molluscs are widely distributed throughout the world and many bioactive compounds exhibiting antiviral, antitumor, antileukemic, and antibacterial activity have been reported worldwide. The present study was designed to investigate the beneficial effect of methanol extract of Euchelus asper (EAME) on estrogen deficiency induced osteoporosis in ovariectomised mice model. Forty-two female Swiss albino mice were randomly assigned into Sham operated (Sham) group and six ovariectomised (OVX) subgroups such as OVX with vehicle (OVX); OVX with estradiol (2 mg/kg/day); OVX with EAME of graded doses (25, 50, 100, and 200 mg/kg/day). Bone turnover markers like serum alkaline phosphatase (ALP), serum acid phosphatase (ACP), serum calcium, and histological investigations of tibia and uterus were analysed. Metaphyseal DNA content of the femur bone was also studied. Antiosteoclastogenic activity of EAME was examined. Administration of EAME was able to reduce the increased bone turnover markers in the ovariectomised mice. Histomorphometric analysis revealed an increase in bone trabeculation and restoration of trabecular separation by EAME treatment. Metaphyseal DNA content of the femur of the OVX mice was increased by EAME administration. EAME also showed a potent antiosteoclastogenic behaviour. Thus, the present study reveals that EAME was able to successfully reduce the estrogen deficiency induced bone loss. PMID:24995144

  1. Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption.

    PubMed

    Guo, Mian; James, Aaron W; Kwak, Jin Hee; Shen, Jia; Yokoyama, Kazunari K; Ting, Kang; Soo, Chia B; Chiu, Robert H

    2016-01-01

    CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia(-/-) mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia(-/-) osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia(-/-) osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton's tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c-fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis. PMID:26932182

  2. Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption

    PubMed Central

    Guo, Mian; James, Aaron W.; Kwak, Jin Hee; Shen, Jia; Yokoyama, Kazunari K.; Ting, Kang; Soo, Chia B.; Chiu, Robert H.

    2016-01-01

    CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia−/− mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia−/− osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia−/− osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton’s tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c-fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis. PMID:26932182

  3. Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP.

    PubMed

    Takahashi, Naoki; Matsuda, Yumi; Sato, Keisuke; de Jong, Petrus R; Bertin, Samuel; Tabeta, Koichi; Yamazaki, Kazuhisa

    2016-01-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1(-/-) mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1(-/-) mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP. PMID:27388773

  4. Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP

    PubMed Central

    Takahashi, Naoki; Matsuda, Yumi; Sato, Keisuke; de Jong, Petrus R.; Bertin, Samuel; Tabeta, Koichi; Yamazaki, Kazuhisa

    2016-01-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1−/− mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1−/− mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP. PMID:27388773

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

    PubMed

    Nie, Shaobo; Xu, Jiawei; Zhang, Chenghua; Xu, Chen; Liu, Ming; Yu, Degang

    2016-01-29

    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 retarded 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.

  6. Differences in matrix composition between calvaria and long bone in mice suggest differences in biomechanical properties and resorption: Special emphasis on collagen.

    PubMed

    van den Bos, T; Speijer, D; Bank, R A; Brömme, D; Everts, V

    2008-09-01

    The mammalian skeleton consists of bones that are formed in two different ways: long bones via endochondral ossification and flat bones via intramembranous ossification. These different formation modes may result in differences in the composition of the two bone types. Using the 2D-difference in gel electrophoresis technique and mass spectrometry, we analyzed the composition of murine mineral-associated proteins of calvaria and long bone. Considerable differences in protein composition were observed. Flat bones (calvariae) contained more soluble collagen (8x), pigment epithelium derived factor (3x) and osteoglycin (4x); whereas long bones expressed more chondrocalcin (3x), thrombospondin- 1 (4x), fetuin (4x), secreted phosphoprotein 24 (3x), and thrombin (7x). Although cystatin motifs containing proteins, such as secreted phosphoprotein 24 and fetuin are highly expressed in long bone, they did not inhibit the activity of the cysteine proteinases cathepsin B and K. The solubility of collagen differed which coincided with differences in collagen crosslinking, long bone containing 3x more (hydroxylysine)-pyridinoline. The degradation of long bone collagen by MMP2 (but not by cathepsin K) was impaired. These differences in collagen crosslinking may explain the differences in the proteolytic pathways osteoclasts use to degrade bone. Our data demonstrate considerable differences in protein composition of flat and long bones and strongly suggest functional differences in formation, resorption, and mechanical properties of these bone types. PMID:18583211

  7. [Bone and Calcium Metabolisms Associated with Dental and Oral-Maxillofacial Diseases. Destructive bone resorption by osteoclasts and oral disease].

    PubMed

    Nakamura, Midori; Koide, Masanori; Nakamura, Hiroshi; Udagawa, Nobuyuki

    2015-09-01

    Osteoclasts are multinucleated cells that resorb bone, originate from monocyte-macrophage lineage cells. Periodontitis is an inflammatory disease characterized by destruction of periodontal tissues including alveolar bones. Oral implant system is established average dental treatment method. However, peri-implantitis affects the convalescence. Osteonecrosis of the jaw (ONJ) is also inflammatory disease associated with antiresorptive therapy of bisphosphonates. Diagnosis and management of ONJ is more important issue.

  8. Changes in urinary bone resorption markers (pyridinoline, deoxypyridinoline) resulting from experimentally-induced osteoarthritis in the temporomandibular joint of rats.

    PubMed

    Imada, Masae; Tanimoto, Kotaro; Ohno, Shigeru; Sasaki, Akiko; Sugiyama, Hiroki; Tanne, Kazuo

    2003-01-01

    The purpose of this study was to quantify the urinary bone resorption markers, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), excreted from experimentally-induced osteoarthritis (OA) in the temporomandibular joint (TMJ) of rats. Osteoarthritic lesions were induced by intra-articular injection of collagenase into the right TMJs of 16-week-old male rats. The whole day's urine was collected from each animal one day before the injection and 5, 7, 11 and 14 days after the injection. Urine samples were analyzed by high-perfomance liquid chromatography and fluorescence spectroscopy. Histological changes in condyle were examined by using paraffin sections with toluidine blue staining. Degenerative changes were observed in the articular cartilage of the experimental group on day 7 and day 14 after the injection of collagenase. The concentration of Pyr was remarkably high in the experimental group, and consequently the Pyr to Dpyr ratio was significantly higher (p<0.05) in the experimental group than in the control group from 7-14 days after the injection. These findings suggest that a urinary Pyr/Dpyr ratio would be available for the detection of degenerative changes in condyle relevant to temporomandibular joint osteoarthritis (TMJ OA). PMID:12555930

  9. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation.

    PubMed

    Thudium, Christian S; Moscatelli, Ilana; Flores, Carmen; Thomsen, Jesper S; Brüel, Annemarie; Gudmann, Natasja Stæhr; Hauge, Ellen-Margrethe; Karsdal, Morten A; Richter, Johan; Henriksen, Kim

    2014-07-01

    Osteopetrosis due to lack of acid secretion by osteoclasts is characterized by abolished bone resorption, increased osteoclast numbers, but normal or even increased bone formation. In contrast, osteoclast-poor osteopetrosis appears to have less osteoblasts and reduced bone formation, indicating that osteoclasts are important for regulating osteoblast activity. To illuminate the role of the osteoclast in controlling bone remodeling, we transplanted irradiated skeletally mature 3-month old wild-type mice with hematopoietic stem cells (HSCs) to generate either an osteoclast-rich or osteoclast-poor adult osteopetrosis model. We used fetal liver HSCs from (1) oc/oc mice, (2) RANK KO mice, and (3) compared these to wt control cells. TRAP5b activity, a marker of osteoclast number and size, was increased in the oc/oc recipients, while a significant reduction was seen in the RANK KO recipients. In contrast, the bone resorption marker CTX-I was similarly decreased in both groups. Both oc/oc and Rank KO recipients developed a mild osteopetrotic phenotype. However, the osteoclast-rich oc/oc recipients showed higher trabecular bone volume (40 %), increased bone strength (66 %), and increased bone formation rate (54 %) in trabecular bone, while RANK KO recipients showed only minor trends compared to control recipients. We here show that maintaining non-resorbing osteoclasts, as opposed to reducing the osteoclasts, leads to increased bone formation, bone volume, and ultimately higher bone strength in vivo, which indicates that osteoclasts are sources of anabolic molecules for the osteoblasts.

  10. Effect of microgravity and mechanical stimulation on the in vitro mineralization and resorption of fetal mouse long bones (7-IML-1)

    NASA Technical Reports Server (NTRS)

    Veldhuijzen, J. Paul

    1992-01-01

    Mechanical forces play an important role in the differentiation, growth, and remodeling of skeletal tissues. An increase in the normal loading pattern of the skeleton leads to an increase in bone mass. An overall decrease in the functional load exerted on the skeleton produces mineral loss and osteoporosis. However, the responses of the skeletal tissue cells to various loading conditions are still largely unresolved, as is the mechanism of the cellular response to changed mechanical environment. Using an in vitro approach, we hope to avoid some problems encountered in the use of in vivo animal and man models, which have been extensively used in the past. In a number of experiments we have demonstrated that 16 and 17 day old fetal mouse long bone rudiments (metatarsalia), cultured in a liquid culture medium, are very suitable to study mineralization and resorption, respectively. We have also demonstrated that under hydrostatic compression, mineralization is increased while resorption is decreased. Culture of long bone rudiments under noncompressed control conditions can be regarded as a situation of partial unloading, showing some phenomena of a disuse situation. Under microgravity conditions, responses of osteoblasts and chondrocytes (involved in mineralization) and osteoclasts (involved in mineral resorption), to culture with and without compression, may be much more outspoken. This will have advantages for the study and the interpretation of the role of cellular events in the process of mineralization and resorption of developing skeletal tissues under various loading conditions. The BONES Experiment is carried out in four type I/O and four type I/E containers. Various aspects of the investigation are discussed.

  11. DNA aptamer beacon assay for C-telopeptide and handheld fluorometer to monitor bone resorption.

    PubMed

    Bruno, John Gordon; Carrillo, Maria P; Phillips, Taylor; Hanson, Douglas; Bohmann, Jonathan A

    2011-09-01

    A novel DNA aptamer beacon is described for quantification of a 26-amino acid C-telopeptide (CTx) of human type I bone collagen. One aptamer sequence and its reverse complement dominated the aptamer pool (31.6% of sequenced clones). Secondary structures of these aptamers were examined for potential binding pockets. Three-dimensional computer models which analyzed docking topologies and binding energies were in agreement with empirical fluorescence experiments used to select one candidate loop for beacon assay development. All loop structures from the aptamer finalists were end-labeled with TYE 665 and Iowa Black quencher for comparison of beacon fluorescence levels as a function of CTx concentration. The optimal beacon, designated CTx 2R-2h yielded a low ng/ml limit of detection using a commercially available handheld fluorometer. The CTx aptamer beacon bound full-length 26-amino acid CTx peptide, but not a shorter 8-amino acid segment of CTx peptide which is a common target for commercial CTx ELISA kits. The prototype assay was shown to detect CTx peptide from human urine after creatinine and urea were removed by size-exclusion chromatography to prevent nonspecific denaturing of the aptamer beacon. This work demonstrates the potential of aptamer beacons to be utilized for rapid and sensitive bone health monitoring in a handheld or point-of-care format.

  12. Polychlorinated biphenyl (118) activates osteoclasts and induces bone resorption in goldfish.

    PubMed

    Yachiguchi, Koji; Matsumoto, Noriko; Haga, Yuki; Suzuki, Motoharu; Matsumura, Chisato; Tsurukawa, Masahiro; Okuno, Toshihiro; Nakano, Takeshi; Kawabe, Kimi; Kitamura, Kei-ichiro; Toriba, Akira; Hayakawa, Kazuichi; Chowdhury, Vishwajit S; Endo, Masato; Chiba, Atsuhiko; Sekiguchi, Toshio; Nakano, Masaki; Tabuchi, Yoshiaki; Kondo, Takashi; Wada, Shigehito; Mishima, Hiroyuki; Hattori, Atsuhiko; Suzuki, Nobuo

    2014-05-01

    To analyze the effect of polychlorinated biphenyl (PCB) 118 on fish bone metabolism, we examined osteoclastic and osteoblastic activities, as well as plasma calcium levels, in the scales of PCB (118)-injected goldfish. In addition, effect of PCB (118) on osteoclasts and osteoblasts was investigated in vitro. Immature goldfish, in which the endogenous effects of sex steroids are negligible, were used. PCB (118) was solubilized in dimethyl sulfoxide at a concentration of 10 ppm. At 1 and 2 days after PCB (118) injection (100 ng/g body weight), both osteoclastic and osteoblastic activities, and plasma calcium levels were measured. In an in vitro study, then, both osteoclastic and osteoblastic activities as well as each marker mRNA expression were examined. At 2 days, scale osteoclastic activity in PCB (118)-injected goldfish increased significantly, while osteoblastic activity did not change significantly. Corresponding to osteoclastic activity, plasma calcium levels increased significantly at 2 days after PCB (118) administration. Osteoclastic activation also occurred in the marker enzyme activities and mRNA expressions in vitro. Thus, we conclude that PCB (118) disrupts bone metabolism in goldfish both in vivo and in vitro experiments.

  13. Phytoestrogens directly inhibit TNF-α-induced bone resorption in RAW264.7 cells by suppressing c-fos-induced NFATc1 expression.

    PubMed

    Karieb, Sahar; Fox, Simon W

    2011-02-01

    TNF-α-induced osteoclastogenesis is central to post-menopausal and inflammatory bone loss, however, the effect of phytoestrogens on TNF-α-induced bone resorption has not been studied. The phytoestrogens genistein, daidzein, and coumestrol directly suppressed TNF-α-induced osteoclastogenesis and bone resorption. TRAP positive osteoclast formation and resorption area were significantly reduced by genistein (10(-7)  M), daidzein (10(-5)  M), and coumestrol (10(-7)  M), which was prevented by the estrogen antagonist ICI 182,780. TRAP expression in mature TNF-α-induced osteoclasts was also significantly reduced by these phytoestrogen concentrations. In addition, in the presence of ICI 182,780 genistein and coumestrol (10(-5) -10(-6)  M) augmented TNF-α-induced osteoclast formation and resorption. However, this effect was not observed in the absence of estrogen antagonist indicating that genistein's and coumestrol's ER-dependent anti-osteoclastic action normally negates this pro-osteoclastic effect. To determine the mechanism mediating the anti-osteoclastic action we examined the effect of genistein, coumestrol, and daidzein on caspase 3/7 activity, cell viability and expression of key genes regulating osteoclast differentiation and fusion. While anti-osteoclastic phytoestrogen concentrations had no effect on caspase 3/7 activity or cell viability they did significantly reduce TNF-α-induced c-fos and NFATc1 expression in an ER dependent manner and also inhibited NFATc1 nuclear translocation. Significant decreases in NFκB and DC-STAMP levels were also noted. Interestingly, constitutive c-fos expression prevented the anti-osteoclastic action of phytoestrogens on differentiation, resorption and NFATc1. This suggests that phytoestrogens suppress TNF-α-induced osteoclastogenesis via inhibition of c-fos-dependent NFATc1 expression. Our data provides further evidence that phytoestrogens have a potential role in the treatment of post-menopausal and inflammatory

  14. Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.

    PubMed

    Xu, Leqin; Luo, Jian; Jin, Rongrong; Yue, Zhiying; Sun, Peng; Yang, Zhengfeng; Yang, Xinghai; Wan, Wei; Zhang, Jishen; Li, Shichang; Liu, Mingyao; Xiao, Jianru

    2016-05-01

    Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-κB signaling-related cytokines, including TNFα, MCP-1, IL1α, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-κB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cell-induced bone destruction in vivo As a result, bortezomib suppressed NF-κB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-κB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB. Mol Cancer Ther; 15(5); 854-65. ©2016 AACR.

  15. [Biological profile of tartrate-resistant acid phosphatase as a marker of bone resorption].

    PubMed

    Rico, H; Iritia, M; Arribas, I; Revilla, M

    1990-12-01

    Tartrate-resistant serum acid phosphatase was measured in 123 subjects, 80 of which were normal and the rest pathologic, in order to define the profile and value of this parameter as a biological marker of osteoclastic activity. Normal subjects were divided into age groups based on the period where skeletal growth ends (under 20 years), at the age of menopause in women (50 years, between 20 and 50 years) and those over 50 years. There was an increase in tartrate-resistant serum acid phosphatase coinciding with puberty and no sex differences were observed after the 50 year mark, when women showed higher values than men (p less than 0.001). Such tartrate-resistant serum acid phosphatase increase, is reflected as higher values in the 50 year group than in the 20 to 50 year group (p less than 0.001), the only age limit where a negative significant correlation between tartrate-resistant serum acid phosphatase values and age could be observed (p less than 0.05). Values were higher up to the age of 20 years (p less than 0.001) than in any other older age group. Levels increased significantly (p less than 0.001 for both groups) in post-menopausal osteoporosis (n = 20) and in Paget's disease of bone (n = 15), and decreased significantly (p less than 0.05) in imperfect osteogenesis (n = 8), thus revealing its value as a biological marker of osteoclastic activity. PMID:2099535

  16. 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'.

  17. Bone Remodeling Under Pathological Conditions.

    PubMed

    Xiao, Wenmei; Li, Shuai; Pacios, Sandra; Wang, Yu; Graves, Dana T

    2016-01-01

    Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID:26599114

  18. The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures*

    PubMed Central

    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

    2013-01-01

    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. PMID:23530032

  19. Cadmium accelerates bone loss in ovariectomized mice and fetal rat limb bones in culture

    SciTech Connect

    Bhattacharyya, M.H.; Whelton, B.D.; Stern, P.H.; Peterson, D.P. )

    1988-11-01

    Loss of bone mineral after ovariectomy was studied in mice exposed to dietary cadmium at 0.25, 5, or 50 ppm. Results show that dietary cadmium at 50 ppm increased bone mineral loss to a significantly greater extent in ovariectomized mice than in sham-operated controls. These results were obtained from two studies, one in which skeletal calcium content was determined 6 months after ovariectomy and a second in which {sup 45}Ca release from {sup 45}Ca-prelabeled bones was measured immediately after the start of dietary cadmium exposure. Furthermore, experiments with {sup 45}Ca-prelabeled fetal rat limb bones in culture demonstrated that Cd at 10 nM in the medium, a concentration estimated to be in the plasma of mice exposed to 50 ppm dietary Cd, strikingly increased bone resorption. These in vitro results indicate that cadmium may enhance bone mineral loss by a direct action on bone. Results of the in vivo studies are consistent with a significant role of cadmium in the etiology of Itai-Itai disease among postmenopausal women in Japan and may in part explain the increased risk of postmenopausal osteoporosis among women who smoke.

  20. V-ATPase subunit ATP6AP1 (Ac45) regulates osteoclast differentiation, extracellular acidification, lysosomal trafficking, and protease exocytosis in osteoclast-mediated bone resorption

    PubMed Central

    Yang, De-Qin; Feng, Shengmei; Chen, Wei; Zhao, Haibo; Paulson, Christie; Li, Yi-Ping

    2014-01-01

    Lysosomal trafficking and protease exocytosis in osteoclasts are essential for ruffled border formation and bone resorption. Yet, the mechanism underlying lysosomal trafficking and the related process of exocytosis remains largely unknown. We found ATP6ap1 (Ac45), an accessory subunit of vacuolar-type H+-ATPases (V-ATPases), to be highly induced by receptor activator for nuclear factor kappa B ligand (RANKL) in osteoclast differentiation. Ac45 knockdown osteoclasts formed normal actin rings, but had severely impaired extracellular acidification and bone resorption. Ac45 knockdown significantly reduced osteoclast formation. The decrease in the number of osteoclasts does not result from abnormal apoptosis; rather, it results from decreased osteoclast precursor cell proliferation and fusion, which may be partially due to the downregulation of ERK phosphorylation and FBJ osteosarcoma oncogene (c-fos), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and Tm7sf4 expression. Notably, Ac45 knockdown osteoclasts exhibited impaired lysosomal trafficking and exocytosis, as indicated by the absence of lysosomal trafficking to the ruffled border and a lack of cathepsin K exocytosis into the resorption lacuna. Our data revealed that the impaired exocytosis is specifically due to Ac45 deficiency, and not the general consequence of a defective V-ATPase. Together, our results demonstrate the essential role of Ac45 in osteoclast-mediated extracellular acidification and protease exocytosis, as well as the ability of Ac45 to guide lysosomal intracellular trafficking to the ruffled border, potentially through its interaction with the small GTPase Rab7. Our work indicates that Ac45 may be a novel therapeutic target for osteolytic disease. PMID:22467241

  1. Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption.

    PubMed

    Sun, Li; Iqbal, Jameel; Dolgilevich, Svetlana; Yuen, Tony; Wu, Xue-Bin; Moonga, Baljit S; Adebanjo, Olugbenga A; Bevis, Peter J R; Lund, Frances; Huang, Christopher L-H; Blair, Harry C; Abe, Etsuko; Zaidi, Mone

    2003-03-01

    We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD+, to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. Its activation in the osteoclast triggers Ca2+ release through ryanodine receptors (RyRs), stimulation of interleukin-6 (IL-6), and an inhibition of bone resorption. Here, we have examined the consequences of deleting the CD38 gene in mice on skeletal remodeling. We report that CD38-/- mice displayed a markedly reduced bone mineral density (BMD) at the femur, tibia, and lumbar spine at 3 months and at the lumbar spine at 4 months, with full normalization of the BMD at all sites at 5 months. The osteoporosis at 3 months was accompanied by a reduction in primary spongiosa and increased osteoclast surfaces on histomorphometric analysis. Hematopoetic stem cells isolated ex vivo from CD38-/- mice showed a dramatic approximately fourfold increase in osteoclast formation in response to incubation for 6 days with RANK-L and M-CSF. The osteoclasts so formed in these cultures showed a approximately 2.5-fold increase in resorptive activity compared with wild-type cells. However, when adherent bone marrow stromal cells were allowed to mature into alkaline phosphatase-positive colony-forming units (CFU-Fs), those derived from CD38-/- mice showed a significant reduction in differentiation compared with wild-type cells. Real-time RT-PCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, alpha, beta, and gamma. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions

  2. Comparison of the effects of eldecalcitol with either raloxifene or bisphosphonate on serum tartrate resistant acid phosphatase-5b, a bone resorption marker, in postmenopausal osteoporosis

    PubMed Central

    Takada, Junichi; Ikeda, Satoshi; Kusanagi, Tetsuya; Mizuno, Satoshi; Wada, Hiroshi; Iba, Kousuke; Yoshizaki, Takashi; Yamashita, Toshihiko

    2016-01-01

    Summary Objective This study analyzes whether concomitant raloxifene (RLX) or bisphosphonates (BP) plus eldecalcitol (ELD) has excessive suppressive effects on a bone resorption marker during the first 6 months of treatment in postmenopausal women in real-world setting. Methods 285 postmenopausal osteoporotic patients who had been treated with RLX or BP plus ELD were evaluated the bone resorption marker, serum tartrate resistant acid phosphatase-5b (TRACP-5b), during the first 6 months of treatment. Results In drug-naïve group (not received osteoporosis medications before the administration, n=70), the concomitant RLX or BP with ELD significantly decreased levels of TRACP-5b without severe suppression. In vitamin D switch group [RLX or BP plus alfacalcidol (ALF) and then switched to RLX or BP plus ELD, n=215], the replacing ALF with ELD further and significantly decreased TRACP-5b and tertile analyses based on baseline values were significantly decreased far more in the highest, compared with the lowest tertile in the ELD+RLX and ELD+BP groups. Conclusion ELD combined with RLX or BP administered for 6 months to postmenopausal women with osteoporosis who were drug-naïve or who had switched medications significantly reduced and maintained TRACP-5b values within the reference range. PMID:27252739

  3. 2-(trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate suppresses osteoclast maturation and bone resorption by targeting macrophage-colony stimulating factor signaling.

    PubMed

    Park, So Jeong; Park, Doo Ri; Bhattarai, Deepak; Lee, Kyeong; Kim, Jaesang; Bae, Yun Soo; Lee, Soo Young

    2014-08-01

    2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity.

  4. Effects of the circuit box jumping on bone resorption, health-related to physical fitness and balance in the premenopausal women.

    PubMed

    Anek, Achariya; Kanungsukasem, Vijit; Bunyaratavej, Narong

    2011-10-01

    The purpose of this research is to develop a circuit box jumping exercise program and to examine the effects of the circuit box jumping exercise program on bone formation, bone resorption, health related to physical fitness and balance of the premenopausal females. The samples consisted of 57 female volunteers from Chulalongkorn University, aged between 35-45. The subjects were divided into two groups: 28 females in the experimental group and 29 females in the control group by the simple random sampling method. The experimental group participated in the circuit box jumping exercise program while wearing heart rate monitors. The exercise speed was determined by the rhythm of the music. The experimental group completed two circuits of jumping at 6 stations with 10 jumps per station three times per week, for a period of twelve weeks. Each jumping box at Station 1 and 4 was 10 cm. high; the boxes at Station 2 and 5 were 15 cm. high; and at Station 3 and 6, the boxes were 20 cm. in height. The intensity is 60%-80% of a maximum heart rate. The control group did not participate in the circuit box jumping exercise program. The collected data before and after the experiment were the results of the physiology test, the biochemical bone markers, the health related physical fitness and the balance ability. The collected data were compared and analyzed by the mean and standard deviation. The differences of the tests are statistically significant at the .05 level. The results of the present study are as follows; 1. After the 12-week experiment training, the findings indicated that the mean scores on bone resorption (beta-Crosslaps) of the experimental group and the control group were significantly different at 0.05 level. In addition, the findings showed that the percentage changes on bone resorption (beta-Crosslaps) variance of the experiment group reduced by -25.6528%, while that of the control group reduced by -0.5933%. Bone formation (PINP/beta-Crosslaps) in the circuit box

  5. Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio.

    PubMed

    Kiviranta, Riku; Morko, Jukka; Alatalo, Sari L; NicAmhlaoibh, Roisin; Risteli, Juha; Laitala-Leinonen, Tiina; Vuorio, Eero

    2005-01-01

    Previous reports indicate that mice deficient for cathepsin K (Ctsk), a key protease in osteoclastic bone resorption, develop osteopetrosis due to their inability to properly degrade organic bone matrix. Some features of the phenotype of Ctsk knockout mice, however, suggest the presence of mechanisms by which Ctsk-deficient mice compensate for the lack of cathepsin K. To study these mechanisms in detail, we generated Ctsk-deficient (Ctsk-/-) mice and analyzed them at the age of 2, 7, and 12 months using peripheral quantitative computed tomography, histomorphometry, resorption marker measurements, osteoclast and osteoblast differentiation cultures, and gene expression analyses. The present study verified the previously published osteopetrotic features of Ctsk-deficient mice. However, these changes did not exacerbate during aging indicating the absence of Ctsk to have its most severe effects during the rapid growth period. Resorption markers ICTP and CTX were decreased in the media of Ctsk-/- osteoclasts cultured on bone slices indicating impaired bone resorption. Ctsk-/- mice exhibited several mechanisms attempting to compensate for Ctsk deficiency. The number of osteoclasts in trabecular bone was significantly increased in Ctsk-/- mice compared to controls, as was the number of osteoclast precursors in bone marrow. The mRNA levels for receptor activator of nuclear factor (kappa)B ligand (RANKL) in Ctsk-/- bones were increased resulting in increased RANKL/OPG ratio favoring osteoclastogenesis. In addition, expression of mRNAs of osteoclastic enzymes (MMP-9, TRACP) and for osteoblastic proteases (MMP-13, MMP-14) were increased in Ctsk-/- mice compared to controls. Impaired osteoclastic bone resorption in Ctsk-/- mice results in activation of osteoblastic cells to produce increased amounts of other proteolytic enzymes and RANKL in vivo. We suggest that increased RANKL expression mediates enhanced osteoclastogenesis and increased protease expression by osteoclasts

  6. Bmp2 and Bmp4 accelerate alveolar bone development.

    PubMed

    Ou, Mingming; Zhao, Yibing; Zhang, Fangming; Huang, Xiaofeng

    2015-06-01

    Alveolar bone remodeling is a continuous process that takes place during development and in response to various physiological and pathological stimuli. However, detailed knowledge regarding the underlying mechanisms involved in alveolar bone development is still lacking. This study aims at improving our understanding of alveolar bone formation and the role of bone morphogenetic proteins (Bmps) in this process. Mice at embryonic (E) day 13.5 to postnatal (PN) day 15.5 were selected to observe the process of alveolar bone development. Alveolar bone development was found to be morphologically observable at E14.5. Molar teeth isolated from mice at PN7.5 were pretreated with Bmp2, Bmp4, Noggin, or BSA, and grafted subcutaneously into mice. The subcutaneously implanted tooth germs formed alveolar bone indicating the role of the dental follicle in alveolar bone development. Alveolar bone formation was increased after pretreatment with Bmp2 and Bmp4, but not with Noggin. Gene expression levels in dental follicle cells from murine molars were also determined by real-time RT-PCR. The expression levels of Runx2, Bsp, and Ocn were significantly higher in dental follicle cells cultured with Bmp2 or Bmp4, and significantly lower in those cultured with Noggin when compared with that of the BSA controls. Our results suggest that the dental follicle participates in alveolar bone formation and Bmp2/4 appears to accelerate alveolar bone development.

  7. A comparative study of the effects of daily minodronate and weekly alendronate on upper gastrointestinal symptoms, bone resorption, and back pain in postmenopausal osteoporosis patients.

    PubMed

    Yoshioka, Toru; Okimoto, Nobukazu; Okamoto, Ken; Sakai, Akinori

    2013-03-01

    The purpose of the present study was to precisely compare both the efficacy and abdominal symptom-related quality of life after treatment with daily minodronate and weekly alendronate in patients with primary postmenopausal osteoporosis. The efficacy of the two drugs was assessed based on improvements in a bone turnover marker, back pain, and gastrointestinal symptoms that impair quality of life, which was assessed using the Izumo scale questionnaire. In the minodronate group, there were no significant changes during the treatment period in the specific scores for heartburn, epigastralgia and epigastric fullness, whereas all of the scores were significantly elevated at some time point after drug administration in the alendronate group. Urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, and bone-specific alkaline phosphatase, a bone formation marker, significantly decreased in both groups, but decreases in uNTX in the minodronate group was observed significantly earlier compared with those in the alendronate group. The back pain scores, which were obtained using a visual analog scale, were significantly reduced in both groups. However, analgesic effects were detected earlier in the minodronate group. In conclusion, compared with weekly alendronate, daily minodronate improved bone turnover and back pain more promptly without causing upper gastrointestinal symptoms.

  8. Role of Polymer Architecture on the Activity of Polymer-Protein Conjugates for the Treatment of Accelerated Bone Loss Disorders.

    PubMed

    Tucker, Bryan S; Stewart, Jon D; Aguirre, J Ignacio; Holliday, L Shannon; Figg, C Adrian; Messer, Jonathan G; Sumerlin, Brent S

    2015-08-10

    Polymers of similar molecular weights and chemical constitution but varying in their macromolecular architectures were conjugated to osteoprotegerin (OPG) to determine the effect of polymer topology on protein activity in vitro and in vivo. OPG is a protein that inhibits bone resorption by preventing the formation of mature osteoclasts from the osteoclast precursor cell. Accelerated bone loss disorders, such as osteoporosis, rheumatoid arthritis, and metastatic bone disease, occur as a result of increased osteoclastogenesis, leading to the severe weakening of the bone. OPG has shown promise as a treatment in bone disorders; however, it is rapidly cleared from circulation through rapid liver uptake, and frequent, high doses of the protein are necessary to achieve a therapeutic benefit. We aimed to improve the effectiveness of OPG by creating OPG-polymer bioconjugates, employing reversible addition-fragmentation chain transfer polymerization to create well-defined polymers with branching densities varying from linear, loosely branched to densely branched. Polymers with each of these architectures were conjugated to OPG using a "grafting-to" approach, and the bioconjugates were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The OPG-polymer bioconjugates showed retention of activity in vitro against osteoclasts, and each bioconjugate was shown to be nontoxic. Preliminary in vivo studies further supported the nontoxic characteristics of the bioconjugates, and measurement of the bone mineral density in rats 7 days post-treatment via peripheral quantitative computed tomography suggested a slight increase in bone mineral density after administration of the loosely branched OPG-polymer bioconjugate.

  9. Carbonic anhydrase II plays a major role in osteoclast differentiation and bone resorption by effecting the steady state intracellular pH and Ca2+.

    PubMed

    Lehenkari, P; Hentunen, T A; Laitala-Leinonen, T; Tuukkanen, J; Väänänen, H K

    1998-07-10

    Carbonic anhydrase II (CA II) expression in characteristic for the early stage of osteoclast differentiation. To study how CA II, which is crucial in proton generation in mature osteoclasts, influences the osteoclast differentiation process we performed rat bone marrow cultures. In this model, acetazolamide, a specific CA inhibitor, decreased the 1,25 (OH)2D3-induced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells, in a dose-dependent manner. We then performed intracellular pH (pHi) and Ca2+ (Cai2+) measurements for cultured osteoclasts and noticed that addition of acetazolamide caused a rapid, transient increase of both parameters. The increase in pHi was dependent neither on the culture substrate nor on the extracellular pH (pHe) but the increase could be diminished by DIDS or by bicarbonate removal. Membrane-impermeable CA inhibitors (benzolamide and pd5000) did not have this effect. Addition of CA II antisense oligonucleotides into the cultures reduced the pHi increase significantly. CA II inhibition was also found to neutralize the intracellular vesicles at extracellular pH (pHe) of 7.4, but at less extent at pHe 7.0. In mouse calvaria cultures, bone resorption was inhibited dose dependently by acetazolamide at pHe 7.4 while inhibition was smaller at pHe 7.0. We conclude that CA II is essential not only in bone resorption but also in osteoclast differentiation. In both processes, however, the crucial role of CA II is at least partially due to the effect on the osteoclast pHi regulation.

  10. Effects of vitamin D binding protein-macrophage activating factor (DBP-MAF) infusion on bone resorption in two osteopetrotic mutations.

    PubMed

    Schneider, G B; Benis, K A; Flay, N W; Ireland, R A; Popoff, S N

    1995-06-01

    Osteopetrosis is a heterogeneous group of bone diseases characterized by an excess accumulation of bone and a variety of immune defects. Osteopetrosis (op) and incisors absent (ia) are two nonallelic mutations in the rat which demonstrated these skeletal defects as a result of reduced bone resorption. Osteopetrotic (op) rats have severe sclerosis as a result of reduced numbers of osteoclasts which are structurally abnormal. The sclerosis in ia rats is not as severe as in op mutants; they have elevated numbers of osteoclasts, but they are also morphologically abnormal, lacking a ruffled border. Both of these mutations have defects in the inflammation-primed activation of macrophages. They demonstrate independent defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF). Because this factor may also play a role in the pathogenesis of osteoclastic dysfunction, the effects of ex vivo-generated DBP-MAF were evaluated on the skeletal system of these two mutations. Newborn ia and op rats and normal littermate controls were injected with DBP-MAF or vehicle once every 4 days from birth until 2 weeks of age, at which time bone samples were collected to evaluate a number of skeletal parameters. DBP-MAF treated op rats had an increased number of osteoclasts and the majority of them exhibited normal structure. There was also reduced bone volume in the treated op animals and an associated increased cellularity of the marrow spaces. The skeletal sclerosis was also corrected in the ia rats; the bone marrow cavity size was significantly enlarged and the majority of the osteoclasts appeared normal with extensive ruffled borders. PMID:7669443

  11. Exceptional case of bone resorption in an osteo-odonto-keratoprosthesis. A scanning electron microscopy and X-ray microanalysis study

    SciTech Connect

    Caiazza, S.; Falcinelli, G.; Pintucci, S. )

    1990-01-01

    This article reports the findings of investigations on an osteo-odonto-keratoprosthesis in an eye that was enucleated owing to severe complications 12 years after implantation. Scanning electron microscopy and electron probe X-ray microanalysis showed extensive resorption of the bone that was used as a supporting element in the kind of transcorneal prosthesis developed by Strampelli. The destructive process, in addition to surgical trauma, has been associated with the early and recurrent bacterial infections relating to the presence of Staphylococcus epidermidis. The need to control the occurrence of primary bacterial infections in traumatized tissues during operations as well as further infectious situations, given the enhanced antibiotic-resistence of bacteria, is emphasized.

  12. A FEM based endosteal implant simulation to determine the effect of peri-implant bone resorption on stress induced implant failure.

    PubMed

    Michailidis, N; Karabinas, G; Tsouknidas, A; Maliaris, G; Tsipas, D; Koidis, P

    2013-01-01

    Although dental implants exhibit only limited failure rates, their fracture is associated to major modifications of the prosthetic treatment and complex surgery for the removal of the remaining embedded implant part. This investigation aims to assess the developing stress fields in the bone-implant interface during mastication and asses the failure modes of oral implants.In order to achieve this, a FEM model of an implant was reverse engineered and virtually loaded at the top of the crown for a force spectrum ranging from 75-225 N in a vertical, horizontal and oblique occlusal direction. The calculated stress fields were compared with clinically retrieved fractured implants with identical geometrical characteristics and the fracture modes of both cases were correlated. The developing stress patterns facilitated the interpretation of the implant failure as the maximum stresses, indicated critical values in both, lingual and buccal sides of the implant-bone interface at a certain critical level of bone resorption, in which failure occurs. PMID:23988704

  13. A FEM based endosteal implant simulation to determine the effect of peri-implant bone resorption on stress induced implant failure.

    PubMed

    Michailidis, N; Karabinas, G; Tsouknidas, A; Maliaris, G; Tsipas, D; Koidis, P

    2013-01-01

    Although dental implants exhibit only limited failure rates, their fracture is associated to major modifications of the prosthetic treatment and complex surgery for the removal of the remaining embedded implant part. This investigation aims to assess the developing stress fields in the bone-implant interface during mastication and asses the failure modes of oral implants.In order to achieve this, a FEM model of an implant was reverse engineered and virtually loaded at the top of the crown for a force spectrum ranging from 75-225 N in a vertical, horizontal and oblique occlusal direction. The calculated stress fields were compared with clinically retrieved fractured implants with identical geometrical characteristics and the fracture modes of both cases were correlated. The developing stress patterns facilitated the interpretation of the implant failure as the maximum stresses, indicated critical values in both, lingual and buccal sides of the implant-bone interface at a certain critical level of bone resorption, in which failure occurs.

  14. Transforming growth factor-β synthesized by stromal cells and cancer cells participates in bone resorption induced by oral squamous cell carcinoma

    SciTech Connect

    Nakamura, Ryosuke; Kayamori, Kou; Oue, Erika; Sakamoto, Kei; Harada, Kiyoshi; Yamaguchi, Akira

    2015-03-20

    Transforming growth factor beta (TGF-β) plays a significant role in the regulation of the tumor microenvironment. To explore the role of TGF-β in oral cancer-induced bone destruction, we investigated the immunohistochemical localization of TGF-β and phosphorylated Smad2 (p-Smad2) in 12 surgical specimens of oral squamous cell carcinoma (OSCC). These studies revealed TGF-β and p-Smad2 expression in cancer cells in all tested cases. Several fibroblasts located between cancer nests and resorbing bone expressed TGF-β in 10 out of 12 cases and p-Smad2 in 11 out of 12 cases. Some osteoclasts also exhibited p ∼ Smad2 expression. The OSCC cell line, HSC3, and the bone marrow-derived fibroblastic cell line, ST2, synthesized substantial levels of TGF-β. Culture media derived from HSC3 cells could stimulate Tgf-β1 mRNA expression in ST2 cells. Recombinant TGF-β1 could stimulate osteoclast formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in RAW264 cells. TGF-β1 could upregulate the expression of p-Smad2 in RAW264 cells, and this action was suppressed by the addition of a neutralizing antibody against TGF-β or by SB431542. Transplantation of HSC3 cells onto the calvarial region of athymic mice caused bone destruction, associated with the expression of TGF-β and p-Smad2 in both cancer cells and stromal cells. The bone destruction was substantially inhibited by the administration of SB431542. The present study demonstrated that TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC-induced bone destruction. - Highlights: • Cancer cell, fibroblastic cells, and osteoclasts at bone resorbing area by oral cancer exhibited TGF-β and p-Smad2. • TGF-β1 stimulated osteoclastogenesis induced by RAKL in RAW264 cell. • Xenograft model of oral cancer-induced bone resorption was substantially inhibited by SB431542. • TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC

  15. Loss of functional NADPH oxidase-2 protects against alcohol-induced bone resorption in female p47phox-/- mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In bone, oxidant signaling through NADPH oxidase (NOX)-derived reactive oxygen species (ROS) is an important stimulus for osteoclast differentiation and activity. We have previously demonstrated that chronic alcohol abuse produces bone loss through NOX-dependent mechanisms. In the current study, s...

  16. A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice.

    PubMed

    Park, Doori; Park, Chan-Won; Choi, YoungJin; Lin, Jingjing; Seo, Dong-Hyun; Kim, Han-Sung; Lee, Soo Young; Kang, In-Cheol

    2016-08-01

    Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvβ3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvβ3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. PMID:27187277

  17. Topical HPMC/S-Nitrosoglutathione Solution Decreases Inflammation and Bone Resorption in Experimental Periodontal Disease in Rats.

    PubMed

    Martins, Conceição S; Leitão, Renata F C; Costa, Deiziane V S; Melo, Iracema M; Santos, Glaylton S; Lima, Vilma; Baldim, Victor; Wong, Deysi V T; Bonfim, Luana E; Melo, Cíntia B; G de Oliveira, Marcelo; Brito, Gerly A C

    2016-01-01

    S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor, which exerts antioxidant, anti-inflammatory, and microbicidal actions. Intragingival application of GSNO was already shown to decrease alveolar bone loss, inflammation and oxidative stress in an experimental periodontal disease (EPD) model. In the present study, we evaluated the potential therapeutic effect of topical applications of hydroxypropylmethylcellulose (HPMC)/GSNO solutions on EPD in Wistar rats. EPD was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the animals, which received topical applications of a HPMC solutions containing GSNO 2 or 10 mM or vehicle (HPMC solution), 1 h prior to the placement of the ligature and then twice daily until sacrifice on day 11. Treatment with HPMC/GSNO 10 mM solution significantly reduced alveolar bone loss, oxidative stress and TNF-α e IL-1β levels in the surrounding gingival tissue, and led to a decreased transcription of RANK and TNF-α genes and elevated bone alkaline phosphatase, compared to the HPMC group. In conclusion, topical application of HPMC/GSNO solution is a potential treatment to reduce inflammation and bone loss in periodontal disease. PMID:27116554

  18. Topical HPMC/S-Nitrosoglutathione Solution Decreases Inflammation and Bone Resorption in Experimental Periodontal Disease in Rats

    PubMed Central

    Martins, Conceição S.; Leitão, Renata F. C.; Costa, Deiziane V. S.; Melo, Iracema M.; Santos, Glaylton S.; Lima, Vilma; Baldim, Victor; Wong, Deysi V. T.; Bonfim, Luana E.; Melo, Cíntia B.; Brito, Gerly A. C.

    2016-01-01

    S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor, which exerts antioxidant, anti-inflammatory, and microbicidal actions. Intragingival application of GSNO was already shown to decrease alveolar bone loss, inflammation and oxidative stress in an experimental periodontal disease (EPD) model. In the present study, we evaluated the potential therapeutic effect of topical applications of hydroxypropylmethylcellulose (HPMC)/GSNO solutions on EPD in Wistar rats. EPD was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the animals, which received topical applications of a HPMC solutions containing GSNO 2 or 10 mM or vehicle (HPMC solution), 1 h prior to the placement of the ligature and then twice daily until sacrifice on day 11. Treatment with HPMC/GSNO 10 mM solution significantly reduced alveolar bone loss, oxidative stress and TNF-α e IL-1β levels in the surrounding gingival tissue, and led to a decreased transcription of RANK and TNF-α genes and elevated bone alkaline phosphatase, compared to the HPMC group. In conclusion, topical application of HPMC/GSNO solution is a potential treatment to reduce inflammation and bone loss in periodontal disease. PMID:27116554

  19. Progression of Cartilage Degradation, Bone Resorption and Pain in Rat Temporomandibular Joint Osteoarthritis Induced by Injection of Iodoacetate

    PubMed Central

    Wang, Xue-Dong; Kou, Xiao-Xing; He, Dan-Qing; Zeng, Min-Min; Meng, Zhen; Bi, Rui-Yun; Liu, Yan; Zhang, Jie-Ni; Gan, Ye-Hua; Zhou, Yan-Heng

    2012-01-01

    Background Osteoarthritis (OA) is an important subtype of temporomandibular disorders. A simple and reproducible animal model that mimics the histopathologic changes, both in the cartilage and subchondral bone, and clinical symptoms of temporomandibular joint osteoarthritis (TMJOA) would help in our understanding of its process and underlying mechanism. Objective To explore whether injection of monosodium iodoacetate (MIA) into the upper compartment of rat TMJ could induce OA-like lesions. Methods Female rats were injected with varied doses of MIA into the upper compartment and observed for up to 12 weeks. Histologic, radiographic, behavioral, and molecular changes in the TMJ were evaluated by light and electron microscopy, MicroCT scanning, head withdrawal threshold test, real-time PCR, immunohistochemistry, and TUNEL assay. Results The intermediate zone of the disc loosened by 1 day post-MIA injection and thinned thereafter. Injection of an MIA dose of 0.5 mg or higher induced typical OA-like lesions in the TMJ within 4 weeks. Condylar destruction presented in a time-dependent manner, including chondrocyte apoptosis in the early stages, subsequent cartilage matrix disorganization and subchondral bone erosion, fibrosis, subchondral bone sclerosis, and osteophyte formation in the late stages. Nociceptive responses increased in the early stages, corresponding to severe synovitis. Furthermore, chondrocyte apoptosis and an imbalance between anabolism and catabolism of cartilage and subchondral bone might account for the condylar destruction. Conclusions Multi-level data demonstrated a reliable and convenient rat model of TMJOA could be induced by MIA injection into the upper compartment. The model might facilitate TMJOA related researches. PMID:22984604

  20. Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption.

    PubMed

    Saita, Makiko; Kaneko, Junya; Sato, Takenori; Takahashi, Shun-suke; Wada-Takahashi, Satoko; Kawamata, Ryota; Sakurai, Takashi; Lee, Masaichi-Chang-il; Hamada, Nobushiro; Kimoto, Katsuhiko; Nagasaki, Yukio

    2016-01-01

    The excessive production of reactive oxygen species (ROS) has been implicated in a variety of disorders, but to date, ROS scavengers have not been widely used for local treatment of inflammation, because they are rapidly eliminated from the inflamed site. We have designed a novel redox injectable gel (RIG) that is formed at 37 °C after disintegration of nano-assembled flower micelles allowing nitroxide radicals to act locally as specific ROS scavengers for the treatment of periodontitis. In the present study, we have confirmed retention of the RIG in the periodontal region, along with its antioxidant-related anti-inflammatory effects, and we have subsequently evaluated the inhibitory effect of the RIG against Porphyromonas gingivalis (P. gingivalis)-induced alveolar bone loss attributed to ROS. Alveolar bone loss was estimated by morphometry, gingival blood flow was measured using laser Doppler flowmetry, and osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase staining. The results show that the RIG can inhibit P. gingivalis-induced bone loss by antioxidant-related anti-inflammatory actions, and this suggests that the RIG is a promising novel therapeutic agent for the treatment of P. gingivalis-induced periodontitis. PMID:26559357

  1. Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption.

    PubMed

    Saita, Makiko; Kaneko, Junya; Sato, Takenori; Takahashi, Shun-suke; Wada-Takahashi, Satoko; Kawamata, Ryota; Sakurai, Takashi; Lee, Masaichi-Chang-il; Hamada, Nobushiro; Kimoto, Katsuhiko; Nagasaki, Yukio

    2016-01-01

    The excessive production of reactive oxygen species (ROS) has been implicated in a variety of disorders, but to date, ROS scavengers have not been widely used for local treatment of inflammation, because they are rapidly eliminated from the inflamed site. We have designed a novel redox injectable gel (RIG) that is formed at 37 °C after disintegration of nano-assembled flower micelles allowing nitroxide radicals to act locally as specific ROS scavengers for the treatment of periodontitis. In the present study, we have confirmed retention of the RIG in the periodontal region, along with its antioxidant-related anti-inflammatory effects, and we have subsequently evaluated the inhibitory effect of the RIG against Porphyromonas gingivalis (P. gingivalis)-induced alveolar bone loss attributed to ROS. Alveolar bone loss was estimated by morphometry, gingival blood flow was measured using laser Doppler flowmetry, and osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase staining. The results show that the RIG can inhibit P. gingivalis-induced bone loss by antioxidant-related anti-inflammatory actions, and this suggests that the RIG is a promising novel therapeutic agent for the treatment of P. gingivalis-induced periodontitis.

  2. Mobilised bone marrow-derived cells accelerate wound healing.

    PubMed

    Wang, Yu; Sun, Yu; Yang, Xiao-Yan; Ji, Shi-Zhao; Han, Shu; Xia, Zhao-Fan

    2013-08-01

    Massive skin defects caused by severe burn and trauma are a clinical challenge to surgeons. Timely and effective wound closure is often hindered by the lack of skin donor site. Bone marrow-derived cells (BMDCs) have been shown to 'differentiate' into multiple tissue cells. In this study we focused on the direct manipulation of endogenous BMDCs, avoiding the immunocompatibility issues and complicated cell isolation, purification, identification and amplification procedures in vitro on wound repair. We found that mobilisation of the BMDCs into the circulation significantly increased the amount of BMDCs at the injury site which in turn accelerated healing of large open wound. We used a chimeric green fluorescent protein (GFP) mouse model to track BMDCs and to investigate their role in full-thickness skin excisional wounds. We have shown that bone marrow mobilisation by granulocyte colony stimulating factor (G-CSF) exerted multiple beneficial effects on skin repair, both by increasing the engraftment of BMDCs into the skin to differentiate into multiple skin cell types and by upregulating essential cytokine mRNAs critical to wound repair. The potential trophic effects of G-CSF on bone marrow stem cells to accelerate wound healing could have a significant clinical impact.

  3. Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor α in mice

    PubMed Central

    Sugawara, Shunji; Shibazaki, Masahiko; Takada, Haruhiko; Kosugi, Hiroshi; Endo, Yasuo

    1998-01-01

    Aminobisphosphonates (aminoBPs), potent inhibitors of bone resorption, have been reported to induce inflammatory reactions such as fever and an increase in acute phase proteins in human patients, and to induce the histamine-forming enzyme, histidine decarboxylase, in mice. In the present study, we examined the effect of aminoBP, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP), on the production of the pro-inflammatory cytokines, IL-1 and TNFα, in mice.Intraperitoneal injection of AHBuBP did not itself produce detectable levels of IL-1 (α and β) and TNFα in the serum. However, the elevation of serum IL-1 induced by lipopolysaccharide (LPS) was greatly augmented in mice injected with AHBuBP 3 days before the LPS injection, whereas the LPS-induced elevation of serum TNFα was almost completely abolished.Spleen and bone marrow cells taken from mice injected with AHBuBP produced IL-1β in vitro spontaneously, and the production was augmented following the addition of LPS. Cells that accumulated in the peritoneal cavity in response to AHBuBP produced a particularly large amount of IL-1β. However, AHBuBP treatment of mice did not lead to an impairment of the in vitro production of TNFα by these three types of cells.Liposomes encapsulating dichloromethylene bisphosphonate (a non-amino BP) selectively deplete phagocytic macrophages. When an intraperitoneal injection of these liposomes was given 2 days after an injection of AHBuBP, there was a marked decrease in the LPS-induced elevation of serum IL-1 (α and β) (LPS being injected 3 days after the injection of AHBuBP).These results indicate that AHBuBP has contrasting effects on the in vivo LPS-induced production of IL-1 and TNFα in mice, enhancing the production of IL-1 by phagocytic macrophages and suppressing the production of TNFα, although underling mechanisms remain to be clarified. PMID:9831909

  4. Effect of resorption rate and osteoconductivity of biodegradable calcium phosphate materials on the acquisition of natural bone strength in the repaired bone.

    PubMed

    Chiba, Shinpei; Anada, Takahisa; Suzuki, Kentaro; Saito, Keisuke; Shiwaku, Yukari; Miyatake, Naohisa; Baba, Kazuyoshi; Imaizumi, Hideki; Hosaka, Masami; Itoi, Eiji; Suzuki, Osamu

    2016-11-01

    The purpose of this study was to compare the biodegradation rate and quality of regenerated bone among four materials. A short time period of 8 weeks was chosen to examine early bone healing. The rod-shaped implants of commercially available two β-tricalcium phosphate (β-TCP) ceramics with porosity 60% and 71-80%, respectively, laboratory prepared octacalcium phosphate/gelatin composite (OCP/Gel), which has been proven to have a highly osteoconductive and biodegradable property in rat calvarial defect, and gelatin sponge (Gelatin) were implanted in rabbit tibia defect of 6 mm diameter and 7 mm depth for 2, 4 and 8 weeks. Analyses by μCT, histomorphometry and push-in test were carried out to evaluate the extent of the tissue regeneration and the material biodegradation in the long bone. OCP/Gel and Gelatin were completely resorbed but only OCP/Gel induced cortical bone bridge until 8 weeks that has strength compatible to that of the natural bone. β-TCP (71%-80%) and β-TCP (60%) were not completely resorbed and never induced the amount of new bone formation beyond that by OCP/Gel. The results indicate that the new bone having enough strength could be regenerated if the material shows not only higher biodegradation rate but also higher osteoconductivity. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2833-2842, 2016.

  5. Green Tea Modulates Cytokine Expression in the Periodontium and Attenuates Alveolar Bone Resorption in Type 1 Diabetic Rats

    PubMed Central

    Gennaro, Gabriela; Claudino, Marcela; Cestari, Tania Mary; Ceolin, Daniele; Germino, Patrícia; Garlet, Gustavo Pompermaier; de Assis, Gerson Francisco

    2015-01-01

    Diabetes mellitus comprises a heterogeneous group of disorders with the main feature of hyperglycemia. Chronic hyperglycemia increases the severity of periodontal disease via an exacerbated inflammatory response, activated by advanced glycation end products and their receptor, RAGE. Therefore, anti-inflammatory agents represent potential inhibitors of this pathological interaction. In particular, green tea has been shown to possess anti-inflammatory properties mediated by its polyphenol content. Objectives: This study investigated the mechanisms by which green tea attenuates the spontaneous onset of diabetes-induced periodontitis. Methods: Diabetes was induced in rats via a single intraperitoneal injection of streptozotocin (STZ). Diabetic and control animals were divided into water-treated and green tea-treated subgroups and were analyzed at 15, 30, 60 and 90 days after diabetes induction. Immunohistochemistry was performed to quantitatively evaluate tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), interleukin-10 (IL-10) and runt-related transcription factor 2 (RUNX-2) expression in serial sections of each hemimaxilla. Morphometric measurements of the distance from the cementum-enamel junction (CEJ) of the superior distal root of the first molar to the alveolar bone crest (ABC) were performed to assess bone loss. Results: Diabetes resulted in significant bone loss and alterations in the number of cells that stained positive for inflammatory mediators. In the diabetic rats treated with green tea, we observed a decreased number of cells expressing RANKL and TNF-α compared with that observed in the diabetic rats treated with water. Additionally, green tea increased the numbers of cells that stained positive for OPG, RUNX-2 and IL-10 in the diabetic rats. Conclusion: Green tea intake reduces expression of the pro-inflammatory cytokine TNF-α and the osteoclastogenic mediator RANKL to normal levels

  6. Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality.

    PubMed

    Koren, Netta; Simsa-Maziel, Stav; Shahar, Ron; Schwartz, Betty; Monsonego-Ornan, Efrat

    2014-06-01

    Omega-3 fatty acids (FAs) are essential nutritional components that must be obtained from foods. Increasing evidence validate that omega-3 FAs are beneficial for bone health, and several mechanisms have been suggested to mediate their effects on bone, including alterations in calcium absorption and urinary calcium loss, prostaglandin synthesis, lipid oxidation, osteoblast formation and inhibition of osteoclastogenesis. However, to date, there is scant information regarding the effect of omega-3 FAs on the developing skeleton during the rapid growth phase. In this study we aim to evaluate the effect of exposure to high levels of omega-3 FAs on bone development and quality during prenatal and early postnatal period. For this purpose, we used the fat-1 transgenic mice that have the ability to convert omega-6 to omega-3 fatty acids and the ATDC5 chondrogenic cell line as models. We show that exposure to high concentrations of omega-3 FAs at a young age accelerates bone growth through alterations of the growth plate, associated with increased chondrocyte proliferation and differentiation. We further propose that those effects are mediated by the receptors G-protein coupled receptor 120 (GPR120) and hepatic nuclear factor 4α, which are expressed by chondrocytes in culture. Additionally, using a combined study on the structural and mechanical bone parameters, we show that high omega-3 levels contribute to superior trabecular and cortical structure, as well as to stiffer bones and improved bone quality. Most interestingly, the fat-1 model allowed us to demonstrate the role of maternal high omega-3 concentration on bone growth during the gestation and postnatal period.

  7. Impaired Bone Resorption and Woven Bone Formation Are Associated with Development of Osteonecrosis of the Jaw-Like Lesions by Bisphosphonate and Anti–Receptor Activator of NF-κB Ligand Antibody in Mice

    PubMed Central

    Williams, Drake W.; Lee, Cindy; Kim, Terresa; Yagita, Hideo; Wu, Hongkun; Park, Sil; Yang, Paul; Liu, Honghu; Shi, Songtao; Shin, Ki-Hyuk; Kang, Mo K.; Park, No-Hee; Kim, Reuben H.

    2015-01-01

    Drug-induced osteonecrosis of the jaw (ONJ) is a detrimental intraoral lesion that often occurs after dental-related interventions in patients undergoing treatment with bisphosphonates or denosumab, the neutralizing human anti–receptor activator of NF-κB ligand (RANKL) antibody (Ab). The cause of ONJ by these drugs has been speculated to their direct effects on osteoclasts. However, the extent to which osteoclasts contribute to ONJ pathogenesis remains controversial. Herein, by using a tooth-extraction mouse model with i.v. administration of mouse anti-RANKL Ab or the bisphosphonate zoledronate (ZOL), we show that unresorbed bone due to impaired formation or suppressed functions of osteoclasts, respectively, is associated with ONJ development. After tooth extraction, ONJ-like lesions developed 50% in the anti-RANKL Ab-treated mice and 30% in the ZOL-treated mice. Nonviable and unresorbed bone was found more in anti-RANKL Ab-treated mice compared with mice receiving ZOL. All mice receiving anti-RANKL Ab had an undetectable tartrate-resistant acid phosphatase (TRAP) level in the serum and no TRAP-positive osteoclasts at the extracted sockets, whereas ZOL-treated mice had a decreased TRAP level without altering the numbers of TRAP-positive osteoclasts. Interestingly, the absence of newly formed woven bone in the extracted sockets was evident in ONJ-like lesions from both anti-RANKL Ab- and ZOL-treated mice. Our study suggests that the lack of osteoclasts' bone-resorptive functions by these drugs and suppression of woven bone formation after dental trauma may be associated with ONJ development. PMID:25173134

  8. Spaceflight-induced Bone Loss: Is there a Risk for Accelerated Osteoporosis after Return?

    NASA Technical Reports Server (NTRS)

    Sibonga, Jean

    2008-01-01

    The evidence-to to-date suggests that the rapid rate of site-specific bone loss in space, due to the unbalanced stimulation of bone resorption, may predispose crew members to irreversible changes in bone structure and microarchitecture. No analyses conducted in the postflight period to assess microarchitectural changes. There is no complete analysis of skeletal recovery in the postflight period to evaluate the structural changes that accompany increases in DXA aBMD. Postflight analyses based upon QCT scans performed on limited crew members indicate reductions in hip bone strength and incomplete recovery at 1 year. No recovery of trabecular vBMD after 1 year return (HRP IWG). Time course of bone loss in space unknown.

  9. [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.

  10. [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. PMID:2576918

  11. 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 Central

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

    2014-01-01

    Objectives 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). Methods 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. Results 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. Conclusion The present study showed that aminoguanidine was significantly effective in reducing alveolar bone loss and can modify the

  12. Effect of acceleration on osteoblastic and osteoclastic activities: Analysis of bone metabolism using goldfish scale as a model for bone

    NASA Astrophysics Data System (ADS)

    Suzuki, S.; Kitamura, K.; Nemoto, N.; Shimizu, S.; Wada, W.; Kondo, K.; Tabata, T.; Sodeyama, S.; Ijiri, I.; Hattori, H.

    It is well known that hypo-gravity and hyper-gravity influence bone metabolism However basic data concerning the mechanism are a few because no in vitro model system of human bone is available Human bone consists of osteoblasts osteoclasts and the bone matrix No technique for the co-culture of these components has ever been developed Fish scale is a calcified tissue that contains osteoblasts osteoclasts and bone matrix all of which are similar to those found in human bone Recently we developed a new in vitro model system using goldfish scale This system can simultaneously detect the activities of both scale osteoclasts and osteoblasts with tartrate-resistant acid phosphatase and alkaline phosphatase as the respective markers Using this system we analyzed the bone metabolism under acceleration with a custom-made G-load apparatus Osteoclastic activity in the goldfish scales was suppressed under low-acceleration 0 5-G while osteoblastic activity did not change under this acceleration Under high-acceleration 6-G however the osteoblastic activity of the scales increased In addition the osteoclastic activity of the scales decreased These results suggest that both osteoblastic and osteoclastic activities are regulated by the strength of acceleration Therefore we strongly believe that our in vitro system is useful for analysis of bone metabolism under acceleration

  13. Bone formation is not impaired by hibernation (disuse) in black bears Ursus americanus

    USGS Publications Warehouse

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

    2003-01-01

    Disuse by bed rest, limb immobilization or space flight causes rapid bone loss by arresting bone formation and accelerating bone resorption. This net bone loss increases the risk of fracture upon remobilization. Bone loss also occurs in hibernating ground squirrels, golden hamsters, and little brown bats by arresting bone formation and accelerating bone resorption. There is some histological evidence to suggest that black bears Ursus americanus do not lose bone mass during hibernation (i.e. disuse). There is also evidence suggesting that muscle mass and strength are preserved in black bears during hibernation. The question of whether bears can prevent bone loss during hibernation has not been conclusively answered. The goal of the current study was to further assess bone metabolism in hibernating black bears. Using the same serum markers of bone remodeling used to evaluate human patients with osteoporosis, we assayed serum from five black bears, collected every 10 days over a 196-day period, for bone resorption and formation markers. Here we show that bone resorption remains elevated over the entire hibernation period compared to the pre-hibernation period, but osteoblastic bone formation is not impaired by hibernation and is rapidly accelerated during remobilization following hibernation.

  14. A novel peptide-modified and gene-activated biomimetic bone matrix accelerating bone regeneration.

    PubMed

    Pan, Haitao; Zheng, Qixin; Yang, Shuhua; Guo, Xiaodong; Wu, Bin; Zou, Zhenwei; Duan, Zhixia

    2014-08-01

    The osteogenic differentiation of bone marrow stromal cells (BMSCs) can be regulated by systemic or local growth factor, especially by transforming growth factor beta 1 (TGF-β1). However, how to maintain the bioactivity of exogenous TGF-β1 is a great challenge due to its short half-life time. The most promising solution is to transfer TGF-β1 gene into seed cells through transgenic technology and then transgenic cells to continuously secret endogenous TGF-β1 protein via gene expression. In this study, a novel non-viral vector (K)16GRGDSPC was chemically linked to bioactive bone matrices PLGA-[ASP-PEG]n using cross-linker to construct a novel non-viral gene transfer system. TGF-β1 gene was incubated with this system and subsequently rabbit-derived BMSCs were co-cultured with this gene-activated PLGA-[ASP-PEG]n, while co-cultured with PLGA-[ASP-PEG]n modified with (K)16GRGDSPC only and original PLGA-[ASP-PEG]n as control. Thus we fabricated three kinds of composites: Group A (BMSCs-TGF-β1DNA-(K)16GRGDSPC-PLGA-[ASP-PEG]n composite); Group B (BMSCs-(K)16GRGDSPC-PLGA-[ASP-PEG]n composite); and Group C (BMSCs-PLGA-[ASP-PEG]n composite). TGF-β1 and other osteogenic phenotype markers of alkaline phosphatase, osteocalcin, osteopontin and type I collagen in Group A were all significantly higher than the other two groups ex vivo. In vivo, 15-mm long segmental rabbit bone defects were created and randomly implanted the aforementioned composites separately, and then fixed with plate-screws. The results demonstrated that the implants in Group A significantly accelerated bone regeneration compared with the other implants based on X-rays, histological and biomechanical examinations. Therefore, we conclude this novel peptide-modified and gene-activated biomimetic bone matrix of TGF-β1DNA-(K)16GRGDSPC-PLGA-[ASP-PEG]n is a very promising scaffold biomaterial for accelerating bone regeneration. PMID:24115366

  15. SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.

    PubMed

    Shakespeare, William C; Wang, Yihan; Bohacek, Regine; Keenan, Terry; Sundaramoorthi, Raji; Metcalf, Chet; Dilauro, Anne; Roeloffzen, Sonya; Liu, Shuangying; Saltmarsh, Jennifer; Paramanathan, Guru; Dalgarno, David; Narula, Surinder; Pradeepan, Selvi; van Schravendijk, Marie Rose; Keats, Jeff; Ram, Mary; Liou, Shuenn; Adams, Susan; Wardwell, Scott; Bogus, Julie; Iuliucci, John; Weigele, Manfred; Xing, Lianping; Boyce, Brendan; Sawyer, Tomi K

    2008-02-01

    Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds. PMID:18179464

  16. 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

  17. The Effect of Ovariectomy and Orchiectomy on Orthodontic Tooth Movement and Root Resorption in Wistar Rats

    PubMed Central

    Seifi, Massoud; Ezzati, Baharak; Saedi, Sara; Hedayati, Mehdi

    2015-01-01

    Statement of the Problem Root resorption (RR) after orthodontic tooth movement (OTM) is known as a multifactorial complication of orthodontic treatments. Hormonal deficiencies and their effect on bone turnover are reported to have influences on the rate of tooth movement and root resorption. Purpose This study was designed to evaluate the effect of female and male steroid sex hormones on tooth movement and root resorption. Materials and Method Orthodontic appliances were placed on the right maxillary first molars of 10 ovariectomized female and 10 orchiectomized male Wistar rats as experimental groups and 10 female and 10 male healthy Wistar rats as control groups. NiTi closed-coil springs (9mm, Medium, 011"×.030", Ortho Technology®; Tampa, Florida) were placed between the right incisors and the first right maxillary molars to induce tipping movement in the first molars with the application of a 60g force. After 21 days, the rats were sacrificed and tooth movement was measured by using a digital caliper (Guanglu, China). Orthodontic induced root resorption (OIRR) was assessed by histomorphometric analysis after hematoxylin and eosin staining of sections of the mesial root. Results The rate of tooth movement was significantly higher in all female rats, with the root resorption being lower in the experimental group. The rate of tooth movement in experimental male rats was significantly higher than the control group (p= 0.001) and the rate of root resorption was significantly lower in the experimental group (p= 0.001). Conclusion It seems that alterations in plasma levels of estrogen, progesterone, and testosterone hormones can influence the rate of OTM and RR. The acceleration in tooth movement increased OTM and decreased RR. PMID:26636117

  18. Simulation analysis for effects of bone loss on acceleration tolerance of human lumbar vertebra

    NASA Astrophysics Data System (ADS)

    Ma, Honglei; Zhang, Feng; Zhu, Yu; Xiao, Yanhua; Wazir, Abrar

    2014-02-01

    The purpose of the present study was to analyze and predict the changes in acceleration tolerance of human vertebra as a result of bone loss caused by long-term space flight. A human L3-L4 vertebra FEM model was constructed, in which the cancellous bone was separated, and surrounding ligaments were also taken into account. The simulation results demonstrated that bone loss has more of an effect on the acceleration tolerance in x-direction. The results serve to aid in the creation of new acceleration tolerance standards, ensuring astronauts return home safely after long-term space flight. This study shows that more attention should be focused on the bone degradation of crew members and to create new protective designs for space capsules in the future.

  19. Milk extracellular vesicles accelerate osteoblastogenesis but impair bone matrix formation.

    PubMed

    Oliveira, Marina C; Arntz, Onno J; Blaney Davidson, Esmeralda N; van Lent, Peter L E M; Koenders, Marije I; van der Kraan, Peter M; van den Berg, Wim B; Ferreira, Adaliene V M; van de Loo, Fons A J

    2016-04-01

    The claimed beneficial effect of milk on bone is still a matter for debate. Recently extracellular vesicles (EVs) that contain proteins and RNA were discovered in milk, but their effect on bone formation has not yet been determined. We demonstrated previously that bovine milk-derived EVs (BMEVs) have immunoregulatory properties. Our aim was to evaluate the effect of BMEVs on osteogenesis by mice and human mesenchymal stem cells (hMSCs). Oral delivery of two concentrations of BMEVs to female DBA/1J mice during 7weeks did not alter the tibia trabecular bone area; however, the osteocytes number increased. In addition, the highest dose of BMEVs markedly increased the woven bone tissue, which is more brittle. The exposure of hMSCs to BMEVs during 21days resulted in less mineralization but higher cell proliferation. Interestingly BMEVs reduced the collagen production, but enhanced the expression of genes characteristic for immature osteoblasts. A kinetic study showed that BMEVs up-regulated many osteogenic genes within the first 4days. However, the production of type I collagen and expression of its genes (COL1A1 and COL1A2) were markedly reduced at days 21 and 28. At day 28, BMEVs again lead to higher proliferation, but mineralization was significantly increased. This was associated with increased expression of sclerostin, a marker for osteocytes, and reduced osteonectin, which is associated to bone matrix formation. Our study adds BMEVs to the list of milk components that can affect bone formation and may shed new light on the contradictory claims of milk on bone formation.

  20. Invasive cervical root resorption: Engineering the lost tissue by regeneration

    PubMed Central

    Johns, Dexton Antony; Shivashankar, Vasundara Yayathi; Maroli, Ramesh Kumar; Joseph, Rosamma

    2013-01-01

    Invasive cervical resorption (ICR) is a localized resorptive process that commences on the surface of the root below the epithelial attachment and the coronal aspect of the supporting alveolar process, namely the zone of the connective tissue attachment’ early diagnosis, elimination of the resorption and restorative management are the keys to a successful outcome. Treatment done was a combined non-surgical root canal therapy, surgical treatment to expose the resorptive defect and the resorptive defect was filled up with reverse sandwich technique and finally the bony defect filled with platelet rich fibrin (PRF), hydroxylapatite and PRF membrane. Significant bone fill was obtained in our case after a 2 year follow-up period. This case report presents a treatment strategy that might improve the healing outcomes for patients with ICR. PMID:24403805

  1. Biodegradable nanocomposite coatings accelerate bone healing: In vivo evaluation

    PubMed Central

    Mehdikhani-Nahrkhalaji, Mehdi; Fathi, Mohammad Hossein; Mortazavi, Vajihesadat; Mousavi, Sayed Behrouz; Akhavan, Ali; Haghighat, Abbas; Hashemi-Beni, Batool; Razavi, Sayed Mohammad; Mashhadiabbas, Fatemeh

    2015-01-01

    Background: The aim of this study was to evaluate the interaction of bioactive and biodegradable poly (lactide-co-glycolide)/bioactive glass/hydroxyapatite (PBGHA) and poly (lactide-co-glycolide)/bioactive glass (PBG) nanocomposite coatings with bone. Materials and Methods: Sol-gel derived 58S bioactive glass nanoparticles, 50/50 wt% poly (lactic acid)/poly (glycolic acid) and hydroxyapatite nanoparticles were used to prepare the coatings. The nanocomposite coatings were characterized by scanning electron microscopy, X-ray diffraction and atomic force microscopy. Mechanical stability of the prepared nanocomposite coatings was studied during intramedullary implantation of coated Kirschner wires (K-wires) into rabbit tibia. Titanium mini-screws coated with nanocomposite coatings and without coating were implanted intramedullary in rabbit tibia. Bone tissue interaction with the prepared nanocomposite coatings was evaluated 30 and 60 days after surgery. The non-parametric paired Friedman and Kruskal-Wallis tests were used to compare the samples. For all tests, the level of significance was P < 0.05. Results: The results showed that nanocomposite coatings remained stable on the K-wires with a minimum of 96% of the original coating mass. Tissue around the coated implants showed no adverse reactions to the coatings. Woven and trabecular bone formation were observed around the coated samples with a minimum inflammatory reaction. PBG nanocomposite coating induced more rapid bone healing than PBGHA nanocomposite coating and titanium without coating (P < 0.05). Conclusion: It was concluded that PBG nanocomposite coating provides an ideal surface for bone formation and it could be used as a candidate for coating dental and orthopedic implants. PMID:25709681

  2. Bone formation: roles of genistein and daidzein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  3. Anti-bone resorption activity of deer antler aqua-acupunture, the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong) in adjuvant-induced arthritic rats.

    PubMed

    Kim, Kyung-Ho; Kim, Kap-Sung; Choi, Byeong-Joon; Chung, Kang-Hyun; Chang, Young-Chae; Lee, Seung-Duk; Park, Kwan-Kyu; Kim, Hyung-Min; Kim, Cheorl-Ho

    2005-01-15

    Effect of deer antler aqua-acupunture (DAA), prepared from the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe, a traditional immunosuppressive acupuncture, was evaluated to assess the reductions in bone mass, strength, and turnover in adjuvant-induced arthritic rats. For measuring the above parameters, a 20-day dosing experiment was performed using 6-week-old female Lewis rats. Arthritis was induced by injecting the adjuvant into the hind paw of the Lewis rats. The age-dependent increases in the body weight, lumbar bone mineral content and density (BMC and BMD) and compressive strength were disturbed in the arthritic rats. At 10 days, the histomorphometric parameters of bone formation (BFR/BS and BFR/BV) and the serum osteocalcin levels were significantly reduced compared with the baseline controls of Lewis rats. However, the BMC values corrected for body weight did not differ significantly between the arthritic and normal rats, and the bone minerals were not reduced when they were compared with the baseline controls. At 20 days, the parameters of bone minerals and strength of the lumbar body in the arthritic rats, both with and without correction for body weight, were significantly reduced compared with the baseline controls. The trabecular mineralizing surface remained significantly reduced and the osteoclast numbers were increased. DAA at the doses of 10, 20, 50 and 100 microg/kg, administered by Shinsu (B23) acupuncture daily from the start of the experiment, significantly prevented the development of the chronic paw edema at 20 days. The reductions in the parameters such as bone minerals, strength, and trabecular bone formation, and the increase in osteoclast number were alleviated by this DAA. Age-dependent increases in the lumbar height, disturbed by the adjuvant injection, were also maintained. These results indicated that a 20-day-period is necessary to obtain sufficient reductions in the bone mass and strength of the lumbar body

  4. In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

    PubMed Central

    Durand, Marjorie; Collombet, Jean-Marc; Frasca, Sophie; Begot, Laurent; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

    2014-01-01

    We investigated the effects of respiratory hypobaric hypoxia on femoral bone-defect repair in mice because hypoxia is believed to influence both mesenchymal stromal cell (MSC) and hematopoietic stem cell mobilization, a process involved in the bone-healing mechanism. To mimic conditions of non-weight-bearing limb immobilization in patients suffering from bone trauma, our hypoxic mouse model was further subjected to hind-limb unloading. A hole was drilled in the right femur of adult male C57/BL6J mice. Four days after surgery, mice were subjected to hind-limb unloading for 1 week. Seven days after surgery, mice were either housed for 4 days in a hypobaric room (FiO2 at 10%) or kept under normoxic conditions. Unsuspended control mice were housed in either hypobaric or normoxic conditions. Animals were sacrificed on postsurgery day 11 to allow for collection of both contralateral and lesioned femurs, blood, and spleen. As assessed by microtomography, delayed hypoxia enhanced bone-healing efficiency by increasing the closing of the cortical defect and the newly synthesized bone volume in the cavity by +55% and +35%, respectively. Proteome analysis and histomorphometric data suggested that bone-repair improvement likely results from the acceleration of the natural bone-healing process rather than from extended mobilization of MSC-derived osteoprogenitors. Hind-limb unloading had hardly any effect beyond delayed hypoxia-enhanced bone-healing efficiency. PMID:24944208

  5. Modeling of Blood Lead Levels in Astronauts Exposed to Lead from Microgravity-Accelerated Bone Loss

    NASA Technical Reports Server (NTRS)

    Garcia, H.; James, J.; Tsuji, J.

    2014-01-01

    Human exposure to lead has been associated with toxicity to multiple organ systems. Studies of various population groups with relatively low blood lead concentrations (<10 µg/dL) have indicated associations of blood lead level with lower cognitive test scores in children, later onset of puberty in girls, and increased blood pressure and cardiovascular mortality rates in adults. Cognitive effects are considered by regulatory agencies to be the most sensitive endpoint at low doses. Although 95% of the body burden of lead is stored in the bones, the adverse effects of lead correlate with the concentration of lead in the blood better than with that in the bones. NASA has found that prolonged exposure to microgravity during spaceflight results in a significant loss of bone minerals, the extent of which varies from individual to individual and from bone to bone, but generally averages about 0.5% per month. During such bone loss, lead that had been stored in bones would be released along with calcium. The effects on the concentration of lead in the blood (PbB) of various concentrations of lead in drinking water (PbW) and of lead released from bones due to accelerated osteoporosis in microgravity, as well as changes in exposure to environmental lead before, during, and after spaceflight were evaluated using a physiologically based pharmacokinetic (PBPK) model that incorporated exposure to environmental lead both on earth and in flight and included temporarily increased rates of osteoporosis during spaceflight.

  6. Role of platelet-rich plasma in acceleration of bone fracture healing.

    PubMed

    Simman, Richard; Hoffmann, Andrea; Bohinc, R Jordan; Peterson, Wylan C; Russ, Andrew J

    2008-09-01

    Platelet-rich plasma (PRP) is a common therapy for acceleration of maxillofacial and spinal fusion bone-graft healing. This study analyzes the therapeutic role of PRP during long-bone fracture healing evaluated Lewis rats. Following creation of unilateral open femur fractures, either 500 microL thrombin-activated PRP (PRP treated group) or 500 microL saline (control group) were applied once to the fracture site. Fracture healing was analyzed after 1 and 4 weeks. Following 4 weeks of fracture healing, radiographic analysis demonstrated higher callus to cortex width ratio (P < 0.05) in the PRP group (PRP: 1.65 +/- 0.06; control: 1.48 +/- 0.05). Three-point load bearing showed increased bone strength following PRP treatment (PRP: 60.85 +/- 6.06 Newton, control: 47.66 +/- 5.49 Newton). Fracture histology showed enhanced bone formation in the PRP group. Immunohistochemistry and Western-blotting demonstrated healing-associated changes in transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP)-2. Our results suggest that PRP accelerates bone fracture healing of rat femurs via modulation of TGF-beta1 and BMP-2 growth factor expression.

  7. Osteogenic growth peptide accelerates bone healing during distraction osteogenesis in rabbit tibia.

    PubMed

    Zhao, Z-Y; Shao, L; Zhao, H-M; Zhong, Z-H; Liu, J-Y; Hao, C-G

    2011-01-01

    Distraction osteogenesis is a valuable treatment method that allows limb lengthening or reconstruction of large bone defects. However, its major disadvantage is the long period required for the consolidation of a distraction callus. Osteogenic growth peptide (OGP) stimulates endochondral bone formation in fracture callus, but its capacity to promote regenerate ossification during distraction osteogenesis has not been evaluated. This study investigated whether intravenously administered OGP accelerated bone healing during distraction osteogenesis in 36 male New Zealand White rabbits, randomized into two groups. The treatment group received OGP (200 ng/kg body weight) in phosphate-buffered saline (PBS), intravenously, each day; the control group received PBS alone. A 15-mm lengthening of the right lower leg was performed using the method of Ilizarov. Evidence from biomechanical, histological and radiographic evaluations demonstrated that systemic OGP treatment promoted optimal new bone formation during distraction osteogenesis in this rabbit model.

  8. Current status of drug therapies for osteoporosis and the search for stem cells adapted for bone regenerative medicine.

    PubMed

    Mikami, Yoshikazu; Matsumoto, Taro; Kano, Koichiro; Toriumi, Taku; Somei, Masanori; Honda, Masaki J; Komiyama, Kazuo

    2014-01-01

    A number of factors can lead to bone disorders such as osteoporosis, in which the balance of bone resorption vs. bone formation is upset (i.e., more bone is resorbed than is formed). The result is a loss of bone mass, with a concomitant decrease in bone density. Drugs for osteoporosis can be broadly classified as "bone resorption inhibitors", which impede bone resorption by osteoclasts, and "bone formation accelerators", which augment bone formation by osteoblasts. Here, we describe representative drugs in each class, i.e., the bisphosphonates and the parathyroid hormone. In addition, we introduce two novel bone formation accelerators, SST-VEDI and SSH-BMI, which are currently under investigation by our research group. On the other hand, regenerative therapy, characterized by (ideally) the use of a patient's own cells to regenerate lost tissue, is now a matter of global interest. At present, candidate cell sources for regenerative therapy include embryonic stem cells (created from embryos based on the fertilization of oocytes), induced pluripotent stem cells (created artificially by using somatic cells as the starting material), and somatic stem cells (found in the tissues of the adult body). This review summarizes the identifying features and the therapeutic potential of each of these stem cell types for bone regenerative medicine. Although a number of different kinds of somatic stem cells have been reported, we turn our attention toward two that are of particular interest for prospective applications in bone repair: the dedifferentiated fat cell, and the deciduous dental pulp-derived stem cell.

  9. Harnessing the bone-seeking ability of Ca(II)-like metal ions in the treatment of metastatic cancer and resorption disorders.

    PubMed

    Weekes, D M; Orvig, C

    2016-04-21

    Metal ions are naturally retained by skeletal tissues in living systems because of their high affinity for the hydroxyapatite-like mineral matrix that makes up cortical bone. This is particularly true for metal ions that bear a close resemblance to calcium(ii) (such as the lanthanides or alkaline earth metals), and in a few key cases this targeting ability has been exploited in order to develop medicinal agents that are intended to treat bones which have become diseased. In this review, we focus on two areas where this has been particularly effective: first is in the diagnosis and therapy of metastatic bone cancer, in which radioactive metal ions including (99m)Tc, (153)Sm, and (223)Ra are used to image, alleviate, and ablate harmful cancerous legions with good specificity versus healthy tissues; second is the use of trivalent lanthanides to treat osteoporosis, an emerging concept which has gathered significance over the last 15 years, and is now entering preclinical trials with carefully designed systems.

  10. The ratio of animal protein intake to potassium intake is a predictor of bone resorption in space flight analogues and in ambulatory subjects

    NASA Technical Reports Server (NTRS)

    Zwart, Sara R.; Hargens, Alan R.; Smith, Scott M.

    2004-01-01

    BACKGROUND: Bone loss is a critical concern for space travelers, and a dietary countermeasure would be of great benefit. Dietary protein and potassium-associated bicarbonate precursors may have opposing effects on the acid-base balance in the body and therefore on bone loss. OBJECTIVE: In 2 studies, we examined the ability of dietary protein and potassium to predict markers of bone metabolism. DESIGN: In the first study, 8 pairs of male identical twins were assigned to 1 of 2 groups: bed rest (sedentary, or SED, group) or bed rest with supine treadmill exercise in a lower-body negative pressure chamber (EX group). In a second study, groups of 4 subjects lived in a closed chamber for 60 or 91 d, and dietary data were collected for two or three 5-d sessions. Urinary calcium, N-telopeptide, and pyridinium cross-links were measured before bed rest; on bed rest days 5-6, 12-13, 19-20, and 26-27; and daily during the chamber studies. Data were analyzed by Pearson's correlation (P < 0.05). RESULTS: The ratio of animal protein intake to potassium intake was significantly correlated with N-telopeptide in the SED group during bed rest weeks 3 and 4 (r = 0.77 and 0.80) and during the 91-d chamber study (r = 0.75). The ratio of animal protein intake to potassium intake was positively correlated with pyridinium cross-links before bed rest in the EX group (r = 0.83), in the EX group during bed rest week 1 (r = 0.84), and in the SED group during bed rest week 2 (r = 0.72) but not during either chamber study. In both studies, these relations were not significant with the ratio of vegetable protein intake to potassium intake. CONCLUSIONS: The ratio of animal protein intake to potassium intake may affect bone in ambulatory and bed-rest subjects. Changing this ratio may help to prevent bone loss on Earth and during space flight.

  11. Tooth resorption part II - external resorption: Case series

    PubMed Central

    Fernandes, Marina; de Ataide, Ida; Wagle, Rahul

    2013-01-01

    External tooth resorption usually follows trauma to the periodontal ligament. It can be classified into five categories based on its clinical and histological manifestations. Calcium hydroxide has long been used as an intracanal medicament to slow down the resorption process due to its alkaline pH. A combination of both external and internal resorptions can also occur on the same tooth, making the management more complex. Five case reports of external resorption have been presented in this article along with pertinent review of literature. Successful management was possible in two cases, while extractions had to be advised in 3 cases due to advanced nature of the lesions. PMID:23716975

  12. Metallic Nanomaterials for Bone Tissue Engineering.

    PubMed

    Dhivya, S; Ajita, J; Selvamurugan, N

    2015-10-01

    Conventional grafting techniques for bone regeneration are currently being replaced by tissue engineering approaches of using 3D biomimetic materials. Of these biomaterials, metals have the highest mechanical strength; moreover, they play a major role in accelerating bone formation and promoting bone regeneration. They act as cofactors for enzymes, serving as a structural component of bone forming enzymes and proteins, stimulating angiogenesis, increasing extra-cellular matrix synthesis, promoting bone formation, and inhibiting bone resorption. Metals have the inherent ability to promote osseointegration and osteoconductivity and possess antimicrobial activity. The current developments in bone tissue engineering focus on metal surface modifications by physical and chemical treatments to improve their bioactivity. Based on the recent literature available, this review aims at discussing the biological role of metals, namely Zn, Ti, Zr, B, Sr, Mg, Ag, and Cu along with their surface modifications for significantly enhanced bone regeneration.

  13. Diets Based on Virgin Olive Oil or Fish Oil but Not on Sunflower Oil Prevent Age-Related Alveolar Bone Resorption by Mitochondrial-Related Mechanisms

    PubMed Central

    Bullon, Pedro; Battino, Maurizio; Varela-Lopez, Alfonso; Perez-Lopez, Patricia; Granados-Principal, Sergio; Ramirez-Tortosa, Maria C.; Ochoa, Julio J.; Cordero, Mario D.; Gonzalez-Alonso, Adrian; Ramirez-Tortosa, César L.; Rubini, Corrado; Zizzi, Antonio; Quiles, José L.

    2013-01-01

    Background/Objectives Aging enhances frequency of chronic diseases like cardiovascular diseases or periodontitis. Here we reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats. Methods/Findings Animals were fed life-long on diets based on monounsaturated fatty acids (MUFA) as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n-3PUFA, as fish oil. Age-related alveolar bone loss was higher in n-6PUFA fed rats, probably as a consequence of the ablation of the cell capacity to adapt to aging. Gene expression analysis suggests that MUFA or n-3PUFA allowed mitochondria to maintain an adequate turnover through induction of biogenesis, autophagy and the antioxidant systems, and avoiding mitochondrial electron transport system alterations. Conclusions The main finding is that the enhanced alveolar bone loss associated to age may be targeted by an appropriate dietary treatment. The mechanisms involved in this phenomenon are related with an ablation of the cell capacity to adapt to aging. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They might also be able to induce the corresponding antioxidant systems to counteract age-related oxidative stress, and do not inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is noteworthy that the potential treatments to attenuate alveolar bone loss (a feature of periodontal disease) associated to age could be similar to some of the proposed for the prevention and treatment of cardiovascular diseases, a group of pathologies recently associated with age-related periodontitis. PMID:24066124

  14. 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.

  15. Improving Bone Microarchitecture in Aging with Diosgenin Treatment: A Study in Senescence-Accelerated OXYS Rats.

    PubMed

    Tikhonova, Maria A; Ting, Che-Hao; Kolosova, Nataliya G; Hsu, Chao-Yu; Chen, Jian-Horng; Huang, Chi-Wen; Tseng, Ging-Ting; Hung, Ching-Sui; Kao, Pan-Fu; Amstislavskaya, Tamara G; Ho, Ying-Jui

    2015-10-31

    Osteoporosis is a major disease associated with aging. We have previously demonstrated that diosgenin prevents osteoporosis in both menopause and D-galactose-induced aging rats. OXYS rats reveal an accelerated senescence and are used as a suitable model of osteoporosis. The aim of the present study was to analyze microarchitecture and morphological changes in femur of OXYS rats using morphological tests and microcomputed tomography scanning, and to evaluate the effects of oral administration of diosgenin at 10 and 50 mg/kg/day on femur in OXYS rats. The result showed that, compared with age-matched Wistar rats, the femur of OXYS rats revealed lower bone length, bone weight, bone volume, frame volume, frame density, void volume, porosity, external and internal diameters, cortical bone area, BV/TV, Tb.N, and Tb.Th, but higher Tb.Sp. Eight weeks of diosgenin treatment decreased porosity and Tb.Sp, but increased BV/TV, cortical bone area, Tb.N and bone mineral density, compared with OXYS rats treated with vehicle. These data reveal that microarchitecture and morphological changes in femur of OXYS rats showed osteoporotic aging features and suggest that diosgenin may have beneficial effects on aging-induced osteoporosis. PMID:26387656

  16. Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation.

    PubMed

    Garman, Russell; Gaudette, Glenn; Donahue, Leah-Rae; Rubin, Clinton; Judex, Stefan

    2007-06-01

    High-frequency whole body vibrations can be osteogenic, but their efficacy appears limited to skeletal segments that are weight bearing and thus subject to the induced load. To determine the anabolic component of this signal, we investigated whether low-level oscillatory displacements, in the absence of weight bearing, are anabolic to skeletal tissue. A loading apparatus, developed to shake specific segments of the murine skeleton without the direct application of deformations to the tissue, was used to subject the left tibia of eight anesthesized adult female C57BL/6J mice to small (0.3 g or 0.6 g) 45 Hz sinusoidal accelerations for 10 min/day, while the right tibia served as an internal control. Video and strain analysis revealed that motions of the apparatus and tibia were well coupled, inducing dynamic cortical deformations of less than three microstrain. After 3 weeks, trabecular metaphyseal bone formation rates and the percentage of mineralizing surfaces (MS/BS) were 88% and 64% greater (p < 0.05) in tibiae accelerated at 0.3 g than in their contralateral controls. At 0.6 g, bone formation rates and mineral apposition rates were 66% and 22% greater (p < 0.05) in accelerated tibiae. Changes in bone morphology were evident only in the epiphysis, where stimulated tibiae displayed significantly greater cortical area (+8%) and thickness (+8%). These results suggest that tiny acceleratory motions--independent of direct loading of the matrix--can influence bone formation and bone morphology. If confirmed by clinical studies, the unique nature of the signal may ultimately facilitate the stimulation of skeletal regions that are prone to osteoporosis even in patients that are suffering from confinement to wheelchairs, bed rest, or space travel.

  17. Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss.

    PubMed

    Turner, Russell T; Dube, Michael; Branscum, Adam J; Wong, Carmen P; Olson, Dawn A; Zhong, Xiaoying; Kweh, Mercedes F; Larkin, Iske V; Wronski, Thomas J; Rosen, Clifford J; Kalra, Satya P; Iwaniec, Urszula T

    2015-12-01

    Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (-4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (-80%), serum leptin (-77%), and serum IGF1 (-34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

  18. Progressive condylar resorption after mandibular advancement.

    PubMed

    Kobayashi, Tadaharu; Izumi, Naoya; Kojima, Taku; Sakagami, Naoko; Saito, Isao; Saito, Chikara

    2012-03-01

    Progressive condylar resorption is an irreversible complication and a factor in the development of late skeletal relapse after orthognathic surgery. We have evaluated cephalometric characteristics, signs and symptoms in the temporomandibular joint (TMJ), and surgical factors in six patients (one man and five women) who developed it after orthognathic surgery. The findings in preoperative cephalograms indicated that the patients had clockwise rotation of the mandible and retrognathism because of a small SNB angle, a wide mandibular plane angle, and a "minus" value for inclination of the ramus. There were erosions or deformities of the condyles, or both, on three-dimensional computed tomography (CT) taken before treatment. The mean (SD) anterior movement of the mandible at operation was 12.1 (3.9)mm and the mean relapse was -6.4 (2.5)mm. The mean change in posterior facial height was 4.5 (2.1)mm at operation and the mean relapse was -5.3 (1.8)mm. Two patients had click, or pain, or both, preoperatively. The click disappeared in one patient postoperatively, but one of the patients who had been symptom-free developed crepitus postoperatively. In the classified resorption pattern, posterior-superior bone loss was seen in three cases, anterior-superior bone loss in two, and superior bone loss in one. Progressive condylar resorption after orthognathic surgery is multifactorial, and some of the risk factors are inter-related. Patients with clockwise rotation of the mandible and retrognathism in preoperative cephalograms; erosion, or deformity of the condyle, or both, on preoperative CT; and wide mandibular advancement and counterclockwise rotation of the mandibular proximal segment at operation, seemed to be at risk. The mandible should therefore be advanced only when the condyles are stable on radiographs, and careful attention should be paid to postoperative mechanical loading on the TMJ in high-risk patients. PMID:21440343

  19. Smad4 is required to inhibit osteoclastogenesis and maintain bone mass

    PubMed Central

    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

    2016-01-01

    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. PMID:27731422

  20. [The roles of interleukin-1 alpha, tumor necrosis factor-alpha and parathyroid hormone-related protein in bone resorption of cholesteatoma otitis].

    PubMed

    Kinoshita, K

    1994-08-01

    It is well known that cholesteatoma otitis is characterized by bone destruction, but the mechanisms of this destruction remain to be clarified. Interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and parathyroid hormone-related protein (PTHrP) were immunohistologically demonstrated in the epithelia of cholesteatoma tissues obtained from patients with cholesteatoma, at ear surgery, in the present study. The staining for IL-1 alpha was marked in epithelial keratinocytes. The existence of PTHrP was demonstrated in the keratinocytes of cholesteatoma epithelium. PTHrP contents in keratinocytes on spinous layers had accumulated to a greater extent than those in basal layers. Compared with the staining of PTHrP in external ear canal epidermis, cholesteatomatous keratinocytes were more strongly stained. Further more, the effects of cholesteatomatous debris on generation of IL-1 alpha and TNF-alpha in cholesteatoma keratinocytes and normal human epidermal keratinocytes (NHEK), derived from chest skin, were examined. Near-confluent medium after seven days incubation of cholesteatomatous keratinocytes and NHEK was discarded and fresh medium was added. Filtrated debris medium, obtained with a milli-pore filter, lipopolysaccharides (LPS) or keratin were added to the incubation culture medium. After 48 hours, the titers of IL-1 alpha and TNF-alpha in the culture medium were measured with enzyme linked immunosorbent assay (ELISA). Debris filtrated medium showed a marked increase in IL-1 alpha, in both cholesteatomatous keratinocytes and NHEK culture, as compared with the effects of LPS, keratin and medium alone.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

    PubMed

    Chen, Shan; Grover, Monica; Sibai, Tarek; Black, Jennifer; Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

    2015-05-01

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

  2. [Paget's disease of bone: diagnosis and treatment].

    PubMed

    Winter, E M; Hamdy, N A T; de Jongh, R T; Eekhoff, E M W; Zillikens, M C; Appelman-Dijkstra, N M

    2016-01-01

    Paget's disease of bone is a focal disorder of bone remodelling that leads to changes in the shape and size of affected bones, and is associated with articular and vascular complications. The disorder is characterised by a localised increase in osteoclast number and activity in one or more affected sites while the rest of the skeleton remains unaffected. The excessive bone resorption leads to recruitment of osteoblasts to the remodelling sites, resulting in increased bone formation. This accelerated bone turnover causes deposition of bone with disorganised architecture and structural weakness. The precise aetiology is unknown. It is thought that the disease is caused by interactions between environmental and genetic factors; the nature of this interaction still has to be determined. The disease is progressive, but can be treated with a single infusion of zoledronic acid. In this manuscript three cases are described, along with a review of the current diagnostic tools and treatment. PMID:27650015

  3. Lanthanum carbonate stimulates bone formation in a rat model of renal insufficiency with low bone turnover.

    PubMed

    Fumoto, Toshio; Ito, Masako; Ikeda, Kyoji

    2014-09-01

    Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover.

  4. Lanthanum carbonate stimulates bone formation in a rat model of renal insufficiency with low bone turnover.

    PubMed

    Fumoto, Toshio; Ito, Masako; Ikeda, Kyoji

    2014-09-01

    Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover. PMID:24126694

  5. Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

    PubMed

    Hamed, Sherifa A

    2016-01-01

    Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

  6. Hypercalciuric Bone Disease

    NASA Astrophysics Data System (ADS)

    Favus, Murray J.

    2008-09-01

    Hypercalciuria plays an important causal role in many patients with calcium oxalate (CaOx) stones. The source of the hypercalciuria includes increased intestinal Ca absorption and decreased renal tubule Ca reabsorption. In CaOx stone formers with idiopathic hypercalciuria (IH), Ca metabolic balance studies have revealed negative Ca balance and persistent hypercalciuria in the fasting state and during low dietary Ca intake. Bone resorption may also contribute to the high urine Ca excretion and increase the risk of bone loss. Indeed, low bone mass by DEXA scanning has been discovered in many IH patients. Thiazide diuretic agents reduce urine Ca excretion and may increase bone mineral density (BMD), thereby reducing fracture risk. Dietary Ca restriction that has been used unsuccessfully in the treatment of CaOx nephrolithiasis in the past may enhance negative Ca balance and accelerate bone loss. DEXA scans may demonstrate low BMD at the spine, hip, or forearm, with no predictable pattern. The unique pattern of bone histologic changes in IH differs from other causes of low DEXA bone density including postmenopausal osteoporosis, male hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. Hypercalciuria appears to play an important pathologic role in the development of low bone mass, and therefore correction of urine Ca losses should be a primary target for treatment of the bone disease accompanying IH.

  7. Zebrafish scales respond differently to in vitro dynamic and static acceleration: analysis of interaction between osteoblasts and osteoclasts.

    PubMed

    Kitamura, Kei-ichiro; Takahira, Koh; Inari, Masato; Satoh, Yusuke; Hayakawa, Kazuichi; Tabuchi, Yoshiaki; Ogai, Kazuhiro; Nishiuchi, Takumi; Kondo, Takashi; Mikuni-Takagaki, Yuko; Chen, Wenxi; Hattori, Atsuhiko; Suzuki, Nobuo

    2013-09-01

    Zebrafish scales consist of bone-forming osteoblasts, bone-resorbing osteoclasts, and calcified bone matrix. To elucidate the underlying molecular mechanism of the effects induced by dynamic and static acceleration, we investigated the scale osteoblast- and osteoclast-specific marker gene expression involving osteoblast-osteoclast communication molecules. Osteoblasts express RANKL, which binds to the osteoclast surface receptor, RANK, and stimulates bone resorption. OPG, on the other hand, is secreted by osteoblast as a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus prevents bone resorption. Therefore, the RANK-RANKL-OPG pathway contributes to the regulation of osteoclastogenesis by osteoblasts. Semaphorin 4D, in contrast, is expressed on osteoclasts, and binding to its receptor Plexin-B1 on osteoblasts results in suppression of bone formation. In the present study, we found that both dynamic and static acceleration at 3.0×g decreased RANKL/OPG ratio and increased osteoblast-specific functional mRNA such as alkaline phosphatase, while static acceleration increased and dynamic acceleration decreased osteoclast-specific mRNA such as cathepsin K. Static acceleration increased semaphorin 4D mRNA expression, while dynamic acceleration had no effect. The results of the present study indicated that osteoclasts have predominant control over bone metabolism via semaphorin 4D expression induced by static acceleration at 3.0×g.

  8. Cell fusion in osteoclasts plays a critical role in controlling bone mass and osteoblastic activity

    SciTech Connect

    Iwasaki, Ryotaro; Ninomiya, Ken; Miyamoto, Kana; Suzuki, Toru; Sato, Yuiko

    2008-12-19

    The balance between osteoclast and osteoblast activity is central for maintaining the integrity of bone homeostasis. Here we show that mice lacking dendritic cell specific transmembrane protein (DC-STAMP), an essential molecule for osteoclast cell-cell fusion, exhibited impaired bone resorption and upregulation of bone formation by osteoblasts, which do not express DC-STAMP, which led to increased bone mass. On the contrary, DC-STAMP over-expressing transgenic (DC-STAMP-Tg) mice under the control of an actin promoter showed significantly accelerated cell-cell fusion of osteoclasts and bone resorption, with decreased osteoblastic activity and bone mass. Bone resorption and formation are known to be regulated in a coupled manner, whereas DC-STAMP regulates bone homeostasis in an un-coupled manner. Thus our results indicate that inhibition of a single molecule provides both decreased osteoclast activity and increased bone formation by osteoblasts, thereby increasing bone mass in an un-coupled and a tissue specific manner.

  9. Non-invasive low-intensity pulsed ultrasound accelerates bone healing in the rabbit.

    PubMed

    Pilla, A A; Mont, M A; Nasser, P R; Khan, S A; Figueiredo, M; Kaufman, J J; Siffert, R S

    1990-01-01

    The effect of ultrasound (US) on the rate of fibula osteotomy healing in 139 mature New Zealand white rabbits was assessed in this study. Bilateral midshaft fibular osteotomies were made using a 1-mm Gigli saw. US was noninvasively applied to one limb for 20 minutes daily, while the contralateral limb served as a control. A 2.5-cm PZT transducer was applied to both limbs, with the treated limb receiving a 200-microseconds burst of 1.5-MHz sine waves repeated at 1.0 kHz. The incident intensity was approximately 30 mW/cm2. Animals were killed at intervals between 14 and 28 days. Maximum strength increases (significant to p less than or equal to 0.01) ranged from 40 to 85% from postoperative day 14 to 23. On day 28, no significant difference in ultimate strength was noted. From day 17 through day 28, all US-treated fractures were as strong as intact bones (p less than or equal to 0.005). On the other hand, the ultimate strength of the control osteotomies attained intact values only by day 28. These results indicate that biomechanical healing is accelerated by a factor of nearly 1.7. This occurs with an overall acceleration of the healing curve in this fresh fracture model. If noninvasive low-intensity pulsed sine wave ultrasound can significantly accelerate bone repair in clinical application with an in-home treatment of 20 minutes daily, then US may be a useful adjunct for fracture care with a concomitant impact on patient morbidity.

  10. Effects of myokines on bone.

    PubMed

    Kaji, Hiroshi

    2016-01-01

    The links between muscle and bone have been recently examined because of the increasing number of patients with osteoporosis and sarcopenia. Myokines are skeletal muscle-derived humoral cytokines and growth factors, which exert physiological and pathological functions in various distant organs, including the regulation of glucose, energy and bone metabolism. Myostatin is a crucial myokine, the expression of which is mainly limited to muscle tissues. The inhibition of myostatin signaling increases bone remodeling, bone mass and muscle mass, and it may provide a target for the treatment of both sarcopenia and osteoporosis. As myostatin is involved in osteoclast formation and bone destruction in rheumatoid arthritis, myostatin may be a target myokine for the treatment of accelerated bone resorption and joint destruction in rheumatoid arthritis. Numerous other myokines, including transforming growth factor-β, follistatin, insulin-like growth factor-I, fibroblast growth factor-2, osteoglycin, FAM5C, irisin, interleukin (IL)-6, leukemia inhibitory factor, IL-7, IL-15, monocyte chemoattractant protein-1, ciliary neurotrophic factor, osteonectin and matrix metalloproteinase 2, also affect bone cells in various manners. However, the effects of myokines on bone metabolism are largely unknown. Further research is expected to clarify the interaction between muscle and bone, which may lead to greater diagnosis and the development of the treatment for muscle and bone disorders, such as osteoporosis and sarcopenia. PMID:27579164

  11. Acceleration of apatite nucleation on microrough bioactive titanium for bone-replacing implants.

    PubMed

    Aparicio, C; Manero, J M; Conde, F; Pegueroles, M; Planell, J A; Vallet-Regí, M; Gil, F J

    2007-09-01

    The viability of a new two-step method for obtaining bioactive microrough titanium surfaces for bone replacing implants has been evaluated. The method consists of (1) Grit blasting on titanium surface to roughen it; and (2) Thermo-chemical treating to obtain a bioactive surface with bone-bonding ability by means of nucleating and growing an apatite layer on the treated surface of the metal. The aim of this work is to evaluate the effect of surface roughness and chemical composition of the grit-blasting particles on the ability of the surfaces of nucleating and growing a homogeneous apatite layer. The determination and kinetics of the nucleation and growing of the apatite layer on the surfaces has mainly been studied with environmental scanning electron microscopy (ESEM) and grazing-incidence X-ray diffractometry. The results show that Al(2)O(3)-blasted and thermochemically-treated titanium surfaces accelerates nucleation of the apatite, whereas SiC-blasted and thermochemically-treated titanium surfaces inhibits apatite nucleation, compared with the well studied polished and thermochemically-treated titanium surfaces. The acceleration of the apatite nucleation on the Al(2)O(3)-blasted microrough titanium surfaces is because concave parts of the microroughness that are obtained during grit blasting provides to the rough and bioactive surfaces with a chemical- and electrostatic-favored situation for apatite nucleation. This consists of a high density of surface negative charges (also assisted by the nanoroughness of the surface obtained after the thermochemical treatment) and an increased concentration of the Ca(2+)-ions of the fluid, which have a limited mobility at the bottom of the concave parts. PMID:17295245

  12. Invasive Cervical Resorption: A Review

    PubMed Central

    Kandalgaonkar, Shilpa D; Gharat, Leena A; Tupsakhare, Suyog D; Gabhane, Mahesh H

    2013-01-01

    Invasive cervical resorption is a relatively uncommon form of external root resorption exhibiting no external signs. The resorptive condition is often detected by routine radiographic examination. The clinical features vary from a small defect at the gingival margin to a pink coronal discoloration of the tooth crown resulting in ultimate cavitation of the overlying enamel which is painless unless pulpal or periodontal infection supervenes. Radiographic features of lesions vary from well-delineated to irregularly bordered mottled radiolucencies, and these can be confused with dental caries. A characteristic radiopaque line generally separates the image of the lesion from that of the root canal, because the pulp remains protected by a thin layer of predentin until late in the process. Histopathologically, the lesions contain fibrovascular tissue with resorbing clastic cells adjacent to the dentin surface. More advanced lesions display fibro-osseous characteristics with deposition of ectopic bonelike calcifications both within the resorbing tissue and directly on the dentin surface. How to cite this article: Kandalgaonkar SD, Gharat LA, Tupsakhare SD, Gabhane MH. Invasive Cervical Resorption: A Review. J Int Oral Health 2013;5(6):124-30 . PMID:24453457

  13. Reduction of precocious peri-implant resorption cone.

    PubMed

    De Santis, D; Zanotti, G; Morandini, S; Bordanzi, A; Gerosa, R; Rodella, L F; Rossetto, A; Chiarini, L; Nocini, P F; Bertossi, D

    2013-08-01

    Aim: After implant-insertion, bone tissue, newly-formed on peri-implant crest, undergoes to a mild marginal osseous readjustment due to build-up of inflammatory cell tissue (ICT). The present study verifies the possibility to limit bone resorption by placing implant fixtures 0.5 mm outside cortical bone edge. Methods: A clinically-controlled randomized study on 100 implants has been performed to compare early resorption process of implant fixtures placed 0.5 mm outside cortical bone edge with implant-fixtures inserted according to juxtacortical bone conventional protocols. Results: After 6 months, bone implant level was higher with emersion approach (-1.01±0.54 mm, mean±SD) than with submerged treatment (-1.56±0.5 mm) (P<0.001). Conclusion: Factors to achieve an excellent result at mean-long term seem to be very good, even though the latter have to be confirmed by follow-up.

  14. [Progress and perspectives in bone research].

    PubMed

    Matsumoto, Toshio

    2011-07-01

    Structural integrity and strength of bone is maintained by a balance between bone resorption and bone formation. The balance in bone remodeling process is maintained by factors including mechanical stress, calcium-regulating hormones and sex hormones. Changes in physiological regulators of bone remodeling such as reduction in mechanical stress, aging and reduction in sex hormones, or an increase in pathological factors such as glucocorticoid and inflammatory cytokines cause disturbances in bone remodeling process. Disturbances in bone remodeling not only reduce the bone volume but also deteriorate material as well as structural properties of bone, resulting in a reduction in bone strength. Mechanisms of how bone resorption is initiated at the surface of damaged or aged bone, and how bone resorption is coulpled to bone formation are under active investigation. Increasing the understanding of physiological regulation and pathological conditions of bone remodeling should be able to develop new therapeutic approaches to osteoporosis and other metabolic bone diseases. PMID:21774354

  15. Controlled Delivery of Zoledronate Improved Bone Formation Locally In Vivo

    PubMed Central

    Peng, Jiang; Lu, Qiang; Wang, Yu; Wang, Aiyuan; Guo, Quanyi; Gao, Xupeng; Xu, Wenjing; Lu, Shibi

    2014-01-01

    Bisphosphonates (BPs) have been widely used in clinical treatment of bone diseases with increased bone resorption because of their strong affinity for bone and their inhibition of bone resorption. Recently, there has been growing interest in their improvement of bone formation. However, the effect of local controlled delivery of BPs is unclear. We used polylactide acid-glycolic acid copolymer (PLGA) as a drug carrier to deliver various doses of the bisphosphonate zoledronate (Zol) into the distal femur of 8-week-old Sprague-Dawley rats. After 6 weeks, samples were harvested and analyzed by micro-CT and histology. The average bone mineral density and mineralized bone volume fraction were higher with medium- and high-dose PLGA-Zol (30 and 300 µg Zol, respectively) than control and low-dose Zol (3 µg PLGA-Zol; p<0.05). Local controlled delivery of Zol decreased the numbers of osteoclast and increased the numbers of osteoblast. Moreover, local controlled delivery of medium- and high-dose Zol accelerated the expression of bone-formation markers. PLGA used as a drug carrier for controlled delivery of Zol may promote local bone formation. PMID:24618585

  16. Clinical technique for invasive cervical root resorption

    PubMed Central

    Silveira, Luiz Fernando Machado; Silveira, Carina Folgearini; Martos, Josué; Piovesan, Edno Moacir; César Neto, João Batista

    2011-01-01

    This clinical case report describes the diagnosis and treatment of an external invasive cervical resorption. A 17-year-old female patient had a confirmed diagnosis of invasive cervical resorption class 4 by cone beam computerized tomography. Although, there was no communication with the root canal, the invasive resorption process was extending into the cervical and middle third of the root. The treatment of the cervical resorption of the lateral incisor interrupted the resorptive process and restored the damaged root surface and the dental functions without any esthetic sequelae. Both the radiographic examination and computed tomography are imperative to reveal the extent of the defect in the differential diagnosis. PMID:22144822

  17. Effect of gamma radiation and accelerated electron beam on stable paramagnetic centers induction in bone mineral: influence of dose, irradiation temperature and bone defatting.

    PubMed

    Jastrzebska, Anna; Kaminski, Artur; Grazka, Ewelina; Marowska, Joanna; Sadlo, Jaroslaw; Gut, Grzegorz; Uhrynowska-Tyszkiewicz, Izabela

    2014-09-01

    Ionizing radiation has been found to induce stable defects in the crystalline lattice of bone mineral hydroxyapatite, defined as CO(2) (-) radical ions possessing spins. The purpose of our study was to evaluate CO(2) (-) radical ions induced in non-defatted or defatted human compact bone by gamma radiation (G) and accelerated electron beam (EB), applied with two doses at different temperatures. Moreover, the potential effect of free radical ion formation on mechanical parameters of compact bone, tested under compression in the previous studies, was evaluated. Bone rings from femoral shafts of six male donors (age 51 ± 3 years) were collected and assigned to sixteen experimental groups according to different processing methods (non-defatted or defatted), G and EB irradiation dose (25 or 35 kGy), and irradiation temperature [ambient temperature (AT) or dry ice (DI)]. Untreated group served as control. Following grinding under LN2 and lyophilization, CO(2) (-) radical ions in bone powder were measured by electron paramagnetic resonance spectrometry. We have found that irradiation of bone with G and EB induces formation of enormous amounts of CO(2) (-) radical ions, absent from native tissue. Free radical ion formation was dose-dependent when irradiation was performed at AT, and significantly lower in EB as compared to G-irradiated groups. In contrast, no marked effect of dose was observed when deep-frozen (DI) bone samples were irradiated with G or EB, and free radical ion numbers seemed to be slightly higher in EB-irradiated groups. Irradiation at AT induced much higher quantities of CO(2) (-) radical ions then on DI. That effect was more pronounced in G-irradiated bone specimens, probably due to longer exposure time. Similarly, bone defatting protective effect on free radical ion formation was found only in groups irradiated for several hours with gamma radiation at ambient temperature. Ambient irradiation temperature together with exposure time seem to be key

  18. The effect of photobiomodulation on root resorption during orthodontic treatment

    PubMed Central

    Nimeri, Ghada; Kau, Chung H; Corona, Rachel; Shelly, Jeffery

    2014-01-01

    Photobiomodulation is used to accelerate tooth movement during orthodontic treatments. The changes in root morphology in a group of orthodontic patients who received photobiomodulation were evaluated using the cone beam computed tomography technique. The device used is called OrthoPulse, which produces low levels of light with a near infrared wavelength of 850 nm and an intensity of 60 mW/cm2 continuous wave. Twenty orthodontic patients were recruited for these experiments, all with class 1 malocclusion and with Little’s Irregularity Index (>2 mm) in either of the arches. Root resorption was detected by measuring changes in tooth length using cone beam computed tomography. These changes were measured before the orthodontic treatment and use of low-level laser therapy and after finishing the alignment level. Little’s Irregularity Index for all the patients was calculated in both the maxilla and mandible and patients were divided into three groups for further analysis, which were then compared to the root resorption measurements. Our results showed that photobiomodulation did not cause root resorption greater than the normal range that is commonly detected in orthodontic treatments. Furthermore, no correlation between Little’s Irregularity Index and root resorption was detected. PMID:24470774

  19. Immune Dysfunction Associated with Abnormal Bone Marrow-Derived Mesenchymal Stroma Cells in Senescence Accelerated Mice

    PubMed Central

    Li, Ming; Guo, Kequan; Adachi, Yasushi; Ikehara, Susumu

    2016-01-01

    Senescence accelerated mice (SAM) are a group of mice that show aging-related diseases, and SAM prone 10 (SAMP10) show spontaneous brain atrophy and defects in learning and memory. Our previous report showed that the thymus and the percentage of T lymphocytes are abnormal in the SAMP10, but it was unclear whether the bone marrow-derived mesenchymal stroma cells (BMMSCs) were abnormal, and whether they played an important role in regenerative medicine. We thus compared BMMSCs from SAMP10 and their control, SAM-resistant (SAMR1), in terms of cell cycle, oxidative stress, and the expression of PI3K and mitogen-activated protein kinase (MAPK). Our cell cycle analysis showed that cell cycle arrest occurred in the G0/G1 phase in the SAMP10. We also found increased reactive oxygen stress and decreased PI3K and MAPK on the BMMSCs. These results suggested the BMMSCs were abnormal in SAMP10, and that this might be related to the immune system dysfunction in these mice. PMID:26840301

  20. Potent inhibitory effect of Foeniculum vulgare Miller extract on osteoclast differentiation and ovariectomy-induced bone loss.

    PubMed

    Kim, Tae-Ho; Kim, Hyun-Ju; Lee, Sang-Han; Kim, Shin-Yoon

    2012-06-01

    Inhibition of osteoclast differentiation and bone resorption is considered an effective therapeutic approach to the treatment of postmenopausal bone loss. To find natural compounds that may inhibit osteoclastogenesis, we screened herbal extracts on bone marrow cultures. In this study, we found that an aqueous extract of Foeniculum vulgare Miller seed (FvMs) at low concentration, which has traditionally been used as a treatment for a variety of ailments, inhibits the osteoclast differentiation and bone resorptive activity of mature osteoclasts. We further investigated the effects of FvMs on ovariectomy (OVX)-induced bone loss using microcomputed tomography, biomechanical tests and serum marker assays for bone remodeling. Oral administration of FvMs (30 mg or 100 mg/kg/day) for 6 weeks had an intermediary effect on the prevention of femoral bone mineral density (BMD), bone mineral content (BMC), and other parameters compared to OVX controls. In addition, FvMs slightly decreased bone turnover markers that were accelerated by OVX. The bone-protective effects of FvMs may be due to suppression of an OVX-induced increase in bone turnover. Collectively, our findings indicate that FvMs have potential in preventing bone loss in postmenopausal osteoporosis by reducing both osteoclast differentiation and function.

  1. 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.

  2. Proximal tibia volumetric bone mineral density is correlated to the magnitude of local acceleration in male long-distance runners.

    PubMed

    Dériaz, Olivier; Najafi, Bijan; Ballabeni, Pierluigi; Crettenand, Antoinette; Gobelet, Charles; Aminian, Kamiar; Rizzoli, René; Gremion, Gerald

    2010-04-01

    The beneficial effect of physical exercise on bone mineral density (BMD) is at least partly explained by the forces exerted directly on the bones. Male runners present generally higher BMD than sedentary individuals. We postulated that the proximal tibia BMD is related to the running distance, as well as to the magnitude of the shocks (while running) in male runners. A prospective study (three yearly measurements) included 81 healthy male subjects: 16 sedentary lean subjects, and 3 groups of runners (5-30 km/wk, n = 19; 30-50 km/wk, n = 29; 50-100 km/wk, n = 17). Several measurements were performed at the proximal tibia level: volumetric BMD (vBMD) and cortical index (CI), i.e., an index of cortical bone thickness and peak accelerations (an index of shocks during heel strike) while running (measured by a three-dimensional accelerometer). A general linear model assessed the prediction of vBMD or CI by 1) simple effects (running distance, peak accelerations, time); and 2) interactions (for instance, if vBMD prediction by peak acceleration depends on running distance). CI and vBMD 1) increase with running distance to reach a plateau over 30 km/wk; and 2) are positively associated with peak accelerations over 30 km/wk. Running may be associated with high peak accelerations to have beneficial effects on BMD. More important strains are needed to be associated with the same increase in BMD during running sessions of short duration than those of long duration. CI and vBMD are associated with the magnitude of the shocks during heel strike in runners.

  3. Proximal tibia volumetric bone mineral density is correlated to the magnitude of local acceleration in male long-distance runners

    PubMed Central

    Najafi, Bijan; Ballabeni, Pierluigi; Crettenand, Antoinette; Gobelet, Charles; Aminian, Kamiar; Rizzoli, René; Gremion, Gerald

    2010-01-01

    The beneficial effect of physical exercise on bone mineral density (BMD) is at least partly explained by the forces exerted directly on the bones. Male runners present generally higher BMD than sedentary individuals. We postulated that the proximal tibia BMD is related to the running distance, as well as to the magnitude of the shocks (while running) in male runners. A prospective study (three yearly measurements) included 81 healthy male subjects: 16 sedentary lean subjects, and 3 groups of runners (5–30 km/wk, n = 19; 30–50 km/wk, n = 29; 50–100 km/wk, n = 17). Several measurements were performed at the proximal tibia level: volumetric BMD (vBMD) and cortical index (CI), i.e., an index of cortical bone thickness and peak accelerations (an index of shocks during heel strike) while running (measured by a three-dimensional accelerometer). A general linear model assessed the prediction of vBMD or CI by 1) simple effects (running distance, peak accelerations, time); and 2) interactions (for instance, if vBMD prediction by peak acceleration depends on running distance). CI and vBMD 1) increase with running distance to reach a plateau over 30 km/wk; and 2) are positively associated with peak accelerations over 30 km/wk. Running may be associated with high peak accelerations to have beneficial effects on BMD. More important strains are needed to be associated with the same increase in BMD during running sessions of short duration than those of long duration. CI and vBMD are associated with the magnitude of the shocks during heel strike in runners. PMID:20133440

  4. [Coupling and communication between bone cells].

    PubMed

    Nakashima, Tomoki

    2014-06-01

    Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Coupling has been understood as a balanced induction of osteoblastic bone formation in response to osteoclastic bone resorption. An imbalance of this coupling is often linked to various bone diseases. TGF-β and IGF released from bone matrix during osteoclastic bone resorption are the favored candidates as classical coupling factor. Recently, several reports suggest that osteoclast-derived molecules/cytokines (clastokine) mediate directional signaling between osteoblasts and osteoclasts into the bone microenvironment. Thus, the elucidation of the regulatory mechanisms involved in bone cell communication and coupling is critical for a deeper understanding of the skeletal system in health and disease.

  5. COMPUTED TOMOGRAPHY OF TOOTH RESORPTION IN CATS.

    PubMed

    Lang, Linda G; Wilkinson, Thomas E; White, Tammy L; Farnsworth, Raelynn K; Potter, Kathleen A

    2016-09-01

    Tooth resorption is the most common dental disease in cats and can be a source of oral pain. The current clinical gold standard for diagnosis includes a combination of oral exam and dental radiography, however early lesions are not always detected. Computed tomography (CT) of the skull, including the dental arches, is a commonly performed diagnostic procedure, however the appearance of tooth resorption on CT and the diagnostic ability of CT to detect tooth resorption have not been evaluated. The purpose of this prospective, descriptive, diagnostic accuracy study was to characterize the CT appearance of tooth resorption in a sample of affected cats and to evaluate the sensitivity and specificity of CT for tooth resorption compared to the clinical gold standard of oral exam and intraoral dental radiography. Twenty-eight cat cadaver specimens were recruited for inclusion. Each specimen was evaluated using oral exam, intraoral dental radiography, and computed tomography (four different slice thicknesses). Each tooth was evaluated for the presence or absence of tooth resorption. Teeth with lesions and a subset of normal teeth were evaluated with histopathology. On CT, tooth resorption appeared as irregularly marginated hypoattenuating defects in the mineral attenuating tooth components, most commonly involving the root or cementoenamel junction. Sensitivity for CT detection of tooth resorption was fair to poor (42.2-57.7%) and specificity was good to excellent (92.8-96.3%). Findings from this study indicated that CT has high specificity but low sensitivity for detection of tooth resorption in cats.

  6. A small interfering RNA targeting Lnk accelerates bone fracture healing with early neovascularization.

    PubMed

    Kawakami, Yohei; Ii, Masaaki; Matsumoto, Tomoyuki; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Akimaru, Hiroshi; Mifune, Yutaka; Shoji, Taro; Fukui, Tomoaki; Asahi, Michio; Kurosaka, Masahiro; Asahara, Takayuki

    2013-09-01

    Lnk, an intracellular adapter protein, is expressed in hematopoietic cell lineages, which has recently been proved as an essential inhibitory signaling molecule for stem cell self-renewal in the stem cell factor-c-Kit signaling pathway with enhanced hematopoietic and osteogenic reconstitution in Lnk-deficient mice. Moreover, the therapeutic potential of hematopoietic stem/endothelial progenitor cells (EPCs) for fracture healing has been demonstrated with mechanistic insight into vasculogenesis/angiogenesis and osteogenesis enhancement in the fracture sites. We report here, Lnk siRNA-transfected endothelial commitment of c-kit+/Sca-1+/lineage- subpopulations of bone marrow cells have high EPC colony-forming capacity exhibiting endothelial markers, VE-Cad, VEGF and Ang-1. Lnk siRNA-transfected osteoblasts also show highly osteoblastic capacity. In vivo, locally transfected Lnk siRNA could successfully downregulate the expression of Lnk at the fracture site up to 1 week, and radiological and histological examination showed extremely accelerated fracture healing in Lnk siRNA-transfected mice. Moreover, Lnk siRNA-transfected mice exhibited sufficient therapeutic outcomes with intrinstic enhancement of angiogenesis and osteogenesis, specifically, the mice demonstrated better blood flow recovery in the sites of fracture. In our series of experiments, we clarified that a negatively regulated Lnk system contributed to a favorable circumstance for fracture healing by enhancing vasculogenesis/angiogenesis and osteogenesis. These findings suggest that downregulation of Lnk system may have the clinical potential for faster fracture healing, which contributes to the reduction of delayed unions or non-unions.

  7. The effects of TNF α antagonist therapy on bone metabolism in rheumatoid arthritis: a systematic review.

    PubMed

    Sakthiswary, Rajalingham; Das, Srijit

    2013-12-01

    Osteoporosis is a common complication observed in rheumatoid arthritis (RA). Accelerated bone loss is always a matter of concern. The pathogenesis of RA may be important for better understanding of the bone loss. The mechanism involved in the bone loss in RA is not well understood although cytokines such as interleukin 1 and tumour necrosis factor α (TNF α) have been strongly implicated. TNF α antagonists have revolutionised the treatment of RA in the recent years. Beyond the control of disease activity in RA, accumulating evidence suggests that this form of therapy may provide beneficial effects to the bone metabolism and remodeling. An extensive search of the literature was performed in the Medline, Scopus and EBSCO databases to evaluate the documented research on the effects of TNF α antagonists in RA on bone mineral density and bone turnover markers. The available data based on our systematic review, depict a significant association between TNF α antagonists treatment and suppression of bone resorption.

  8. Laser-wakefield accelerators as hard x-ray sources for 3D medical imaging of human bone.

    PubMed

    Cole, J M; Wood, J C; Lopes, N C; Poder, K; Abel, R L; Alatabi, S; Bryant, J S J; Jin, A; Kneip, S; Mecseki, K; Symes, D R; Mangles, S P D; Najmudin, Z

    2015-01-01

    A bright μm-sized source of hard synchrotron x-rays (critical energy Ecrit > 30 keV) based on the betatron oscillations of laser wakefield accelerated electrons has been developed. The potential of this source for medical imaging was demonstrated by performing micro-computed tomography of a human femoral trabecular bone sample, allowing full 3D reconstruction to a resolution below 50 μm. The use of a 1 cm long wakefield accelerator means that the length of the beamline (excluding the laser) is dominated by the x-ray imaging distances rather than the electron acceleration distances. The source possesses high peak brightness, which allows each image to be recorded with a single exposure and reduces the time required for a full tomographic scan. These properties make this an interesting laboratory source for many tomographic imaging applications.

  9. Laser-wakefield accelerators as hard x-ray sources for 3D medical imaging of human bone.

    PubMed

    Cole, J M; Wood, J C; Lopes, N C; Poder, K; Abel, R L; Alatabi, S; Bryant, J S J; Jin, A; Kneip, S; Mecseki, K; Symes, D R; Mangles, S P D; Najmudin, Z

    2015-01-01

    A bright μm-sized source of hard synchrotron x-rays (critical energy Ecrit > 30 keV) based on the betatron oscillations of laser wakefield accelerated electrons has been developed. The potential of this source for medical imaging was demonstrated by performing micro-computed tomography of a human femoral trabecular bone sample, allowing full 3D reconstruction to a resolution below 50 μm. The use of a 1 cm long wakefield accelerator means that the length of the beamline (excluding the laser) is dominated by the x-ray imaging distances rather than the electron acceleration distances. The source possesses high peak brightness, which allows each image to be recorded with a single exposure and reduces the time required for a full tomographic scan. These properties make this an interesting laboratory source for many tomographic imaging applications. PMID:26283308

  10. Accelerated Growth Plate Mineralization and Foreshortened Proximal Limb Bones in Fetuin-A Knockout Mice

    PubMed Central

    Gupta, Himadri S.; Schäfer, Cora; Krauss, Stefanie; Dunlop, John W. C.; Masic, Admir; Kerschnitzki, Michael; Zaslansky, Paul; Boesecke, Peter; Catalá-Lehnen, Philip; Schinke, Thorsten; Fratzl, Peter; Jahnen-Dechent, Willi

    2012-01-01

    The plasma protein fetuin-A/alpha2-HS-glycoprotein (genetic symbol Ahsg) is a systemic inhibitor of extraskeletal mineralization, which is best underscored by the excessive mineral deposition found in various tissues of fetuin-A deficient mice on the calcification-prone genetic background DBA/2. Fetuin-A is known to accumulate in the bone matrix thus an effect of fetuin-A on skeletal mineralization is expected. We examined the bones of fetuin-A deficient mice maintained on a C57BL/6 genetic background to avoid bone disease secondary to renal calcification. Here, we show that fetuin-A deficient mice display normal trabecular bone mass in the spine, but increased cortical thickness in the femur. Bone material properties, as well as mineral and collagen characteristics of cortical bone were unaffected by the absence of fetuin-A. In contrast, the long bones especially proximal limb bones were severely stunted in fetuin-A deficient mice compared to wildtype littermates, resulting in increased biomechanical stability of fetuin-A deficient femora in three-point-bending tests. Elevated backscattered electron signal intensities reflected an increased mineral content in the growth plates of fetuin-A deficient long bones, corroborating its physiological role as an inhibitor of excessive mineralization in the growth plate cartilage matrix - a site of vigorous physiological mineralization. We show that in the case of fetuin-A deficiency, active mineralization inhibition is a necessity for proper long bone growth. PMID:23091616

  11. Accelerated growth plate mineralization and foreshortened proximal limb bones in fetuin-A knockout mice.

    PubMed

    Seto, Jong; Busse, Björn; Gupta, Himadri S; Schäfer, Cora; Krauss, Stefanie; Dunlop, John W C; Masic, Admir; Kerschnitzki, Michael; Zaslansky, Paul; Boesecke, Peter; Catalá-Lehnen, Philip; Schinke, Thorsten; Fratzl, Peter; Jahnen-Dechent, Willi

    2012-01-01

    The plasma protein fetuin-A/alpha2-HS-glycoprotein (genetic symbol Ahsg) is a systemic inhibitor of extraskeletal mineralization, which is best underscored by the excessive mineral deposition found in various tissues of fetuin-A deficient mice on the calcification-prone genetic background DBA/2. Fetuin-A is known to accumulate in the bone matrix thus an effect of fetuin-A on skeletal mineralization is expected. We examined the bones of fetuin-A deficient mice maintained on a C57BL/6 genetic background to avoid bone disease secondary to renal calcification. Here, we show that fetuin-A deficient mice display normal trabecular bone mass in the spine, but increased cortical thickness in the femur. Bone material properties, as well as mineral and collagen characteristics of cortical bone were unaffected by the absence of fetuin-A. In contrast, the long bones especially proximal limb bones were severely stunted in fetuin-A deficient mice compared to wildtype littermates, resulting in increased biomechanical stability of fetuin-A deficient femora in three-point-bending tests. Elevated backscattered electron signal intensities reflected an increased mineral content in the growth plates of fetuin-A deficient long bones, corroborating its physiological role as an inhibitor of excessive mineralization in the growth plate cartilage matrix--a site of vigorous physiological mineralization. We show that in the case of fetuin-A deficiency, active mineralization inhibition is a necessity for proper long bone growth.

  12. [Bone diseases].

    PubMed

    Uebelhart, Brigitte; Rizzoli, René

    2016-01-13

    Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.

  13. Alternate light sources in the detection of bone after an accelerated fire: a pilot study.

    PubMed

    Gallant, Amber S

    2013-01-01

    This study examines the ability of alternate light sources to detect bone that has been exposed to fire when identification of bone remains is difficult to ascertain. It is intended as a tool for fire investigators to quickly determine whether an area should be considered a forensic scene. After being subjected to a test burn, pig bones were viewed and photographed with the use of a laser, and later compared with a UV light source. A secondary study observing stages of a human cremation was conducted to assess how various levels of burnt flesh affect the ability of bone to fluoresce utilizing a laser. Both studies demonstrated success in detecting bone while fluorescing with a molten lava type of appearance that has the potential to distinguish bone from its surrounding environment. Limitations and recommendations are discussed by the author including the need for future studies to expand on this research.

  14. Alternate light sources in the detection of bone after an accelerated fire: a pilot study.

    PubMed

    Gallant, Amber S

    2013-01-01

    This study examines the ability of alternate light sources to detect bone that has been exposed to fire when identification of bone remains is difficult to ascertain. It is intended as a tool for fire investigators to quickly determine whether an area should be considered a forensic scene. After being subjected to a test burn, pig bones were viewed and photographed with the use of a laser, and later compared with a UV light source. A secondary study observing stages of a human cremation was conducted to assess how various levels of burnt flesh affect the ability of bone to fluoresce utilizing a laser. Both studies demonstrated success in detecting bone while fluorescing with a molten lava type of appearance that has the potential to distinguish bone from its surrounding environment. Limitations and recommendations are discussed by the author including the need for future studies to expand on this research. PMID:22994928

  15. A MODIFIED PMMA CEMENT (SUB-CEMENT) FOR ACCELERATED FATIGUE TESTING OF CEMENTED IMPLANT CONSTRUCTS USING CADAVERIC BONE

    PubMed Central

    Race, Amos; Miller, Mark A.; Mann, Kenneth A.

    2008-01-01

    Pre-clinical screening of cemented implant systems could be improved by modeling the longer-term response of the implant/cement/bone construct to cyclic loading. We formulated bone cement with degraded fatigue fracture properties (Sub-cement) such that long-term fatigue could be simulated in short-term cadaver tests. Sub-cement was made by adding a chain-transfer agent to standard polymethylmethacrylate (PMMA) cement. This reduced the molecular weight of the inter-bead matrix without changing reaction-rate or handling characteristics. Static mechanical properties were approximately equivalent to normal cement. Over a physiologically reasonable range of stress intensity factor, fatigue crack propagation rates for sub-cement were higher by a factor of 25 ± 19. When tested in a simplified 2 1/2D physical model of a stem-cement-bone system, crack growth from the stem was accelerated by a factor of 100. Sub-cement accelerated both crack initiation and growth rate. Sub-cement is now being evaluated in full stem/cement/femur models. PMID:18774136

  16. A modified PMMA cement (Sub-cement) for accelerated fatigue testing of cemented implant constructs using cadaveric bone.

    PubMed

    Race, Amos; Miller, Mark A; Mann, Kenneth A

    2008-10-20

    Pre-clinical screening of cemented implant systems could be improved by modeling the longer-term response of the implant/cement/bone construct to cyclic loading. We formulated bone cement with degraded fatigue fracture properties (Sub-cement) such that long-term fatigue could be simulated in short-term cadaver tests. Sub-cement was made by adding a chain-transfer agent to standard polymethylmethacrylate (PMMA) cement. This reduced the molecular weight of the inter-bead matrix without changing reaction-rate or handling characteristics. Static mechanical properties were approximately equivalent to normal cement. Over a physiologically reasonable range of stress-intensity factor, fatigue crack propagation rates for Sub-cement were higher by a factor of 25+/-19. When tested in a simplified 2 1/2-D physical model of a stem-cement-bone system, crack growth from the stem was accelerated by a factor of 100. Sub-cement accelerated both crack initiation and growth rate. Sub-cement is now being evaluated in full stem/cement/femur models.

  17. Conservative Management of Invasive Cervical Resorption: A Case Report

    PubMed Central

    Umer, Fahad; Adnan, Samira; Raza Khan, Farhan

    2013-01-01

    Invasive cervical resorption is a condition that affects the root surface area below the epithelial attachment. Multiple treatment modalities are advocated, involving exposure of the invasive defect, removal of the granulation tissue and sealing with various restorative materials. This report demonstrates conservative treatment of a patient presenting with peri-apical periodontitis in upper right central and lateral incisors, along with Class II invasive resorption defect cervically on the mesial aspect of the central incisor, as a result of trauma. As the patient was not willing for any surgical intervention, only ortho-grade root canal treatment was carried out in both teeth, with Calcium hydroxide as intra-canal medicament. At three year follow-up, the patient remains asymptomatic demonstrating radiographic evidence of infilling of defect with bone-like tissue. Within the limitations of this report, it was seen that this conservative method for halting the progression of invasive cervical resorption could be under taken in patients who are un-willing for surgical intervention or in whom surgery is contra-indicated. PMID:25512757

  18. TGF-β in cancer and bone: implications for treatment of bone metastases.

    PubMed

    Juárez, Patricia; Guise, Theresa A

    2011-01-01

    Bone metastases are common in patients with advanced breast, prostate and lung cancer. Tumor cells co-opt bone cells to drive a feed-forward cycle which disrupts normal bone remodeling to result in abnormal bone destruction or formation and tumor growth in bone. Transforming growth factor-beta (TGF-β) is a major bone-derived factor, which contributes to this vicious cycle of bone metastasis. TGF-β released from bone matrix during osteoclastic resorption stimulates tumor cells to produce osteolytic factors further increasing bone resorption adjacent to the tumor cells. TGF-β also regulates 1) key components of the metastatic cascade such as epithelial-mesenchymal transition, tumor cell invasion, angiogenesis and immunosuppression as well as 2) normal bone remodeling and coupling of bone resorption and formation. Preclinical models demonstrate that blockade of TGF-β signaling is effective to treat and prevent bone metastases as well as to increase bone mass.

  19. Effect of accelerated electron beam on mechanical properties of human cortical bone: influence of different processing methods.

    PubMed

    Kaminski, Artur; Grazka, Ewelina; Jastrzebska, Anna; Marowska, Joanna; Gut, Grzegorz; Wojciechowski, Artur; Uhrynowska-Tyszkiewicz, Izabela

    2012-08-01

    Accelerated electron beam (EB) irradiation has been a sufficient method used for sterilisation of human tissue grafts for many years in a number of tissue banks. Accelerated EB, in contrast to more often used gamma photons, is a form of ionizing radiation that is characterized by lower penetration, however it is more effective in producing ionisation and to reach the same level of sterility, the exposition time of irradiated product is shorter. There are several factors, including dose and temperature of irradiation, processing conditions, as well as source of irradiation that may influence mechanical properties of a bone graft. The purpose of this study was to evaluate the effect e-beam irradiation with doses of 25 or 35 kGy, performed on dry ice or at ambient temperature, on mechanical properties of non-defatted or defatted compact bone grafts. Left and right femurs from six male cadaveric donors, aged from 46 to 54 years, were transversely cut into slices of 10 mm height, parallel to the longitudinal axis of the bone. Compact bone rings were assigned to the eight experimental groups according to the different processing method (defatted or non-defatted), as well as e-beam irradiation dose (25 or 35 kGy) and temperature conditions of irradiation (ambient temperature or dry ice). Axial compression testing was performed with a material testing machine. Results obtained for elastic and plastic regions of stress-strain curves examined by univariate analysis are described. Based on multivariate analysis, including all groups, it was found that temperature of e-beam irradiation and defatting had no consistent significant effect on evaluated mechanical parameters of compact bone rings. In contrast, irradiation with both doses significantly decreased the ultimate strain and its derivative toughness, while not affecting the ultimate stress (bone strength). As no deterioration of mechanical properties was observed in the elastic region, the reduction of the energy

  20. Variation in the sizes of resorption lacunae made in vitro.

    PubMed

    Jones, S J; Boyde, A; Ali, N N; Maconnachie, E

    1986-01-01

    The assessment of in vitro osteoclastic activity has, until recently, been dependent on the analysis of organ culture experiments. We have developed a single cell resorption assay so that the resorptive function of individual osteoclasts could be studied. This paper examines the biological variation in the sizes of resorption lacunae produced by bone cell cultures derived from neonate rats and rabbits, and prehatch or hatchling chicks. Cultures were run for 24h for all species; and in addition for 48h for rat, 9 or 12 hours for rabbit and 3-7 hours for chick. The numbers of the nuclei of osteoclasts seeded on to plastic were counted for all three species. SEM stereophotogrammetry was used to measure areas, volumes, and maximum and average depths of the lacunae using specially designed instruments and software. Rat osteoclasts were smallest, and more chick osteoclasts were very large. There was a species difference in the onset of resorption and the sizes of pits produced, the chick osteoclasts being more vigorous resorbers than the rabbit ones, and the rat least so. For a given plan area, chick lacunae were deeper. There was a high correlation between area and volume. The range of maximum depths for a given area was high, however. Thus the mean of a few measurements of depths should not be used to calculate volume from area. At 24 hours, 77% of the rat, 47% of the rabbit and 28% of the chick lacunae were less than 1,000 microns 3 in volume; and 11% of the rat, 17% of the rabbit and 22% of the chick lacunae were between 1,000 and 2,000 microns 3 in volume. The mean values at 24 hours were 981, 2796, and 4582 microns 3 for rat, rabbit and chick lacunae respectively.

  1. How are osteoclasts induced to resorb bone?

    PubMed

    Chambers, T J; Fuller, K

    2011-12-01

    Although much is known about how osteoclasts are formed, we know little about how they are activated, or how they recognize bone as the substrate appropriate for resorption. Bone mineral is considered to be essential to this recognition process, but a "mineral receptor" has never been identified. Recently, we found that resorptive behavior, as judged by the formation of ruffled borders and actin rings, occurs on ordinary tissue culture substrates if they are first coated with vitronectin. Similarly, vitronectin-coated substrates induce osteoclasts to secrete tartrate-resistant acid phosphatase and to form podosome belts, and to make resorption trails in the protein that coat the substrate. The same applies to bone mineral, which only induces resorptive behavior if coated with vitronectin. In contrast, fibronectin has none of these effects, despite inducing adhesion and spreading. It appears that osteoclasts recognize bone as the substrate appropriate for resorption through the high affinity of vitronectin-receptor ligands for bone mineral. PMID:22172032

  2. Bone

    NASA Astrophysics Data System (ADS)

    Helmberger, Thomas K.; Hoffmann, Ralf-Thorsten

    The typical clinical signs in bone tumours are pain, destruction and destabilization, immobilization, neurologic deficits, and finally functional impairment. Primary malignant bone tumours are a rare entity, accounting for about 0.2% of all malignancies. Also benign primary bone tumours are in total rare and mostly asymptomatic. The most common symptomatic benign bone tumour is osteoid osteoma with an incidence of 1:2000.

  3. Hypercalcemia and altered biochemical bone markers in post-bone marrow transplantation osteopetrosis: a case report and literature review.

    PubMed

    Kulpiya, Alisa; Mahachoklertwattana, Pat; Pakakasama, Samart; Hongeng, Suradej; Poomthavorn, Preamrudee

    2012-08-01

    Autosomal recessive osteopetrosis is a rare disorder of bone resorption defect that results in generalized sclerotic bones and bone marrow failure. Allogeneic BMT is the only treatment for cure. One of the complications following a successful BMT is hypercalcemia that is a unique complication in this group of patients. We report a three-yr-old boy with osteopetrosis who developed hypercalcemia following the successful BMT. His maximal calcium level was 13.3 mg/dL. Markedly increased both bone formation and resorption markers were demonstrated along with hypercalcemia. These findings indicated an active donor-derived osteoclastic function and thus bone resorption following the successful donor engraftment in the patient. Treatment with hyperhydration, furosemide and bone resorption inhibitors, calcitonin, and bisphosphonate led to normalization of the serum calcium level. Bone resorption but not bone formation marker was persistently elevated despite having normocalcemia during a 16.5-month follow-up period.

  4. In vitro degradation and in vivo resorption of dicalcium phosphate cement based grafts.

    PubMed

    Sheikh, Zeeshan; Zhang, Yu Ling; Grover, Liam; Merle, Géraldine E; Tamimi, Faleh; Barralet, Jake

    2015-10-01

    There are two types of DCP: dihydrated (brushite) and anhydrous (monetite). After implantation, brushite converts to hydroxyapatite (HA) which resorbs very slowly. This conversion is not observed after implantation of monetite cements and result in a greater of resorption. The precise mechanisms of resorption and degradation however of these ceramics remain uncertain. This study was designed to investigate the effect of: porosity, surface area and hydration on in vitro degradation and in vivo resorption of DCP. Brushite and two types of monetite cement based grafts (produced by wet and dry thermal conversion) were aged in phosphate buffered saline (PBS) and bovine serum solutions in vitro and were implanted subcutaneously in rats. Here we show that for high relative porosity grafts (50-65%), solubility and surface area does not play a significant role towards in vitro mass loss with disintegration and fragmentation being the main factors dictating mass loss. For grafts having lower relative porosity (35-45%), solubility plays a more crucial role in mass loss during in vitro ageing and in vivo resorption. Also, serum inhibited dissolution and the formation of HA in brushite cements. However, when aged in PBS, brushite undergoes phase conversion to a mixture of octacalcium phosphate (OCP) and HA. This phase conversion was not observed for monetite upon ageing (in both serum and PBS) or in subcutaneous implantation. This study provides greater understanding of the degradation and resorption process of DCP based grafts, allowing us to prepare bone replacement materials with more predictable resorption profiles.

  5. Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF

    PubMed Central

    Stemig, Melissa; Astelford, Kristina; Emery, Ann; Cho, Jangyeun J.; Allen, Ben; Huang, Tsang-hai; Gopalakrishnan, Rajaram; Mansky, Kim C.; Jensen, Eric D.

    2015-01-01

    Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor. PMID:25875108

  6. The Effect of Root Coating with Titanium on Prevention of Root Resorption in Avulsed Teeth: An Animal Study

    PubMed Central

    Heydari, Azar; Tahmasbi, Soodeh; Badiee, Mohammadreza; Izadi, SeyedSadra; Mashhadi Abbas, Fatemeh; Mokhtari, Sepideh

    2016-01-01

    Introduction: Tooth avulsion is a real dental emergency. If immediate replantation is not performed, the avulsed tooth may be lost due to inflammatory or replacement resorption. This animal study aimed to evaluate the bone response to the titanium coating of the root surface as an artificial barrier, and prevention of resorption of avulsed teeth. Methods and Materials: This experimental study was conducted on four male dogs. The dogs were randomly divided into two groups for assessment at two and eight weeks. Four teeth were extracted in each animal. The root surfaces of the test group were coated with a titanium layer using the Electron Beam Deposition system. After 24 h, replantation of the teeth was performed. Two animals were sacrificed after two weeks and the remaining dogs were killed after eight weeks. The presence of inflammation, inflammatory resorption, replacement resorption, periodontal regeneration, periapical granuloma and ankylosis were evaluated through histological analyses. Results: Inflammatory root resorption was not present in any tooth except one tooth in the coated group after eight weeks. Replacement resorption was noted just in three of the non-coated teeth after two weeks and two teeth after eight weeks. The McNemar's test revealed that the frequency of replacement resorption in the non-coated group was significantly higher than the coated group (P=0.031). Conclusion: Based on the results of this study, it seems that coating the root surfaces of avulsed teeth with titanium may control the replacement root resorption. PMID:27790261

  7. Prevention and management of external inflammatory resorption following trauma to teeth.

    PubMed

    Abbott, P V

    2016-03-01

    External inflammatory resorption is one of the potential consequences of trauma to the teeth. It occurs when there has been loss of cementum due to damage to the external surface of the tooth root during trauma, plus the root canal system has become infected with bacteria. It is characterized by the radiographic appearance of loss of tooth substance with a radiolucency in the adjacent periodontal ligament and bone. The loss of cementum allows the intracanal bacteria and/or their endotoxins to reach the periodontal ligament more readily and this can lead to the development of the inflammatory resorptive process. External inflammatory resorption can ultimately lead to loss of the tooth if it is not managed in a timely manner. There are some injuries that are very likely to develop this type of resorption and a preventive approach can be adopted by commencing root canal treatment immediately as part of the emergency management of such cases. In cases where the resorptive process is already established, root canal treatment can arrest the resorption and encourage hard tissue repair. The use of a corticosteroid-antibiotic intracanal medicament has been shown to be particularly useful in the prevention and management of external inflammatory resorption. Calcium hydroxide should not be used as an immediate medicament because of its inherent toxicity and irritant properties but it is valuable as a subsequent medicament to encourage hard tissue repair where required. This review outlines the external inflammatory resorptive process and the management strategies that can be employed to prevent it from occurring, and to treat it if already present. PMID:26923450

  8. Effects of Zinc and Strontium Substitution in Tricalcium Phosphate on Osteoclast Differentiation and Resorption

    PubMed Central

    Roy, Mangal; Fielding, Gary; Bandyopadhyay, Amit; Bose, Susmita

    2013-01-01

    Bone replacement materials must be able to regulate both osteoblastic synthesis of new bone and osteoclastic resorption process in order to maintain the balance of bone remodeling. Osteoclasts generate from differentiation of mononuclear cells. In the present study, we have studied the osteoclast-like-cells responses (differentiation from mononuclear cells and resorption) to beta tricalcium phosphate (β-TCP) doped with zinc (Zn) and strontium (Sr). Osteoclast-like-cells differentiation and resorption was studied in vitro using osteoclast-like-cells precursor RAW 264.7 cell, supplemented with receptor activator of nuclear factor κβ ligand (RANKL). Morphological and immunohistochemical analysis confirmed successful differentiation of osteoclast-like-cells on the doped and undoped β-TCP substrates after 8 days of culture. Cells on the substrate surface expressed specific osteoclast markers such as; actin ring, multiple nucleus, tartrate-resistant acid phosphatase (TRAP) synthesis, and vitronectin receptor. However, quantitative TRAP assay indicated the inhibiting effect of Zn on osteoclast differentiation. Although, Zn doped β-TCP restricted osteoclast-like-cells differentiation, the samples were resorbed much faster. An increased resorption pit volume was noticed on Zn doped β-TCP samples after 28 days of culture compared to pure and Sr doped β-TCP. In this work, we demonstrated that β-TCP bone substitute materials can be successfully resorbed by osteoclast-like-cells, where both osteoclast-like-cells differentiation and resorption were modulated by Zn and/or Sr doping- a much needed property for successful bone remodeling. PMID:24244866

  9. Time course of "escape" from calcitonin-induced inhibition of motility and resorption of disaggregated osteoclasts.

    PubMed

    Kanehisa, J

    1989-01-01

    The reversible calcitonin (CT)-induced inhibition of osteoclastic activity has been studied to clarify the mechanisms responsible for the so-called "escape phenomenon." Osteoclasts disaggregated from neonatal rabbits were cultured on glass coverslips or thin bovine bone slices. Resorption activity was evaluated by using time-lapse recording and scanning electron microscopy. Addition of CT to the cultures caused most osteoclasts on glass surfaces to be immotile and contracted. From 1.5 h onward, in cultures with CT, osteoclasts started to escape from CT-induced quiescence independently of other cells. CT also prevented osteoclasts on bone slices from excavating bone while concomitant cell immobility occurred. Inhibited osteoclasts were able to regain apparent bone-resorbing potency only after resumption of cytoplasmic immobility. The resumption of bone resorption could begin as early as 9.7 h after CT addition. The observations indicate that CT-induced inhibition of osteoclastic bone resorption is associated with inhibition of cytoplasmic motility and that the "escape" phenomenon reflects resumption of activity of osteoclasts that were previously inhibited by CT action rather than the resportive activity of newly formed osteoclasts. PMID:2765310

  10. High-intensity Nd:YAG laser accelerates bone regeneration in calvarial defect models.

    PubMed

    Kim, Kwansik; Kim, In Sook; Cho, Tae Hyung; Seo, Young-Kwon; Hwang, Soon Jung

    2015-08-01

    High-power pulsed lasers have been recently regarded to be anabolic to bone, but in vivo evidence is still lacking. This study aimed to investigate the capacity of bone repair using a high-power, Q-switched, pulsed, neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, using bilateral calvarial defect models having non-critical sized, 5 mm (rat) or 8 mm (rabbit) diameter. One of the bilateral defects, which were all filled with collagen sponge or left empty, was irradiated with a Nd:YAG laser once every 2 days for 2 weeks at a constant total fluence rate (344 J/cm(2) ), output power (0.75 W), pulse repetition rate (15 pps) and wavelength (1064 nm) and examined for the laser effect. The same experimental scheme was designed using a rabbit calvarial defect model implanted with sponge, which was explored for the dose effect of output power at 0.75 and 3 W with the same quantities of the other parameters. New bone formation was evaluated by micro-computed tomography-based analysis and histological observation at 4 weeks after surgery. Laser irradiation significantly increased new bone formation by approximately 45%, not only in the sponge-filled defects of rats but also when the defects were left empty, compared to the non-irradiated group. Consistently, both doses of output power (0.75 and 3 W) enhanced new bone formation, but there was no significant difference between the two doses. This study is one of the first to demonstrate the beneficial effect of Nd:YAG lasers on the regeneration of bone defects which were left empty or filled with collagen sponge, suggesting its great potential in postoperative treatment targeting local bone healing.

  11. Accelerated bone turnover identifies hemiplegic patients at higher risk of demineralization.

    PubMed

    Del Puente, A; Pappone, N; Servodio Iammarrone, C; Esposito, A; Scarpa, R; Costa, L; Caso, F; Bardoscia, A; Del Puente, A

    2016-01-01

    Immobilization osteoporosis represents a severe complication in hemiplegic patients (HPs), causing fragility fractures, which may occur during rehabilitation reducing functional recovery and survival. The aim of the study was to investigate determinants of bone loss, independent from length of immobilization, which may be useful in early identification of HPs at higher risk of demineralization. Forty-eight HPs of both sexes underwent anthropometric measurements, evaluation of scores of spasticity and of lower limb motory capacity. Laboratory tests were performed. On serum: calcium; phosphorus; creatinine; ALP; iPTH; 25(OH) vitamin-D; sex hormones; Δ4-androstenedione; DHEA-S; insulin; IGF-1; FT3; FT4; TSH; c-AMP. On urine: c-AMP and calcium/creatinine ratio. Two bone turnover markers were measured: serum osteocalcin (BGP) and urinary deoxypyridinoline (DPD). Bone mineral density was determined at both femoral necks, defining a percentage difference in bone loss between paretic and non-paretic limb, thus controlling for the complex cofactors involved. Only bone turnover markers significantly and directly correlated with the entity of demineralization, controlling for age, sex and length of immobilization in the multivariate analysis (BGP coefficient estimate=0.008; SE=0.003; p=0.020; DPD coefficient estimate=0.005; SE=0.002; p=0.036). BGP and DPD are not dependent on anthropometric and endocrine-metabolic parameters, disability patterns and duration of immobilization, thus represent independent determinants of the degree of demineralization. A cutoff was defined for BGP and DPD above which subjects show significantly greater risk of demineralization. The immobilization event generates more severe bone loss when it occurs in subjects with higher bone turnover. BGP and DPD measurements may be of primary importance for early identification of HPs at risk, with relevant preventive implications. PMID:27049105

  12. Accelerated bone turnover identifies hemiplegic patients at higher risk of demineralization.

    PubMed

    Del Puente, A; Pappone, N; Servodio Iammarrone, C; Esposito, A; Scarpa, R; Costa, L; Caso, F; Bardoscia, A; Del Puente, A

    2016-01-01

    Immobilization osteoporosis represents a severe complication in hemiplegic patients (HPs), causing fragility fractures, which may occur during rehabilitation reducing functional recovery and survival. The aim of the study was to investigate determinants of bone loss, independent from length of immobilization, which may be useful in early identification of HPs at higher risk of demineralization. Forty-eight HPs of both sexes underwent anthropometric measurements, evaluation of scores of spasticity and of lower limb motory capacity. Laboratory tests were performed. On serum: calcium; phosphorus; creatinine; ALP; iPTH; 25(OH) vitamin-D; sex hormones; Δ4-androstenedione; DHEA-S; insulin; IGF-1; FT3; FT4; TSH; c-AMP. On urine: c-AMP and calcium/creatinine ratio. Two bone turnover markers were measured: serum osteocalcin (BGP) and urinary deoxypyridinoline (DPD). Bone mineral density was determined at both femoral necks, defining a percentage difference in bone loss between paretic and non-paretic limb, thus controlling for the complex cofactors involved. Only bone turnover markers significantly and directly correlated with the entity of demineralization, controlling for age, sex and length of immobilization in the multivariate analysis (BGP coefficient estimate=0.008; SE=0.003; p=0.020; DPD coefficient estimate=0.005; SE=0.002; p=0.036). BGP and DPD are not dependent on anthropometric and endocrine-metabolic parameters, disability patterns and duration of immobilization, thus represent independent determinants of the degree of demineralization. A cutoff was defined for BGP and DPD above which subjects show significantly greater risk of demineralization. The immobilization event generates more severe bone loss when it occurs in subjects with higher bone turnover. BGP and DPD measurements may be of primary importance for early identification of HPs at risk, with relevant preventive implications.

  13. 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.

  14. Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption.

    PubMed

    Mabilleau, Guillaume; Perrot, Rodolphe; Mieczkowska, Aleksandra; Boni, Sébastien; Flatt, Peter R; Irwin, Nigel; Chappard, Daniel

    2016-10-01

    A role for glucose-dependent insulinotropic polypeptide (GIP) in controlling bone resorption has been suspected. However uncertainty remains to identify whether GIP act directly on osteoclasts. The aim of the present study were (i) to identify in different osteoclast differentiation models (human peripheral blood mononuclear cells-PBMC, murine bone marrow macrophage-BMM and murine Raw 264.7 cells) whether GIP was capable of reducing osteoclast formation and resorption; (ii) ascertain whether the highly potent GIP analogue N-AcGIP was capable of inducing a response at lower concentrations and (iii) to decipher the molecular mechanisms responsible for such effects. [d-Ala(2)]-GIP dose-dependently reduced osteoclast formation at concentration as low as 1nM in human PBMC and 10nM in murine BMM cultures. Furthermore, [d-Ala(2)]-GIP also reduced the extent of osteoclast resorption at concentration as low as 1nM in human PBMC and murine BMM cultures. The mechanism of action of [d-Ala(2)]-GIP appeared to be mediated by reduction in intracellular calcium concentration and oscillation that subsequently inhibited calcineurin activity and NFATc1 nuclear translocation. The potency of the highly potent N-AcGIP was determined and highlighted an effect on osteoclast formation and resorption at concentration ten times lower than observed with [d-Ala(2)]-GIP in vitro. Furthermore, N-AcGIP was also capable of reducing the number of osteoclast in ovariectomized mice as well as the circulating level of type I collagen C-telopeptide. Pharmacological concentrations required for reducing osteoclast formation and resorption provide the impetus to design and exploit enzymatically stable GIP analogues for the treatment of bone resorption disorders in humans. PMID:27451082

  15. Skeletal unloading and dietary copper depletion are detrimental to bone quality of mature rats

    NASA Technical Reports Server (NTRS)

    Smith, Brenda J.; King, Jarrod B.; Lucas, Edralin A.; Akhter, Mohammed P.; Arjmandi, Bahram H.; Stoecker, Barbara J.

    2002-01-01

    This study was designed to examine the skeletal response to copper depletion and mechanical unloading in mature animals. In a 2 x 2 experimental design, 5.5-mo-old male Sprague-Dawley rats (n = 36) consumed either the control (AIN-93M) or Cu-depletion ((-)Cu) diet beginning 21 d before suspension and throughout the remainder of the study. Half of the rats in each dietary treatment group were either tail-suspended (TS) or kept ambulatory (AMB) for 28 d. Lower bone mineral densities (BMD) of 5th lumbar vertebra (L5) (P < 0.05) and femur were observed with (-)Cu and TS, but no differences were noted in the BMD of the humerus. Mechanical strength in the femur and vertebra decreased in response to TS, but were unaffected by copper depletion. Urinary deoxypyridinoline, an index of bone resorption, was significantly greater in TS rats, but unaltered by (-)Cu. No changes in serum or bone alkaline phosphatase activity, an indicator of bone formation, were observed. Our findings suggest that TS and (-)Cu decreased BMD in unloaded femur and vertebra but had no effect on normally loaded humerus. Bone loss with TS appeared to be related to accelerated bone resorption. Alterations in bone metabolism and bone mechanical properties in the mature skeleton resulting from (-)Cu warrant further investigation.

  16. Convergent responses of nitrogen and phosphorus resorption to nitrogen inputs in a semiarid grassland

    USGS Publications Warehouse

    Lü, Xiao-Tao; Reed, Sasha; Yu, Qiang; He, Nian-Peng; Wang, Zheng-Wen; Han, Xing-Guo

    2013-01-01

    Human activities have significantly altered nitrogen (N) availability in most terrestrial ecosystems, with consequences for community composition and ecosystem functioning. Although studies of how changes in N availability affect biodiversity and community composition are relatively common, much less remains known about the effects of N inputs on the coupled biogeochemical cycling of N and phosphorus (P), and still fewer data exist regarding how increased N inputs affect the internal cycling of these two elements in plants. Nutrient resorption is an important driver of plant nutrient economies and of the quality of litter plants produce. Accordingly, resorption patterns have marked ecological implications for plant population and community fitness, as well as for ecosystem nutrient cycling. In a semiarid grassland in northern China, we studied the effects of a wide range of N inputs on foliar nutrient resorption of two dominant grasses, Leymus chinensis and Stipa grandis. After 4 years of treatments, N and P availability in soil and N and P concentrations in green and senesced grass leaves increased with increasing rates of N addition. Foliar N and P resorption significantly decreased along the N addition gradient, implying a resorption-mediated, positive plant–soil feedback induced by N inputs. Furthermore, N : P resorption ratios were negatively correlated with the rates of N addition, indicating the sensitivity of plant N and P stoichiometry to N inputs. Taken together, the results demonstrate that N additions accelerate ecosystem uptake and turnover of both N and P in the temperate steppe and that N and P cycles are coupled in dynamic ways. The convergence of N and P resorption in response to N inputs emphasizes the importance of nutrient resorption as a pathway by which plants and ecosystems adjust in the face of increasing N availability.

  17. Convergent responses of nitrogen and phosphorus resorption to nitrogen inputs in a semiarid grassland.

    PubMed

    Lü, Xiao-Tao; Reed, Sasha; Yu, Qiang; He, Nian-Peng; Wang, Zheng-Wen; Han, Xing-Guo

    2013-09-01

    Human activities have significantly altered nitrogen (N) availability in most terrestrial ecosystems, with consequences for community composition and ecosystem functioning. Although studies of how changes in N availability affect biodiversity and community composition are relatively common, much less remains known about the effects of N inputs on the coupled biogeochemical cycling of N and phosphorus (P), and still fewer data exist regarding how increased N inputs affect the internal cycling of these two elements in plants. Nutrient resorption is an important driver of plant nutrient economies and of the quality of litter plants produce. Accordingly, resorption patterns have marked ecological implications for plant population and community fitness, as well as for ecosystem nutrient cycling. In a semiarid grassland in northern China, we studied the effects of a wide range of N inputs on foliar nutrient resorption of two dominant grasses, Leymus chinensis and Stipa grandis. After 4 years of treatments, N and P availability in soil and N and P concentrations in green and senesced grass leaves increased with increasing rates of N addition. Foliar N and P resorption significantly decreased along the N addition gradient, implying a resorption-mediated, positive plant-soil feedback induced by N inputs. Furthermore, N : P resorption ratios were negatively correlated with the rates of N addition, indicating the sensitivity of plant N and P stoichiometry to N inputs. Taken together, the results demonstrate that N additions accelerate ecosystem uptake and turnover of both N and P in the temperate steppe and that N and P cycles are coupled in dynamic ways. The convergence of N and P resorption in response to N inputs emphasizes the importance of nutrient resorption as a pathway by which plants and ecosystems adjust in the face of increasing N availability.

  18. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket

    PubMed Central

    Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

  19. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket.

    PubMed

    Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

  20. Demineralized Bone Matrix Add-On for Acceleration of Bone Healing in Atypical Subtrochanteric Femoral Fracture: A Consecutive Case-Control Study

    PubMed Central

    Kulachote, Noratep; Sirisreetreerux, Norachart; Chanplakorn, Pongsthorn; Fuangfa, Praman; Suphachatwong, Chanyut; Wajanavisit, Wiwat

    2016-01-01

    Background. Delayed union and nonunion are common complications in atypical femoral fractures (AFFs) despite having good fracture fixation. Demineralized bone matrix (DBM) is a successfully proven method for enhancing fracture healing of the long bone fracture and nonunion and should be used in AFFs. This study aimed to compare the outcome after subtrochanteric AFFs (ST-AFFs) fixation with and without DBM. Materials and Methods. A prospective study was conducted on 9 ST-AFFs patients using DBM (DBM group) during 2013-2014 and compared with a retrospective consecutive case series of ST-AFFs patients treated without DBM (2010–2012) (NDBM group, 9 patients). All patients were treated with the same standard guideline and followed up until fractures completely united. Postoperative outcomes were then compared. Results. DBM group showed a significant shorter healing time than NDBM group (28.1 ± 14.4 versus 57.9 ± 36.8 weeks, p = 0.04). Delayed union was found in 4 patients (44%) in DBM group compared with 7 patients (78%) in NDBM group (p > 0.05). No statistical difference of nonunion was demonstrated between both groups (DBM = 1 and NDBM = 2, p > 0.05). Neither postoperative infection nor severe local tissue reaction was found. Conclusions. DBM is safe and effective for accelerating the fracture healing in ST-AFFx and possibly reduces nonunion after fracture fixation. Trial registration number is TCTR20151021001. PMID:27022610

  1. 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

  2. Optical and scanning electron microscopy in the single osteoclast resorption assay.

    PubMed

    Boyde, A; Ali, N N; Jones, S J

    1985-01-01

    The present studies relate to the single or isolated osteoclastic resorption function assay which we introduced in 1983 to overcome objections to assays based upon measurements of calcium release from bones, in which it was never strictly controlled whether the mechanism involved the destruction of bone with the formation of classical Howship's lacunae. The method may prove to be quite popular in the near future and has already been adopted by other research groups. In previous work, we had utilised stereophotogrammetry of scanning electron micrographs to measure the depth, volume and other parameters of the individual lacunae. However, increasing experience with the method has suggested that we can await a wide range of biological variability in single cell function in any one experiment. We have therefore tested other methods from which data could be obtained more rapidly to permit a better statistical analysis, albeit with reduced accuracy, of each resorption complex. The main aim of the studies reported here was to evaluate various methods of optical and scanning electron microscopy that can be used for the visualization of osteoclasts and their associated resorption lacunae generated in vitro in slabs of dentine and bone. Optical microscopy was found to be complementary to SEM, enabling vital microscopy of unstained and stained cells. In particular, oblique illumination LM and tandem scanning reflected LM (TSRLM) proved to be of paramount value for this purpose. Fixed coated specimens could be most rapidly scanned for resorption lacunae using darkfield reflected LM or TSRLM.

  3. IL-1β differently stimulates proliferation and multinucleation of distinct mouse bone marrow osteoclast precursor subsets.

    PubMed

    Cao, Yixuan; Jansen, Ineke D C; Sprangers, Sara; Stap, Jan; Leenen, Pieter J M; Everts, Vincent; de Vries, Teun J

    2016-09-01

    Osteoclasts are bone-resorbing cells and targets for treating bone diseases. Previously, we reported that distinct murine osteoclast precursor subsets, such as early blasts (CD31(hi) Ly-6C(-)), myeloid blasts (CD31(+) Ly-6C(+)), and monocytes (CD31(-) Ly-6C(hi)), respond differently to the osteoclastogenesis-inducing cytokines, macrophage colony-stimulating factor, and receptor activator for nuclear factor κB ligand. It is unknown, however, how these cell types respond to the osteoclast-stimulating inflammatory cytokine interleukin 1β. This study aims to investigate the effect of interleukin 1β on osteoclastogenesis derived from different mouse bone marrow precursors. Early blasts, myeloid blasts, and monocytes were sorted from mouse bone marrow cells using flow cytometry. Cells were cultured on plastic or on bone slices in the presence of macrophage colony-stimulating factor and receptor activator for nuclear factor κB ligand, without or with interleukin 1β (0.1-10 ng/ml). We found that interleukin 1β stimulated multinucleation and bone resorption of osteoclasts derived from the 3 precursors at different rates. The most large osteoclasts (>20 nuclei) and highest level of bone resorption (16.3%) was by myeloid blast-derived osteoclasts. Interleukin 1β particularly accelerated proliferation of early blasts and the most small osteoclasts (3-5 nuclei) formed on plastic. Life span varied among osteoclasts derived from different precursors: large osteoclasts (>2400 µm(2)) formed most rapidly (75 h) from myeloid blasts but had a short life span (30 h). Monocytes needed the longest time (95 h) for the generation of such large osteoclasts, but these cells had a longer life span (50 h). Our results indicate that the different bone marrow osteoclast precursors are differently stimulated by interleukin 1β with respect to proliferation, multinucleation, life span, and bone resorption. PMID:26957213

  4. Bone Density and High Salt Diets in a Space Flight Model

    NASA Technical Reports Server (NTRS)

    Arnaud, S. B.; Navidi, M.; Liang, M. T. C.; Wolinsky, I.

    1999-01-01

    High salt diets accelerate bone loss with aging in patients with postmenopausal osteoporosis except when calcium supplementation is provided. We have observed that the decrease in mineral content of growing femurs in juvenile rats, exposed to a space flight model which unloads the hind limbs , is substantially less in animals fed excess salt. To determine whether excess dietary salt has the same effect on the skeleton of the mature animal whose response to unloading is increased resorption and bone loss rather than impaired growth, we carried out a metabolic study in mature rats with hindlimbs unloaded by tailsuspension.

  5. Porous poly(propylene fumarate) foam coating of orthotopic cortical bone grafts for improved osteoconduction.

    PubMed

    Lewandrowski, Kai-Uwe; Bondre, Shrikar; Hile, David D; Thompson, Benjamin M J; Wise, Donald L; Tomford, William W; Trantolo, Debra J

    2002-12-01

    A porous biodegradable scaffold coating for perforated and demineralized cortical bone allografts could maintain immediate structural recovery and subsequently allow normal healing and remodeling by promoting bony ingrowth and avoiding accelerated graft resorption. This new type of osteoconductive surface modification should improve allograft incorporation by promoting new bone growth throughout the biodegradable scaffold, hence encasing the graft with the recipient's own bone. We investigated the feasibility of augmenting orthotopically transplanted cortical bone grafts with osteoconductive biodegradable polymeric scaffold coatings. Five types of bone grafts were prepared: type I, untreated fresh-frozen cortical bone grafts (negative control); type II, perforated and partially demineralized cortical bone grafts without additional coating (positive control); type III, perforated and partially demineralized cortical bone coated with a low-porosity poly(propylene fumarate) (PPF) foam; type IV, perforated and partially demineralized cortical bone coated with a medium-porosity PPF foam; and type V, perforated and partially demineralized cortical bone coated with a high-porosity PPF foam. Grafts were implanted into the rat tibial diaphysis. Fixation was achieved with an intramedullary threaded K-wire. Two sets of animals were operated on. Animals were killed in groups of eight with one set being killed 12 weeks, and the other 16 weeks, postoperatively. Radiographic, histologic, and histomorphometric analyses of grafts showed that the amount of new bone forming around the foam-coated grafts was significantly higher than that in the type I control group (uncoated) or that in type II group (perforated and partially demineralized cortical bone grafts). Although all foam formulations appeared initially equally osteoconductive, histologic evaluation of medium-porosity PPF foam-based coatings appeared to result in a sustained response 16 weeks postoperatively. Significant

  6. Apical root resorption in orthodontically treated adults.

    PubMed

    Baumrind, S; Korn, E L; Boyd, R L

    1996-09-01

    This study analyzed the relationship in orthodontically treated adults between upper central incisor displacement measured on lateral cephalograms and apical root resorption measured on anterior periapical x-ray films. A multiple linear regression examined incisor displacements in four directions (retraction, advancement, intrusion, and extrusion) as independent variables, attempting to account for observed differences in the dependent variable, resorption. Mean apical resorption was 1.36 mm (sd +/- 1.46, n = 73). Mean horizontal displacement of the apex was -0.83 mm (sd +/- 1.74, n = 67); mean vertical displacement was 0.19 mm (sd +/- 1.48, n = 67). The regression coefficients for the intercept and for retraction were highly significant; those for extrusion, intrusion, and advancement were not. At the 95% confidence level, an average of 0.99 mm (se = +/- 0.34) of resorption was implied in the absence of root displacement and an average of 0.49 mm (se = +/- 0.14) of resorption was implied per millimeter of retraction. R2 for all four directional displacement variables (DDVs) taken together was only 0.20, which implied that only a relatively small portion of the observed apical resorption could be accounted for by tooth displacement alone. In a secondary set of univariate analyses, the associations between apical resorption and each of 14 additional treatment-related variables were examined. Only Gender, Elapsed Time, and Total Apical Displacement displayed statistically significant associations with apical resorption. Additional multiple regressions were then performed in which the data for each of these three statistically significant variables were considered separately, with the data for the four directional displacement variables. The addition of information on Elapsed Time or Total Apical Displacement did not explain a significant additional portion of the variability in apical resorption. On the other hand, the addition of information on Gender to the

  7. Acceleration and holographic studies on different types of dynamization of external fixators of the bones

    NASA Astrophysics Data System (ADS)

    Podbielska, Halina; Kasprzak, Henryk T.; Voloshin, Arkady S.; Pennig, Dietmar; von Bally, Gert

    1992-08-01

    The unilateral axially dynamic fixator (Orthofix) was mounted on a sheep tibial shaft. Three fixation modes: static, dynamic controlled, and dynamic free were examined by means of double exposure holographic interferometry. Simultaneously, the acceleration was measured by an accelerometer and displayed on the monitor together with loading characteristics. The first exposure was made before the acting force was applied to the tibia plateau. The second one after the moment when the acceleration wave started to propagate through the specimen. We stated that in the case of dynamization less torsion occurs at the fracture site. So far, we have not been able to determine any correlation between results of holographic and accelerometric measurements.

  8. Intracanal bisphosphonate does not inhibit replacement resorption associated with delayed replantation of monkey incisors.

    PubMed

    Thong, Yo Len; Messer, Harold H; Zain, Rosnah Binti; Saw, Lip Hean; Yoong, Lai Thong

    2009-08-01

    Progressive replacement resorption following delayed replantation of avulsed teeth has proved to be an intractable clinical problem. A wide variety of therapeutic approaches have failed to result in the predictable arrest of resorption, with a good long-term prognosis for tooth survival. Bisphosphonates are used in the medical management of a range of bone disorders and topically applied bisphosphonate has been reported to inhibit root resorption in dogs. This study evaluated the effectiveness of a bisphosphonate (etidronate disodium) as an intracanal medicament in the root canals of avulsed monkey teeth, placed before replantation after 1 h of extraoral dry storage. Incisors of six Macaca fascicularis monkeys were extracted and stored dry for 1 h. Teeth were then replanted after canal contamination with dental plaque (negative control) or after root canal debridement and placement of etidronate sealed in the canal space. A positive control of calcium hydroxide placed 8-9 days after replantation was also included. All monkeys were sacrificed 8 weeks later and block sections were prepared for histomorphometric assessment of root resorption and periodontal ligament status. Untreated teeth showed the greatest extent of root resorption (46% of the root surface), which was predominantly inflammatory in nature. Calcium hydroxide treated teeth showed the lowest overall level of resorption (<30% of the root surface), while the bisphosphonate-treated group was intermediate (39%). Ankylosis, defined as the extent of the root surface demonstrating direct bony union to both intact and resorbed root surface, was the lowest in the untreated control group (15% of the root surface), intermediate in the calcium hydroxide group (27%) and the highest in the bisphosphonate group (41%). Bony attachment to the tooth root was divided approximately equally between attachment to intact cementum and to previously resorbed dentin. Overall, bisphosphonate resulted in a worse outcome than

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

    PubMed Central

    Florencio-Silva, Rinaldo; Sasso, Gisela Rodrigues da Silva; 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

  10. Anti-Resorptive Activity of Anti-Hypertensive Agent ACEi in Older Men

    NASA Technical Reports Server (NTRS)

    Rianon, Nahid; Edwards, BeJier; Nhonthachit, Phetsamong; Messick, Amanda; Gagel, Robert; Smith, Scott M.

    2016-01-01

    Hypertension (HTN) is associated with bone loss due to activation of the renin- angiotensin system (RAS) which in turn affects bone turnover. Animal studies have shown decreased bone resorption (up to 19%) and increased bone mass (up to 2%) following treatment with RAStargeted antihypertensive medications (e.g., angiotensin converting enzyme inhibitors, ACEi). Cross-sectional human studies have documented greater femoral neck BMD in older hypertensive men and women treated with ACEi compared to those not-treated with ACEi (nor other RAS-targeted medications). These findings raise the potential for ACEi use in preventing, or at a minimum slowing bone loss due to age or even microgravity. Based on this, we conducted a cohort study to investigate if ACEi treatment would decrease bone resorption in humans. We investigated changes in serum CTX and P1NP in 10 hypertensive men (45 years or older) treated with (N=5) without (N=5) exposure to ACEi for 3-months. Lisinopril was the ACEi used, and dose was adjusted as deemed appropriate by the attending physicians. Participants did not have any known skeletal health problem and were not exposed to any bisphosphonates or hydrochlorothiazides. A small sample size prevented detailed statistical analysis and hence, we present a preliminary descriptive report of our findings. Participants' age was 57+/-7 years (mean +/-SD), baseline body mass index was 27+/-5 kg/sq m, serum concentration of 25-hydroxyvitamin D was 66+/-17 nmol/L and parathyroid hormone was 30+/-13 pg/ml. After Lisinopril treatment, men demonstrated a 10% decrease in the bone resorption marker C-terminal telopeptide (CTX) and 5% decrease in formation marker procollagen type 1 amino-terminal pro-peptide (P1NP). On the contrary, serum CTX increased 41% and P1NP increased 10% in those who were not treated with ACEi. This is the first human study to report reduction in bone resorptive activity following ACEi treatment for hypertension in older men. Our results indicates

  11. [Vascularization and resorption of different supporting tissues by the greater omentum in the formation of compound microvascular transplants].

    PubMed

    Voy, E D

    1985-11-01

    In former investigations the author described the use of omentum majus in building microsurgical compound island flaps employing supporting tissue. Now different kinds of hard tissue, such as autogenous bone and cartilage, allogenous bone and cartilage (preserved by Cialit-solution), Teflon-Fluorocarbon Polymer (Proplast) and tri-calcium phosphate were presented in omentum-sandwich flaps in a histological investigation. We paid special attention to resorption and vascularisation of hard tissue. Allogenous cartilage grafts or artificial materials like Proplast were the most suitable to put into a compound omental island flap. There was good vascularisation with no resorption, especially with Proplast. PMID:2416640

  12. Acceleration of bone development and regeneration through the Wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β

    SciTech Connect

    Arioka, Masaki; Takahashi-Yanaga, Fumi; Sasaki, Masanori; Yoshihara, Tatsuya; Morimoto, Sachio; Takashima, Akihiko; Mori, Yoshihide; Sasaguri, Toshiyuki

    2013-11-01

    Highlights: •The Wnt/β-catenin signaling pathway was activated in GSK-3β{sup +/−} mice. •The cortical and trabecular bone volumes were increased in GSK-3β{sup +/−} mice. •Regeneration of a partial bone defect was accelerated in GSK-3β{sup +/−} mice. -- Abstract: Glycogen synthase kinase (GSK)-3β plays an important role in osteoblastogenesis by regulating the Wnt/β-catenin signaling pathway. Therefore, we investigated whether GSK-3β deficiency affects bone development and regeneration using mice heterozygously deficient for GSK-3β (GSK-3β{sup +/−}). The amounts of β-catenin, c-Myc, cyclin D1, and runt-related transcription factor-2 (Runx2) in the bone marrow cells of GSK-3β{sup +/−} mice were significantly increased compared with those of wild-type mice, indicating that Wnt/β-catenin signals were enhanced in GSK-3β{sup +/−} mice. Microcomputed tomography of the distal femoral metaphyses demonstrated that the volumes of both the cortical and trabecular bones were increased in GSK-3β{sup +/−} mice compared with those in wild-type mice. Subsequently, to investigate the effect of GSK-3β deficiency on bone regeneration, we established a partial bone defect in the femur and observed new bone at 14 days after surgery. The volume and mineral density of the new bone were significantly higher in GSK-3β{sup +/−} mice than those in wild-type mice. These results suggest that bone formation and regeneration in vivo are accelerated by inhibition of GSK-3β, probably through activation of the Wnt/β-catenin signaling pathway.

  13. Low-Magnitude High-Frequency Mechanical Signals Accelerate and Augment Endochondral Bone Repair: Preliminary Evidence of Efficacy

    PubMed Central

    Goodship, Allen E.; Lawes, Timothy J.; Rubin, Clinton T.

    2010-01-01

    Fracture healing can be enhanced by load bearing, but the specific components of the mechanical environment which can augment or accelerate the process remain unknown. The ability of low-magnitude, high-frequency mechanical signals, anabolic in bone tissue, are evaluated here for their ability to influence fracture healing. The potential for short duration (17 min), extremely low-magnitude (25 μm), high-frequency (30 Hz) interfragmentary displacements to enhance fracture healing was evaluated in a mid-diaphyseal, 3-mm osteotomy of the sheep tibia. In a pilot study of proof of concept and clinical relevance, healing in osteotomies stabilized with rigid external fixation (Control: n = 4), were compared to the healing status of osteotomies with the same stiffness of fixation, but supplemented with daily mechanical loading (Experimental: n = 4). These 25-μm displacements, induced by a ferroactive shape-memory alloy (“smart” material) incorporated into the body of the external fixator, were less than 1% of the 3-mm fracture gap, and less than 6% of the 0.45-mm displacement measured at the site during ambulation (p <0.001). At 10-weeks post-op, the callus in the Experimental group was 3.6-fold stiffer (p <0.03), 2.5-fold stronger (p =0.05), and 29% larger (p <0.01) than Controls. Bone mineral content was 52% greater in the Experimental group (p <0.02), with a 2.6-fold increase in bone mineral content (BMC) in the region of the periosteum (p <0.001). These data reinforce the critical role of mechanical factors in the enhancement of fracture healing, and emphasize that the signals need not be large to be influential and potentially clinically advantageous to the restoration of function. PMID:19117066

  14. Designer Dual Therapy Nanolayered Implant Coatings Eradicate Biofilms and Accelerate Bone Tissue Repair.

    PubMed

    Min, Jouha; Choi, Ki Young; Dreaden, Erik C; Padera, Robert F; Braatz, Richard D; Spector, Myron; Hammond, Paula T

    2016-04-26

    Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we demonstrate that a single-stage revision using prostheses coated with self-assembled, hydrolytically degradable multilayers that sequentially deliver the antibiotic (gentamicin) and the osteoinductive growth factor (BMP-2) in a time-staggered manner enables both eradication of established biofilms and complete and rapid bone tissue repair around the implant in rats with induced osteomyelitis. The nanolayered construct allows precise independent control of release kinetics and loading for each therapeutic agent in an infected implant environment. Antibiotics contained in top layers can be tuned to provide a rapid release at early times sufficient to eliminate infection, followed by sustained release for several weeks, and the underlying BMP-2 component enables a long-term sustained release of BMP-2, which induced more significant and mechanically competent bone formation than a short-term burst release. The successful growth factor-mediated osteointegration of the multilayered implants with the host tissue improved bone-implant interfacial strength 15-fold when compared with the uncoated one. These findings demonstrate the potential of this layered release strategy to introduce a durable next-generation implant solution, ultimately an important step forward to future large animal models toward the clinic.

  15. Monte Carlo design study for in vivo bone aluminum measurement using a low energy accelerator beam.

    PubMed

    Pejović-Milić, A; Arnold, M L; McNeill, F E; Chettle, D R

    2000-01-01

    The need for aluminum monitoring exists in occupational medicine, as well as for the clinical monitoring of patients with renal dysfunction. After the development of an appropriate neutron source card, Monte Carlo simulations were made to design moderator/reflector assembly consisting of a polyethylene moderator (2 cm) and graphite reflector (30 cm), surrounded by a boronated (5%) wax (20 cm) and lead (1 cm) shield. This design should allow for the bone aluminum measurement of healthy subjects, but prior to that detailed microdosimetry is necessary to address a noticed disagreement between theoretical and experimental dose data.

  16. 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

  17. Resorption kinetics of eggshell: an in vivo study.

    PubMed

    Dupoirieux, L; Pourquier, D; Neves, M; Téot, L

    2001-01-01

    Eggshell has been recently introduced as a bone substitute candidate in reconstructive surgery. The aim of this experimental study study was to determine its degradation rate in both a skeletal and extraskeletal site. In experiment 1, eggshell particles with four different sizes (50, 75, 150, and 300 microns in diameter) were implanted in subcutaneous pouches of 30 rats. In experiment 2, a fragment of ostrich eggshell was implanted on the nasal dorsum of 10 rats. Animals were sacrificed at 1 (N = 10), 2 (N = 10), and 4 months (N = 10) during the first stage of the study, and at 1 year during the second stage of the study. The results were assessed by X-ray examination and routine histological techniques. In experiment 1, all animals healed uneventfully. At 1 month, only 50-micron particles had undergone resorption. At 2 months, both 50- and 75-micron particles had undergone resorption. At 4 months, the 150- and 300-micron particles were resorbed incompletely. Histologically, the eggshell elicited a mild inflammatory reaction at 1 month that decreased progressively at further stages. In experiment 2, all animals except one healed uneventfully. Radiologically, the eggshell implant displayed a noticeable stability. Histologically, seven of nine implants were encapsulated, but two of them were surrounded by a bony rim. In conclusion, eggshell is a resorbable implant, but the degradation kinetic is size dependent. Large ostrich grafts are also suitable as onlay graft, but a complementary osteosynthesis is recommended to enhance osteointegration. PMID:11314188

  18. 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

  19. Overexpression of DMP1 Accelerates Mineralization and Alters Cortical Bone Biomechanical Properties in Vivo

    PubMed Central

    Bhatia, Ankush; Albazzaz, Michael; Espinoza Orías, Alejandro A.; Inoue, Nozomu; Miller, Lisa M.; Acerbo, Alvin; George, Anne; Sumner, Dale R.

    2011-01-01

    Dentin matrix protein-1 (DMP1) is a key regulator of biomineralization. Here, we examine changes in structural, geometric, and material properties of cortical bone in a transgenic mouse model overexpressing DMP1. Micro-computed tomography and three-point bending were performed on 90 femora of wild type and transgenic mice at 1, 2, 4, and 6 months. Fourier transform infrared imaging was performed at 2 months. We found that the transgenic femurs were longer (p<0.01), more robust in cross-section (p<0.05), stronger (p<0.05), but had less post-yield strain and displacement (p<0.01), and higher tissue mineral density (p<0.01) than the wild type femurs at 1 and 2 months. At 2 months, the transgenic femurs also had a higher mineral-to-matrix ratio (p<0.05) and lower carbonate substitution (p<0.05) compared to wild type femurs. These findings indicate that increased mineralization caused by overexpressing DMP1 led to increased structural cortical bone properties associated with decreased ductility during the early post-natal period. PMID:22100074

  20. Overexpression of DMP1 accelerates mineralization and alters cortical bone biomechanical properties in vivo

    SciTech Connect

    Bhatia A.; Miller L.; Albazza, M.; Espinoza Orias, A.A.; Inoue, N.; Acerbo, A.; George, A.; Sumner, D.R.

    2011-09-29

    Dentin matrix protein-1 (DMP1) is a key regulator of biomineralization. Here, we examine changes in structural, geometric, and material properties of cortical bone in a transgenic mouse model overexpressing DMP1. Micro-computed tomography and three-point bending were performed on 90 femora of wild type and transgenic mice at 1, 2, 4, and 6 months. Fourier transform infrared imaging was performed at 2 months. We found that the transgenic femurs were longer (p < 0.01), more robust in cross-section (p < 0.05), stronger (p < 0.05), but had less post-yield strain and displacement (p < 0.01), and higher tissue mineral density (p < 0.01) than the wild type femurs at 1 and 2 months. At 2 months, the transgenic femurs also had a higher mineral-to-matrix ratio (p < 0.05) and lower carbonate substitution (p < 0.05) compared to wild type femurs. These findings indicate that increased mineralization caused by overexpressing DMP1 led to increased structural cortical bone properties associated with decreased ductility during the early post-natal period.

  1. Melatonin: Bone Metabolism in Oral Cavity

    PubMed Central

    López-Martínez, Fanny; Olivares Ponce, Patricia N.; Guerra Rodríguez, Miriam; Martínez Pedraza, Ricardo

    2012-01-01

    Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991). PMID:22927853

  2. [Clinical usefulness of bone turnover markers with the treatment of osteoporosis].

    PubMed

    Miura, Masakazu

    2014-03-01

    Bone turnover markers (BTMs) are known the bone formation marker, the bone resorption marker and the bone matrix related marker participating in bone quality, respectively. In the Guidelines for the Use of Bone Metabolic Markers in the Diagnosis and Treatment of Osteoporosis (2012 Edition) from publishing Japan Osteoporosis Society Committee, the newly and commonly BTMs were considered to give the normal reference value in Japanese people, the reevaluation of MSC, and the influence of renal function on BTMs, respectively. The flow chart of the measurement of bone resorption markers and bone formation markers when selecting drug treatment for osteoporosis, the measurement of ucOC and bone resorption markers when selecting drug treatment in osteoporosis, and the evaluation of therapeutic effects of bone antiresorption drugs using bone resorption markers were corrected newly in the guideline 2012 edition. It is thought that the BTMs have been continued more developing as essential biomarker with the treatment of osteoporosis in the future.

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

    PubMed

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

    2015-07-01

    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.

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

    PubMed

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

    2015-07-01

    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

  5. Thyroxine Induced Resorption of Xenopus Laevis Tail Tissue in Vitro.

    ERIC Educational Resources Information Center

    Scadding, Steven R.

    1984-01-01

    A simple method of studying thyroxine-induced resorption of tadpole tails in vitro is described. This procedure demonstrates that resorption is dependent on thyroxine and requires protein synthesis. It introduces students to the use of tissue culture methods. (Author)

  6. Acceleration of bone regeneration by local application of lithium: Wnt signal-mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis.

    PubMed

    Arioka, Masaki; Takahashi-Yanaga, Fumi; Sasaki, Masanori; Yoshihara, Tatsuya; Morimoto, Sachio; Hirata, Masato; Mori, Yoshihide; Sasaguri, Toshiyuki

    2014-08-15

    Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/β-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments, we examined the effects of GSK-3 inhibitors LiCl and SB216763 on osteoblastogenesis of mesenchymal progenitor C3H10T1/2 cells and osteoclastogenesis of osteoclast precursor RAW-D cells. Both inhibitors promoted osteoblast differentiation, assessed by alkaline phosphatase activity and calcium deposition, stimulating the Wnt/β-catenin signaling pathway and thereby inducing Runx2. On the other hand, the GSK-3 inhibitors suppressed osteoclast differentiation, assessed by tartrate-resistant acid phosphatase staining and number of nuclei in the cells, reducing NFATc1 expression independently of the Wnt/β-catenin signaling pathway. In subsequently performed in vivo studies, we examined the effect of locally administered Li2CO3 on the recovery from a partial defect made on the rat tibia. Computerized tomography and bone histomorphometry showed that Li2CO3 accelerated bone regeneration in defect lesion with increased lamellar bone ratio compared with the controls. These results suggested that local application of lithium (or other GSK-3 inhibitors) might effectively facilitate recovery from bone injury by promoting osteoblastogenesis and inhibiting osteoclastogenesis.

  7. Acceleration of bone regeneration by local application of lithium: Wnt signal-mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis.

    PubMed

    Arioka, Masaki; Takahashi-Yanaga, Fumi; Sasaki, Masanori; Yoshihara, Tatsuya; Morimoto, Sachio; Hirata, Masato; Mori, Yoshihide; Sasaguri, Toshiyuki

    2014-08-15

    Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/β-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments, we examined the effects of GSK-3 inhibitors LiCl and SB216763 on osteoblastogenesis of mesenchymal progenitor C3H10T1/2 cells and osteoclastogenesis of osteoclast precursor RAW-D cells. Both inhibitors promoted osteoblast differentiation, assessed by alkaline phosphatase activity and calcium deposition, stimulating the Wnt/β-catenin signaling pathway and thereby inducing Runx2. On the other hand, the GSK-3 inhibitors suppressed osteoclast differentiation, assessed by tartrate-resistant acid phosphatase staining and number of nuclei in the cells, reducing NFATc1 expression independently of the Wnt/β-catenin signaling pathway. In subsequently performed in vivo studies, we examined the effect of locally administered Li2CO3 on the recovery from a partial defect made on the rat tibia. Computerized tomography and bone histomorphometry showed that Li2CO3 accelerated bone regeneration in defect lesion with increased lamellar bone ratio compared with the controls. These results suggested that local application of lithium (or other GSK-3 inhibitors) might effectively facilitate recovery from bone injury by promoting osteoblastogenesis and inhibiting osteoclastogenesis. PMID:24955980

  8. 5. Accelerated Fracture Healing Targeting Periosteal Cells: Possibility of Combined Therapy of Low-Intensity Pulsed Ultrasound (LIPUS), Bone Graft, and Growth Factor (bFGF).

    PubMed

    Uchida, Kentaro; Urabe, Ken; Naruse, Koji; Mikuni-Takagaki, Yuko; Inoue, Gen; Takaso, Masashi

    2016-08-01

    We have studied the mechanism of fracture healing, and the effect of LIPUS, bone graft and growth factor on accelerating fracture healing. We present here the results of our research. To examine callus formation cells in fracture healing, we made marrow GFP chimera mice and a fracture model of marrow mesenchymal stem cell GFP chimera mice. It was demonstrated that periosteal cells were essential for callus formation. We focused on periosteal cells and examined the effect of LIPUS. In an in vitro experiment using a cultured part of the femur, LIPUS promoted ossification of the periosteal tissue. Further, LIPUS accelerated VEGF expression in the experiment using the femoral fracture model of mice. From these results, it was suggested that activation of periosteal cells might play a role in the fracture healing mechanism of LIPUS. Next, we discussed the possibility of combined therapy of LIPUS, bone graft and growth factor. Therapy involving the topical administration of bFGF using a controlled release system and bone graft could promote callus formation. In addition, LIPUS was able to promote membranaceous ossification after the bone graft. It was suggested that combined therapy of LIPUS, bone graft and bFGF could be a new option for treating fractures. PMID:27441766

  9. Accelerated and enhanced effect of CCR5-transduced bone marrow neural stem cells on autoimmune encephalomyelitis

    PubMed Central

    Yang, Jingxian; Yan, Yaping; Ma, Cun-Gen; Kang, Tingguo; Zhang, Nan; Gran, Bruno; Xu, Hui; Li, Ke; Ciric, Bogoljub; Zangaladze, Andro; Curtis, Mark; Rostami, Abdolmohamad; Zhang, Guang-Xian

    2013-01-01

    The suppressive effect of neural stem cells (NSCs) on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been reported. However, the migration of NSCs to inflammatory sites was relatively slow as was the onset of rather limited clinical benefit. Lack of, or low expression of particular chemokine receptors on NSCs could be an important factor underlying the slow migration of NSCs. To enhance the therapeutic effect of NSCs, in the present study we transduced bone marrow (BM)-derived NSCs with CCR5, a receptor for CCL3, CCL4, and CCL5, chemokines that are abundantly produced in CNS-inflamed foci of MS/EAE. After i.v. injection, CCR5-NSCs rapidly reached EAE foci in larger numbers, and more effectively suppressed CNS inflammatory infiltration, myelin damage, and clinical EAE than GFP-NSCs used as controls. CCR5-NSC-treated mice also exhibited augmented remyelination and neuron/oligodendrocyte repopulation compared to PBS- or GFP-NSC-treated mice. We inferred that the critical mechanism underlying enhanced effect of CCR5-transduced NSCs on EAE is the early migration of chemokine receptor-transduced NSCs into the inflamed foci. Such migration at an earlier stage of inflammation enables NSCs to exert more effective immunomodulation, to reduce the extent of early myelin/neuron damage by creating a less hostile environment for remyelinating cells, and possibly to participate in the remyelination/neural re-population process. These features of BM-derived transduced NSCs, combined with their easy availability (the subject’s own BM) and autologous properties, may lay the groundwork for an innovative approach to rapid and highly effective MS therapy. PMID:22526024

  10. Bone Biochemistry on the International Space Station

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Heer, Martina; Zwart, Sara R.

    2016-01-01

    Bone biochemical measures provide valuable insight into the nature and time course of microgravity effects on bone during space flight, where imaging technology cannot be employed. Increased bone resorption is a hallmark of space flight, while markers of bone formation are typically unchanged or decreased. Recent studies (after the deployment to ISS of the advanced resistive exercise device, ARED), have documented that astronauts with good nutritional intake (e.g., maintenance of body mass), good vitamin D status, and exercise maintained bone mineral density. These data are encouraging, but crewmembers exercising on the ARED do have alterations in bone biochemistry, specifically, bone resorption is still increased above preflight levels, but bone formation is also significantly increased. While this bone remodeling raises questions about the strength of the resulting bone, however documents beneficial effects of nutrition and exercise in counteracting bone loss of space flight.

  11. Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy

    PubMed Central

    2015-01-01

    We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κβ ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy. PMID:26137498

  12. Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy.

    PubMed

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

    2015-01-01

    We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κβ ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy. PMID:26137498

  13. Strontium ranelate improved tooth anchorage and reduced root resorption in orthodontic treatment of rats.

    PubMed

    Kirschneck, Christian; Wolf, Michael; Reicheneder, Claudia; Wahlmann, Ulrich; Proff, Peter; Roemer, Piero

    2014-12-01

    The anchorage mechanisms currently used in orthodontic treatment have various disadvantages. The objective of this study was to determine the applicability of the osteoporosis medication strontium ranelate in pharmacologically induced orthodontic tooth anchorage. In 48 male Wistar rats, a constant orthodontic force of 0.25 N was reciprocally applied to the upper first molar and the incisors by means of a Sentalloy(®) closed coil spring for two to four weeks. 50% of the animals received strontium ranelate at a daily oral dosage of 900 mg per kilogramme of body weight. Bioavailability was determined by blood analyses. The extent of tooth movement was measured both optometrically and cephalometrically (CBCT). Relative alveolar gene expression of osteoclastic markers and OPG-RANKL was assessed by qRT-PCR and root resorption area and osteoclastic activity were determined in TRAP-stained histologic sections of the alveolar process. Compared to controls, the animals treated with strontium ranelate showed up to 40% less tooth movement after four weeks of orthodontic treatment. Gene expression and histologic analyses showed significantly less osteoclastic activity and a significantly smaller root resorption area. Blood analyses confirmed sufficient bioavailability of strontium ranelate. Because of its pharmacologic effects on bone metabolism, strontium ranelate significantly reduced tooth movement and root resorption in orthodontic treatment of rats. Strontium ranelate may be a viable agent for inducing tooth anchorage and reducing undesired root resorption in orthodontic treatment. Patients under medication of strontium ranelate have to expect prolonged orthodontic treatment times. PMID:25281203

  14. Bisphosphonates and bone quality

    PubMed Central

    Pazianas, Michael; van der Geest, Stefan; Miller, Paul

    2014-01-01

    Bisphosphonates (BPs) are bone-avid compounds used as first-line medications for the prevention and treatment of osteoporosis. They are also used in other skeletal pathologies such as Paget's and metastatic bone disease. They effectively reduce osteoclast viability and also activity in the resorptive phase of bone remodelling and help preserve bone micro-architecture, both major determinants of bone strength and ultimately of the susceptibility to fractures. The chemically distinctive structure of each BP used in the clinic determines their unique affinity, distribution/penetration throughout the bone and their individual effects on bone geometry, micro-architecture and composition or what we call ‘bone quality'. BPs have no clinically significant anabolic effects. This review will touch upon some of the components of bone quality that could be affected by the administration of BPs. PMID:24876930

  15. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility.

    PubMed

    Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A

    2016-06-01

    Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.

  16. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility.

    PubMed

    Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A

    2016-06-01

    Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility. PMID:26847434

  17. Stoichiometric patterns in foliar nutrient resorption across multiple scales

    USGS Publications Warehouse

    Reed, Sasha C.; Townsend, Alan R.; Davidson, Eric A.; Cleveland, Cory C.

    2012-01-01

    *Nutrient resorption is a fundamental process through which plants withdraw nutrients from leaves before abscission. Nutrient resorption patterns have the potential to reflect gradients in plant nutrient limitation and to affect a suite of terrestrial ecosystem functions. *Here, we used a stoichiometric approach to assess patterns in foliar resorption at a variety of scales, specifically exploring how N : P resorption ratios relate to presumed variation in N and/or P limitation and possible relationships between N : P resorption ratios and soil nutrient availability. *N : P resorption ratios varied significantly at the global scale, increasing with latitude and decreasing with mean annual temperature and precipitation. In general, tropical sites (absolute latitudes < 23°26′) had N : P resorption ratios of < 1, and plants growing on highly weathered tropical soils maintained the lowest N : P resorption ratios. Resorption ratios also varied with forest age along an Amazonian forest regeneration chronosequence and among species in a diverse Costa Rican rain forest. *These results suggest that variations in N : P resorption stoichiometry offer insight into nutrient cycling and limitation at a variety of spatial scales, complementing other metrics of plant nutrient biogeochemistry. The extent to which the stoichiometric flexibility of resorption will help regulate terrestrial responses to global change merits further investigation.

  18. Etiology and sequelae of root resorption.

    PubMed

    Vlaskalic, V; Boyd, R L; Baumrind, S

    1998-06-01

    This article reviews the current status of investigation into apical root resorption within the context of orthodontic treatment. Treatment and patient factors that have traditionally been investigated are discussed, along with the results of current research in this area. The need for rethinking traditional research strategies in the quest for identifying both control and causative mechanisms is explored. Finally, proposals for key areas of future interest are highlighted.

  19. Maxillary sinus augmentation using recombinant bone morphogenetic protein-2/acellular collagen sponge in combination with a mineralized bone replacement graft: a report of three cases.

    PubMed

    Tarnow, Dennis P; Wallace, Stephen S; Testori, Tiziano; Froum, Stuart J; Motroni, Alessandro; Prasad, Hari S

    2010-04-01

    The objective of the following case reports was to assess whether mineralized bone replacement grafts (eg, xenografts and allografts) could be added to recombinant human bone morphogenetic protein-2/acellular collagen sponge (rhBMP-2/ACS) in an effective manner that would: (1) reduce the graft shrinkage observed when using rhBMP-2/ACS alone, (2) reduce the volume and dose of rhBMP-2 required, and (3) preserve the osteoinductivity that rhBMP-2/ACS has shown when used alone. The primary outcome measures were histomorphometric analysis of vital bone production and analysis of serial computed tomographic scans to determine changes in bone graft density and stability. Over the 6-month course of this investigation, bone graft densities tended to increase (moreso with the xenograft than the allograft). The increased density in allograft cases was likely the result of both compression of the mineralized bone replacement graft and vital bone formation, seen histologically. Loss of volume was greater with the four-sponge dose than the two-sponge dose because of compression and resorption of the sponges. Vital bone formation in the allograft cases ranged from 36% to 53% but, because of the small sample size, it was not possible to determine any significant difference between the 5.6 mL (four-sponge) dose and the 2.8 mL (two-sponge) dose. Histology revealed robust new woven bone formation with only minimal traces of residual allograft, which appeared to have undergone accelerated remodeling or rhBMP-2-mediated resorption. PMID:20228973

  20. THE IMMUNE SYSTEM AND BONE

    PubMed Central

    Pacifici, Roberto

    2010-01-01

    T cells and B cells produce large amounts of cytokines which regulate bone resorption and bone formation. These factors play a critical role in the regulation of bone turnover in health and disease. In addition, immune cells of the bone marrow regulate bone homeostasis by cross-talking with bone marrow stromal cells and osteoblastic cells via cell surface molecules. These regulatory mechanisms are particularly relevant for postmenopausal osteoporosis and hyperparathyroidism, two common forms of bone loss caused primarily by an expansion of the osteoclastic pool only partially compensated by a stimulation of bone formation. This article describes the cytokines and immune factors that regulate bone cells, the immune cells relevant to bone, examines the connection between T cells and bone in health and disease, and reviews the evidence in favor of a link between T cells and the mechanism of action of estrogen and PTH in bone. PMID:20599675

  1. [Space flight/bedrest immobilization and bone. Bone metabolism in space flight and long-duration bed rest].

    PubMed

    Ohshima, Hiroshi; Matsumoto, Toshio

    2012-12-01

    Bone loss and urolithiasis are inevitable outcome in human space flight and long-duration bet rest. The rate of space flight induced bone loss is 10 times faster than in those with osteoporosis. Significant bone loss at weight bearing bones, elevated urinary calcium excretion, and un-coupling of bone resorption and bone formation are observed during the long-term bed rest study. Improvements of resistive exercise device and vitamin-D supplementation for astronauts in International Space Station can partially maintain bone mass, however, they can not fully supress bone resorption and urinary calcium excretion during space flight. JAXA and NASA are performing joint study to validate the mitigration effects on bone resorption and urolithiasis of bisphosphonate supplement in conjunction with excercise.

  2. 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.

  3. The Effect of An Angiogenic Cytokine on Orthodontically Induced Inflammatory Root Resorption

    PubMed Central

    Seifi, Massoud; Lotfi, Ali; Badiee, Mohammad Reza; Abdolazimi, Zahra; Amdjadi, Parisa; Bargrizan, Majid

    2016-01-01

    Objective Orthodontically induced inflammatory root resorption (OIIRR) is an undesirable sequel of tooth movement after sterile necrosis that takes place in periodontal ligament due to blockage of blood vessels following exertion of orthodontic force. This study sought to assess the effect of an angiogenic cytokine on OIIRR in rat model. Materials and Methods In this experimental animal study, 50 rats were randomly divided into 5 groups of 10 each: E10, E100 and E1000 receiving an injection of 10, 100 and 1000 ng of basic fibroblast growth factor (bFGF), respectively, positive control group (CP) receiving an orthodontic appliance and injection of phosphate buffered saline (PBS) and the negative control group (CN) receiving only the anesthetic agent. A nickel titanium coil spring was placed between the first molar and the incisor on the right side of maxilla. Twenty-one days later, the rats were sacrificed. Histopathological sections were made to assess the number and area of resorption lacunae, number of blood vessels, osteoclasts and Howship’s lacunae. Data were statistically analyzed using ANOVA and Tukey’s honest significant difference (HSD) test. Results Number of resorption lacunae and area of resorption lacunae in E1000 (0.97 ± 0.80 and 1. 27 ± 0.01×10-3, respectively) were significantly lower than in CP (4.17 ± 0.90 and 2.77 ± 0.01×10-3, respectively, P=0.000). Number of blood vessels, osteoclasts and Howship’s lacunae were significantly higher in E1000 compared to CP (P<0.05). Conclusion Tooth movement as the outcome of bone remodeling is concomitant with the formation of sterile necrosis in the periodontal ligament following blocked blood supply. Thus, bFGF can significantly decrease the risk of root resorption by providing more oxygen and angiogenesis. PMID:27551674

  4. Acceleration of segmental bone regeneration in a rabbit model by strontium-doped calcium polyphosphate scaffold through stimulating VEGF and bFGF secretion from osteoblasts.

    PubMed

    Gu, Zhipeng; Zhang, Xu; Li, Li; Wang, Qiguang; Yu, Xixun; Feng, Ting

    2013-01-01

    The development of suitable bioactive three-dimensional scaffold for the promotion of bone regeneration is critical in bone tissue engineering. The purpose of this study was to investigate in vivo osteogenesis of the porous strontium-doped calcium polyphosphate (SCPP) scaffolds for bone repair, as well as the relationship between osteogenic properties of SCPP scaffolds and the secretion of bFGF and VEGF from osteoblasts stimulated by SCPP. Besides, the advantages of scaffolds seeded with mesenchymal stem cells (MSCs) for bone repair were also studied. Firstly, the bone repair evaluation of scaffolds was performed on a rabbit segmental bony defects model over a period of 16 weeks by histology combined with X-ray microradiography. And then, in order to avoid the influence from the other factors such as hypoxia which emerge in vivo study and affect the secretion of VEGF and bFGF from host cells, human osteoblast-like cells (MG63) were seeded to SCPP, CPP and HA scaffolds in vitro to determine the ability of these scaffolds to stimulate the secretion of angiogenic growth factors (VEGF and bFGF) from MG63 and further explore the reason for the better osteogenic properties of SCPP scaffolds. The histological and X-ray microradiographic results showed that the SCPP scaffolds presented better osteogenic potential than CPP and HA scaffolds, when combined with MSCs, the SCPP scaffolds could further accelerate the bone repair. And the amounts of VEGF measured by ELISA assay in SCPP, CPP and HA groups after cultured for 7 days were about 364.989 pg/mL, 244.035 pg/mL and 232.785 pg/mL, respectively. Accordingly, the amounts of bFGF were about 27.085 pg/mL, 15.727 pg/mL and 8.326 pg/mL. The results revealed that the SCPP scaffolds significantly enhanced the bFGF and VEGF secretion compared with other scaffolds. The results presented in vivo and in vitro study demonstrated that the SCPP could accelerate bone formation through stimulating the secretion of VEGF and bFGF from

  5. [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. PMID:24369600

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  7. Quantification of osteoclastic resorption of the bovine otic capsule in vitro by an enzyme-linked immunosorbent assay.

    PubMed

    Frisch, T; Foged, N T; Sørensen, M S; Bretlau, P

    2000-01-01

    The bony shell surrounding the inner ear is known to have a very pronounced centripetal inhibition of remodelling in vivo, with almost no bone turnover immediately adjacent to the perilymphatic spaces and a gradually increasing turnover rate towards outer parts of the bony otic capsule. By the use of in vitro markers of bone resorption, including an enzyme-linked immunosorbent assay for quantification of type I collagen degradation and a colorimetric enzyme assay for quantification of osteoclast tartrate-resistant acid phosphatase activity, this study demonstrates that there are no ex vivo differences in bone matrix resorption between the inner and outer parts of the otic capsule when exposed to seeded osteoclasts from rabbits. Thus, the unique spatial distribution of perilabyrinthine bone turnover is not caused by a shift in resorbability from inner to outer capsular bone that is due to inherent bone quality differences particular to these bone compartments. More likely, the sustained action of some intravital 'field force', originating from the inner ear spaces, is responsible for the unique spatial distribution of the otic capsular bone turnover found in vivo. Though the character of this force is not yet defined, it is appealing to relate it to the large electromagnetic potential gradient present in the inner ear. PMID:10965257

  8. Amelogenesis Imperfecta with Coronal Resorption: Report of Three Cases.

    PubMed

    Bhatia, Shannu K; Hunter, M Lindsay; Ashley, Paul F

    2015-12-01

    Intracoronal resorption of the permanent dentition in cases of amelogenesis imperfecta (AI) is a rare finding which poses an added complication to the already complex management of this condition. This paper presents three cases of AI associated with delayed eruption of permanent teeth in which asymptomatic intracoronal resorption occurred. CPD/Clinical Relevance: This paper highlights the fact that teeth affected with amelogenesis imperfecta may undergo asymptomatic intracoronal resorption which is only identifiable radiographically.

  9. Metabolic bone disease in chronic renal failure. I. Dialyzed uremics.

    PubMed Central

    Huffer, W. E.; Kuzela, D.; Popovtzer, M. M.

    1975-01-01

    Garner and ball's point counting technic was used to compare metabolic bone disease in dialyzed and nondialyzed uremic patients. Histologic measurements of bone from dialyzed and nondialyzed uremic patients dying between 1966 and 1971 showed that dialyzed patients have quantitatively more severe bone resorption, distortion of trabecular architecture and mineralization defects. Mineralization defects become more severe as the duration of dialysis increases but are not related to serum calcium and phosphorus levels. Bone volume in both groups is normal or increased and in dialysis patients increases in proportion to the elevation of serum phosphorus. Mean serum phosphorus and calcium levels, bone volume, and volume: surface ratios all decreased in dialysis patients between 1966 and 1971, while bone resorption and mineralization defects did not change. These results suggest that lowering of serum phosphorus without increasing serum calcium may aggrevate the uremic bone disease by reducing bone volume without improvement of mineralization and resorption defects. Images Fig 1 PMID:1119535

  10. Oxytocin and bone

    PubMed Central

    Sun, Li; Zaidi, Mone; Zallone, Alberta

    2014-01-01

    One of the most meaningful results recently achieved in bone research has been to reveal that the pituitary hormones have profound effect on bone, so that the pituitary-bone axis has become one of the major topics in skeletal physiology. Here, we discuss the relevant evidence about the posterior pituitary hormone oxytocin (OT), previously thought to exclusively regulate parturition and breastfeeding, which has recently been established to directly regulate bone mass. Both osteoblasts and osteoclasts express OT receptors (OTR), whose stimulation enhances bone mass. Consistent with this, mice deficient in OT or OTR display profoundly impaired bone formation. In contrast, bone resorption remains unaffected in OT deficiency because, even while OT stimulates the genesis of osteoclasts, it inhibits their resorptive function. Furthermore, in addition to its origin from the pituitary, OT is also produced by bone marrow osteoblasts acting as paracrine-autocrine regulator of bone formation modulated by estrogens. In turn, the power of estrogen to increase bone mass is OTR-dependent. Therefore, OTR−/− mice injected with 17β-estradiol do not show any effects on bone formation parameters, while the same treatment increases bone mass in wild-type mice. These findings together provide evidence for an anabolic action of OT in regulating bone mass and suggest that bone marrow OT may enhance the bone-forming action of estrogen through an autocrine circuit. This established new physiological role for OT in the maintenance of skeletal integrity further suggests the potential use of this hormone for the treatment of osteoporosis. PMID:25209411

  11. Bone stress lesions in ballet dancers: scintigraphic assessment.

    PubMed

    Nussbaum, A R; Treves, S T; Micheli, L

    1988-04-01

    Ballet dancers are athletes susceptible to ligamentous and bony injury. We reviewed retrospectively the bone scans (technetium-99m methylene diphosphonate) of 23 ballet dancers with pain in the back and/or lower extremities to determine the usefulness of scintigraphy in the detection of stress lesions of bone. The scintigraphic studies in 19 dancers identified multiple areas of stress injury in both symptomatic and asymptomatic locations. Thirteen dancers had 22 stress fractures (microfractures of trabeculae with associated bone repair) manifested by an intense focus of increased uptake of radiopharmaceutical, and 19 dancers had stress reactions (areas of accelerated remodeling and resorption of bone) demonstrated by diffusely increased uptake of radiotracer. Ten of the 13 dancers with stress fractures were symptomatic and six of the 19 dancers with stress reactions were symptomatic. The radiographs of 10 dancers with positive bone scans were normal or showed no distinction between acute and chronic injuries. Stress fractures were most prevalent in the feet, and stress reactions were most prevalent in the tibiae. The study confirmed that ballet dancers sustain significant bone stress in their legs and feet. Our results show that scintigraphy can be used to detect stress fractures and stress reactions at both symptomatic and asymptomatic sites in this population.

  12. Bone stability around dental implants: Treatment related factors.

    PubMed

    Heinemann, Friedhelm; Hasan, Istabrak; Bourauel, Christoph; Biffar, Reiner; Mundt, Torsten

    2015-05-01

    The bone bed around dental implants is influenced by implant and augmentation materials, as well as the insertion technique used. The primary influencing factors include the dental implant design, augmentation technique, treatment protocol, and surgical procedure. In addition to these treatment-related factors, in the literature, local and systemic factors have been found to be related to the bone stability around implants. Bone is a dynamic organ that optimises itself depending on the loading condition above it. Bone achieves this optimisation through the remodelling process. Several studies have confirmed the importance of the implant design and direction of the applied force on the implant system. Equally dispersed strains and stresses in the physiological range should be achieved to ensure the success of an implant treatment. If a patient wishes to accelerate the treatment time, different protocols can be chosen. However, each one must consider the amount and quality of the available local bone. Immediate implantation is only successful if the primary stability of the implant can be provided from residual bone in the socket after tooth extraction. Immediate loading demands high primary stability and, sometimes, the distribution of mastication forces by splinting or even by inserting additional implants to ensure their success. Augmentation materials with various properties have been developed in recent years. In particular, resorption time and stableness affect the usefulness in different situations. Hence, treatment protocols can optimise the time for simultaneous implant placements or optimise the follow-up time for implant placement.

  13. Combined application of low-intensity pulsed ultrasound and functional electrical stimulation accelerates bone-tendon junction healing in a rabbit model.

    PubMed

    Hu, Jianzhong; Qu, Jin; Xu, Daqi; Zhang, Tao; Qin, Ling; Lu, Hongbin

    2014-02-01

    The objective of this study was to elucidate the combined use of low-intensity pulsed ultrasound (LIPUS) and functional electrical stimulation (FES) on patella-patellar tendon (PPT) junction healing using a partial patellectomy model in rabbits. LIPUS was delivered continuously starting day 3 postoperative until week 6. FES was applied on quadriceps muscles to induce tensile force to the repaired PPT junction 5 days per week for 6 weeks since week 7 postoperatively. Forty rabbits with partial patellectomy were randomly divided into four groups: control, LIPUS alone, FES alone, and LIPUS + FES groups. At week 12, the PPT complexes were harvested for histology, radiographs, peripheral quantitative computed tomography, and biomechanical testing. There was better remodeling of newly formed bone and fibrocartilage zone in the three treatment groups compared with the control group. LIPUS and/or FES treatments significantly increased the area and bone mineral content of new bone. The failure load and ultimate strength of PPT complex were also highly improved in the three treatment groups. More new bone formed and higher tensile properties were showed in the LIPUS + FES group compared with the LIPUS or FES alone groups. Early LIPUS treatment and later FES treatment showed the additive effects of accelerating PPT junction healing.

  14. Management of Buccal Gap and Resorption of Buccal Plate in Immediate Implant Placement: A Clinical Case Report

    PubMed Central

    Mehta, Hardik; Shah, Sheekha

    2015-01-01

    When a dental implant is placed into a fresh extraction socket, a space between the implant periphery and surrounding bone occurs. A gap can occur on any aspect of an immediately placed implant: Buccal, lingual or proximally. The objective of immediate implant placement is to provide an osseointegrated fixture suitable for an aesthetic and functional restoration. Bone fill in the gap between the implant and the peripheral bone is important. Surgical management of the buccal gap to obtain an optimal result is controversial and confusing with respect to the best techniques to achieve the following: Optimal bone fills in the gap, most coronal level of bone-to-implant contact, and the least amount of buccal bone loss and soft tissue recession. This clinical case report illustrates the management of the buccal gap and reducing buccal plate resorption when contemplating immediate implant placement. PMID:26225110

  15. 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. PMID:27617358

  16. Acceleration of tendon-bone healing in anterior cruciate ligament reconstruction using an enamel matrix derivative in a rat model.

    PubMed

    Kadonishi, Y; Deie, M; Takata, T; Ochi, M

    2012-02-01

    We examined whether enamel matrix derivative (EMD) could improve healing of the tendon-bone interface following reconstruction of the anterior cruciate ligament (ACL) using a hamstring tendon in a rat model. ACL reconstruction was performed in both knees of 30 Sprague-Dawley rats using the flexor digitorum tendon. The effect of commercially available EMD (EMDOGAIN), a preparation of matrix proteins from developing porcine teeth, was evaluated. In the left knee joint the space around the tendon-bone interface was filled with 40 µl of EMD mixed with propylene glycol alginate (PGA). In the right knee joint PGA alone was used. The ligament reconstructions were evaluated histologically and biomechanically at four, eight and 12 weeks (n = 5 at each time point). At eight weeks, EMD had induced a significant increase in collagen fibres connecting to bone at the tendon-bone interface (p = 0.047), whereas the control group had few fibres and the tendon-bone interface was composed of cellular and vascular fibrous tissues. At both eight and 12 weeks, the mean load to failure in the treated specimens was higher than in the controls (p = 0.009). EMD improved histological tendon-bone healing at eight weeks and biomechanical healing at both eight and 12 weeks. EMD might therefore have a human application to enhance tendon-bone repair in ACL reconstruction.

  17. Resorption Rate Tunable Bioceramic: Si, Zn-Modified Tricalcium Phosphate

    SciTech Connect

    Wei, Xiang

    2006-01-01

    This dissertation is organized in an alternate format. Several manuscripts which have already been published or are to be submitted for publication have been included as separate chapters. Chapter 1 is a general introduction which describes the dissertation organization and introduces the human bone and ceramic materials as bone substitute. Chapter 2 is the background and literature review on dissolution behavior of calcium phosphate, and discussion of motivation for this research. Chapter 3 is a manuscript entitled ''Si,Zn-modified tricalcium phosphate: a phase composition and crystal structure study'', which was published in ''Key Engineering Materials'' [1]. Chapter 4 gives more crystal structure details by neutron powder diffraction, which identifies the position for Si and Zn substitution and explains the stabilization mechanism of the structure. A manuscript entitled ''Crystal structure analysis of Si, Zn-modified Tricalcium phosphate by Neutron Powder Diffraction'' will be submitted to Biomaterials [2]. Chapter 5 is a manuscript, entitled ''Dissolution behavior and cytotoxicity test of Si, Zn-modified tricalcium phosphate'', which is to be submitted to Biomaterials [3]. This paper discusses the additives effect on the dissolution behavior of TCP, and cytotoxicity test result is also included. Chapter 6 is the study of hydrolysis process of {alpha}-tricalcium phosphate in the simulated body fluid, and the phase development during drying process is discussed. A manuscript entitled ''Hydrolysis of {alpha}-tricalcium phosphate in simulated body fluid and phase transformation during drying process'' is to be submitted to Biomaterials [4]. Ozan Ugurlu is included as co-authors in these two papers due to his TEM contributions. Appendix A is the general introduction of the materials synthesis, crystal structure and preliminary dissolution result. A manuscript entitled ''Resorption rate tunable bioceramic: Si and Zn-modified tricalcium phosphate'' was published in

  18. Uranium inhibits bone formation in physiologic alveolar bone modeling and remodeling

    SciTech Connect

    Ubios, A.M.; Guglielmotti, M.B.; Steimetz, T.; Cabrini, R.L. )

    1991-02-01

    The toxic effect of uranium (U) on bone modeling and remodeling was studied by performing histomorphometric measurements in the periodontal cortical bone of rats. Two different single intraperitoneal doses of uranyl nitrate (238U) were administered to two sets of rats respectively (2 and 0.8 mg/kg body wt). Rats treated with the first dose were killed 14 days postinjection (PI) and those treated with the second were killed 14, 30, and 60 days PI. The results revealed a decrease in bone formation in rats treated with uranium. On the remodeling side the decrease in bone formation was coupled to an increase in bone resorption on the 14th day PI. On the modeling side no bone resorption was observed and the decrease in bone formation was linked to an increase in resting bone zones. Bone formation depression as a key event in U intoxication is stressed.

  19. Sika Deer Antler Collagen Type I-Accelerated Osteogenesis in Bone Marrow Mesenchymal Stem Cells via the Smad Pathway

    PubMed Central

    Li, Na; Zhang, Min; Drummen, Gregor P. C.; Zhao, Yu; Tan, Yin Fen; Luo, Su; Qu, Xiao Bo

    2016-01-01

    Deer antler preparations have been used to strengthen bones for centuries. It is particularly rich in collagen type I. This study aimed to unravel part of the purported bioremedial effect of Sika deer antler collagen type I (SDA-Col I) on bone marrow mesenchymal stem cells. The results suggest that SDA-Col I might be used to promote and regulate osteoblast proliferation and differentiation. SDA-Col I might potentially provide the basis for novel therapeutic strategies in the treatment of bone injury and/or in scaffolds for bone replacement strategies. Finally, isolation of SDA-Col I from deer antler represents a renewable, green, and uncomplicated way to obtain a biomedically valuable therapeutic. PMID:27066099

  20. Sika Deer Antler Collagen Type I-Accelerated Osteogenesis in Bone Marrow Mesenchymal Stem Cells via the Smad Pathway.

    PubMed

    Li, Na; Zhang, Min; Drummen, Gregor P C; Zhao, Yu; Tan, Yin Fen; Luo, Su; Qu, Xiao Bo

    2016-01-01

    Deer antler preparations have been used to strengthen bones for centuries. It is particularly rich in collagen type I. This study aimed to unravel part of the purported bioremedial effect of Sika deer antler collagen type I (SDA-Col I) on bone marrow mesenchymal stem cells. The results suggest that SDA-Col I might be used to promote and regulate osteoblast proliferation and differentiation. SDA-Col I might potentially provide the basis for novel therapeutic strategies in the treatment of bone injury and/or in scaffolds for bone replacement strategies. Finally, isolation of SDA-Col I from deer antler represents a renewable, green, and uncomplicated way to obtain a biomedically valuable therapeutic. PMID:27066099

  1. BAR Proteins PSTPIP1/2 Regulate Podosome Dynamics and the Resorption Activity of Osteoclasts

    PubMed Central

    Sztacho, Martin; Segeletz, Sandra; Sanchez-Fernandez, Maria Arantzazu; Czupalla, Cornelia; Niehage, Christian; Hoflack, Bernard

    2016-01-01

    Bone resorption in vertebrates relies on the ability of osteoclasts to assemble F-actin-rich podosomes that condense into podosomal belts, forming sealing zones. Sealing zones segregate bone-facing ruffled membranes from other membrane domains, and disassemble when osteoclasts migrate to new areas. How podosome/sealing zone dynamics is regulated remains unknown. We illustrate the essential role of the membrane scaffolding F-BAR-Proline-Serine-Threonine Phosphatase Interacting Proteins (PSTPIP) 1 and 2 in this process. Whereas PSTPIP2 regulates podosome assembly, PSTPIP1 regulates their disassembly. PSTPIP1 recruits, through its F-BAR domain, the protein tyrosine phosphatase non-receptor type 6 (PTPN6) that de-phosphophorylates the phosphatidylinositol 5-phosphatases SHIP1/2 bound to the SH3 domain of PSTPIP1. Depletion of any component of this complex prevents sealing zone disassembly and increases osteoclast activity. Thus, our results illustrate the importance of BAR domain proteins in podosome structure and dynamics, and identify a new PSTPIP1/PTPN6/SHIP1/2-dependent negative feedback mechanism that counterbalances Src and PI(3,4,5)P3 signalling to control osteoclast cell polarity and activity during bone resorption. PMID:27760174

  2. Tooth resorption in the Swedish Eurasion lynx (Lynx lynx).

    PubMed

    Pettersson, Ann

    2010-01-01

    The etiology of tooth resorption in the domestic cat remains unknown. The high prevalence and progressive nature of the disease complicates defining healthy control groups. In order to evaluate the possible influence of various life style changes on the prevalence of tooth resorption, healthy control groups are a prerequisite. This paper presents a prevalence study for tooth resorption in a free-ranging wild felidae population. Skulls from 46 free-ranging Eurasian lynx (Lynx lynx) were examined. The age of the animals had previously been estimated based on cementum annuli in the maxillary right canine tooth. The dental examination included both dental probing and radiographic imaging. Complicated fractures of the canine teeth were found in 9/46 (19.5%) skulls. In one fractured canine, apical root resorption and periapical lucency was detected. The root resorption was attributed to inflammatory resorption as a consequence of the initial dental trauma and necrotic pulp. No signs of tooth resorption were found in the remaining teeth. Supernumerary roots were detected in 18/46 skulls (39.1 %). Supernumerary "peg" teeth caudal to the mandibular first molar tooth were detected in 6/46 (13.0%) skulls. Although further studies on dental ultra-structure are needed, the Swedish Eurasian lynx may, in the future, be useful as a healthy comparative model for studies on the etiopathogenesis of tooth resorption in the domestic cat. PMID:21322429

  3. Tooth resorption in the Swedish Eurasion lynx (Lynx lynx).

    PubMed

    Pettersson, Ann

    2010-01-01

    The etiology of tooth resorption in the domestic cat remains unknown. The high prevalence and progressive nature of the disease complicates defining healthy control groups. In order to evaluate the possible influence of various life style changes on the prevalence of tooth resorption, healthy control groups are a prerequisite. This paper presents a prevalence study for tooth resorption in a free-ranging wild felidae population. Skulls from 46 free-ranging Eurasian lynx (Lynx lynx) were examined. The age of the animals had previously been estimated based on cementum annuli in the maxillary right canine tooth. The dental examination included both dental probing and radiographic imaging. Complicated fractures of the canine teeth were found in 9/46 (19.5%) skulls. In one fractured canine, apical root resorption and periapical lucency was detected. The root resorption was attributed to inflammatory resorption as a consequence of the initial dental trauma and necrotic pulp. No signs of tooth resorption were found in the remaining teeth. Supernumerary roots were detected in 18/46 skulls (39.1 %). Supernumerary "peg" teeth caudal to the mandibular first molar tooth were detected in 6/46 (13.0%) skulls. Although further studies on dental ultra-structure are needed, the Swedish Eurasian lynx may, in the future, be useful as a healthy comparative model for studies on the etiopathogenesis of tooth resorption in the domestic cat.

  4. NSAIDs can have adverse effects on bone healing.

    PubMed

    van Esch, Robert W; Kool, Maurice M; van As, Saskia

    2013-08-01

    The science of osteoimmunology, a relatively new field of research, reveals the important interactions between the immune system and skeletal system. Interactions occur between prostaglandin metabolism, inflammatory proteins and bone metabolism. Systemic as well as local sources of inflammation appear to be actively involved in both bone formation and resorption. Non Steroidal Anti-Inflammatory Drugs (NSAIDs) can play a detrimental role in bone fractures, opposing the aim of the intervention, and can have such a negative impact on the synthesis of prostaglandins that they could even promote bone resorption. When used for a prolonged time, NSAIDs can also cause the development of an inflammatory cascade starting from the gastro-intestinal system, possibly resulting in bone resorption. Several studies show that the use of either selective or non-selective NSAIDs are intimately related to disturbances in immunological allostasis, bone metabolism and the inhibition or impediment of bone healing. PMID:23680000

  5. 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. PMID:24322885

  6. Quantification of Condylar Resorption in TMJ Osteoarthritis

    PubMed Central

    Cevidanes, LHS; Hajati, A-K; Paniagua, B; Lim, PF; Walker, DG; Palconet, G; Nackley, AG; Styner, M; Ludlow, JB; Zhu, H; Phillips, C

    2010-01-01

    OBJECTIVE This study was performed to determine the condylar morphological variation of osteoarthritic (OA) and asymptomatic temporomandibular joints (TMJ) and to determine its correlation with pain intensity and duration. STUDY DESIGN Three dimensional surface models of mandibular condyles were constructed from Cone-Beam CT images of 29 female patients with TMJ OA (Research Diagnostic Criteria for Temporomandibular Disorders Group III) and 36 female asymptomatic subjects. Shape Correspondence was used to localize and quantify the condylar morphology. Statistical analysis was performed with MANCOVA analysis using Hotelling T2 metric based on covariance matrices, and Pearson correlation. RESULTS OA condylar morphology was statistically significantly different from the asymptomatic condyles (p<0.05). 3D morphological variation of the OA condyles was significantly correlated with pain intensity and duration. CONCLUSION 3D quantification of condylar morphology revealed profound differences between OA and asymptomatic condyles and the extent of the resorptive changes paralleled pain severity and duration. PMID:20382043

  7. [Resorption of hydrocyanic acid from linseed].

    PubMed

    Schulz, V; Löffler, A; Gheorghiu, T

    1983-01-01

    Resorption of hydrocyanic acid after ingestion of linseed was investigated in 20 healthy volunteers and 5 patients. The persons investigated took a single dose of 30 g or of 100 g of linseed or they received throughout several weeks 15 g. t.i.d. One volunteer also took for purposes of comparison bitter almonds or potassium cyanide. Before, during and after the periods of ingestion plasma levels of hydrocyanic acid and of thiocyanate were normal. During long-term trials urinary excretion of thiocyanate was monitored regularly. Intake of linseed even in extremely high dosages never caused significant rises of plasma thiocyanate levels; this, however, was the case after intake of bitter almonds or potassium cyanide. Thus, it can be excluded, that intoxication by hydrocyanic acid can be caused by linseed. Long-term intake of linseed however, raised plasma levels of thiocyanate significantly; at the same time urinary excretion of thiocyanate increased. PMID:6302421

  8. [Resorption of hydrocyanic acid from linseed].

    PubMed

    Schulz, V; Löffler, A; Gheorghiu, T

    1983-01-01

    Resorption of hydrocyanic acid after ingestion of linseed was investigated in 20 healthy volunteers and 5 patients. The persons investigated took a single dose of 30 g or of 100 g of linseed or they received throughout several weeks 15 g. t.i.d. One volunteer also took for purposes of comparison bitter almonds or potassium cyanide. Before, during and after the periods of ingestion plasma levels of hydrocyanic acid and of thiocyanate were normal. During long-term trials urinary excretion of thiocyanate was monitored regularly. Intake of linseed even in extremely high dosages never caused significant rises of plasma thiocyanate levels; this, however, was the case after intake of bitter almonds or potassium cyanide. Thus, it can be excluded, that intoxication by hydrocyanic acid can be caused by linseed. Long-term intake of linseed however, raised plasma levels of thiocyanate significantly; at the same time urinary excretion of thiocyanate increased.

  9. Clinical Management of Two Root Resorption Cases in Endodontic Practice.

    PubMed

    Mincik, Jozef; Urban, Daniel; Timkova, Silvia

    2016-01-01

    Root resorption is a pathological process involving loss of hard dental tissues. It may occur as a consequence of dental trauma, orthodontic treatment, and bleaching, and occasionally it accompanies periodontal disease. Although the mechanism of resorption process is examined in detail, its etiology is not fully understood. Wide open apical foramen is more difficult to manage and the root canal may often overfill. In this report we present two cases of root resorption and describe means for its clinical management. We conclude that useful measure of a success or failure in managing root resorption is the persistence of the resorption process. It is a clear sign of an active ongoing inflammatory process and shows the clinical need for retreatment. PMID:27648314

  10. Clinical Management of Two Root Resorption Cases in Endodontic Practice

    PubMed Central

    2016-01-01

    Root resorption is a pathological process involving loss of hard dental tissues. It may occur as a consequence of dental trauma, orthodontic treatment, and bleaching, and occasionally it accompanies periodontal disease. Although the mechanism of resorption process is examined in detail, its etiology is not fully understood. Wide open apical foramen is more difficult to manage and the root canal may often overfill. In this report we present two cases of root resorption and describe means for its clinical management. We conclude that useful measure of a success or failure in managing root resorption is the persistence of the resorption process. It is a clear sign of an active ongoing inflammatory process and shows the clinical need for retreatment. PMID:27648314

  11. Clinical Management of Two Root Resorption Cases in Endodontic Practice

    PubMed Central

    2016-01-01

    Root resorption is a pathological process involving loss of hard dental tissues. It may occur as a consequence of dental trauma, orthodontic treatment, and bleaching, and occasionally it accompanies periodontal disease. Although the mechanism of resorption process is examined in detail, its etiology is not fully understood. Wide open apical foramen is more difficult to manage and the root canal may often overfill. In this report we present two cases of root resorption and describe means for its clinical management. We conclude that useful measure of a success or failure in managing root resorption is the persistence of the resorption process. It is a clear sign of an active ongoing inflammatory process and shows the clinical need for retreatment.

  12. Encapsulation of bone morphogenic protein-2 with Cbfa1-overexpressing osteogenic cells derived from human embryonic stem cells in hydrogel accelerates bone tissue regeneration.

    PubMed

    Kim, Min Jung; Park, Ji Sun; Kim, Sinae; Moon, Sung-Hwan; Yang, Han Na; Park, Keun-Hong; Chung, Hyung-Min

    2011-08-01

    Bone tissue defects caused by trauma and disease are significant problems in orthopedic surgery. Human embryonic stem cells (hESCs) hold great promise for the treatment of bone tissue disease in regenerative medicine. In this study, we have established an effective method for the differentiation of osteogenic cells derived from hESCs using a lentiviral vector containing the transcription factor Cbfa1. Differentiation was initiated in embryoid body formation of Cbfa1-expressing hESCs, resulting in a highly purified population of osteogenic cells based on flow cytometric analysis. These cells also showed characteristics of osteogenic cells in vitro, as determined by reverse-transcription (RT)-polymerase chain reaction and immunocytochemistry using osteoblast-specific markers. We also evaluated the regenerative potential of Cbfa1-expressing cells derived from hESCs (hESC-CECs) compared with hESCs and the osteogenic effects of bone morphogenic protein-2 (BMP2) encapsulated in thermoreversible hydrogel in vivo. hESC-CECs were embedded in hydrogel constructs enriched with BMP2 to promote bone regeneration. We observed prominent mineralization and the formation of nodule-like structures using von Kossa and alizarin red S staining. In addition, the expression patterns of osteoblast-specific genes were verified by RT-polymerase chain reaction, and immunohistochemical analysis revealed that collagen type 1 and Cbfa1 were highly expressed in hESC-CECs compared with other cell types. Taken together, our results