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

NASA Technical Reports Server (NTRS)

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

2015-01-01

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

Trace elements have beneficial, as well as detrimental effects on bone homeostasis.

PubMed

Zofkova, I; Davis, M; Blahos, J

2017-07-18

The protective role of nutrition factors such as calcium, vitamin D and vitamin K for the integrity of the skeleton is well understood. In addition, integrity of the skeleton is positively influenced by certain trace elements (e.g. zinc, copper, manganese, magnesium, iron, selenium, boron and fluoride) and negatively by others (lead, cadmium, cobalt). Deficiency or excess of these elements influence bone mass and bone quality in adulthood as well as in childhood and adolescence. However, some protective elements may become toxic under certain conditions, depending on dosage (serum concentration), duration of treatment and interactions among individual elements. We review the beneficial and toxic effects of key elements on bone homeostasis.

Protective Effects of Selected Botanical Agents on Bone.

PubMed

Jolly, James Jam; Chin, Kok-Yong; Alias, Ekram; Chua, Kien Hui; Soelaiman, Ima Nirwana

2018-05-11

Osteoporosis is a serious health problem affecting more than 200 million elderly people worldwide. The early symptoms of this disease are hardly detectable. It causes progressive bone loss, which ultimately renders the patients susceptible to fractures. Osteoporosis must be prevented because the associated fragility fractures result in high morbidity, mortality, and healthcare costs. Many plants used in herbal medicine contain bioactive compounds possessing skeletal protective effects. This paper explores the anti-osteoporotic properties of selected herbal plants, including their actions on osteoblasts (bone forming cells), osteoclasts (bone resorbing cells), and bone remodelling. Some of the herbal plant families included in this review are Berberidaceae, Fabaceae, Arecaceae, Labiatae, Simaroubaceaea, and Myrsinaceae. Their active constituents, mechanisms of action, and pharmaceutical applications were discussed. The literature shows that very few herbal plants have undergone human clinical trials to evaluate their pharmacological effects on bone to date. Therefore, more intensive research should be performed on these plants to validate their anti-osteoporotic properties so that they can complement the currently available conventional drugs in the battle against osteoporosis.

Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Yoon, Sung-Hee; Chen, Jinghan; Grynpas, Marc D; Mitchell, Jane

2016-09-01

Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate. Copyright © 2016. Published by Elsevier Inc.

Synergistic Effect of Green Tea Polyphenols and Vitamin D on Chronic Inflammation-Induced Bone Loss in Female Rats

USDA-ARS?s Scientific Manuscript database

Our recent study demonstrated a bone-protective role of green tea polyphenols (GTPs), extracted from green tea, in chronic inflammation-induced bone loss of female rats through reduction of inflammation and oxidative stress. This study further examines effects of GTPs in conjunction with vitamin D (...

Peripheral-specific y2 receptor knockdown protects mice from high-fat diet-induced obesity.

PubMed

Shi, Yan-Chuan; Lin, Shu; Castillo, Lesley; Aljanova, Aygul; Enriquez, Ronaldo F; Nguyen, Amy D; Baldock, Paul A; Zhang, Lei; Bijker, Martijn S; Macia, Laurence; Yulyaningsih, Ernie; Zhang, Hui; Lau, Jackie; Sainsbury, Amanda; Herzog, Herbert

2011-11-01

Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone. These changes occur in association with significant increases in energy expenditure, respiratory exchange ratio, and physical activity and despite concurrent hyperphagia. On a chow diet, knockdown of peripheral Y2 receptors results in increased respiratory exchange ratio and physical activity with no effect on lean or bone mass, but decreases energy expenditure without effecting body weight or food intake. These results suggest that peripheral Y2 receptor signaling is critical in the regulation of oxidative fuel selection and physical activity and protects against the diet-induced obesity. The lack of effects on bone mass seen in this model further indicates that bone mass is primarily controlled by non-peripheral Y2 receptors. This study provides evidence that novel drugs that target peripheral rather than central Y2 receptors could provide benefits for the treatment of obesity and glucose intolerance without adverse effects on lean and bone mass, with the additional benefit of avoiding side effects often associated with pharmaceuticals that act on the central nervous system.

Bone-Protective Effects of Dried Plum in Postmenopausal Women: Efficacy and Possible Mechanisms

PubMed Central

Arjmandi, Bahram H.; Johnson, Sarah A.; Pourafshar, Shirin; Navaei, Negin; George, Kelli S.; Hooshmand, Shirin; Chai, Sheau C.; Akhavan, Neda S.

2017-01-01

Osteoporosis is an age-related chronic disease characterized by a loss of bone mass and quality, and is associated with an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to the cessation in ovarian hormone production, which causes accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. Certain lifestyle factors, including nutrition and exercise, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, accumulating evidence suggests that dried plum (Prunus domestica L.) is potentially an efficacious intervention for preventing and reversing bone mass and structural loss in an ovariectomized rat model of osteoporosis, as well as in osteopenic postmenopausal women. Here, we provide evidence supporting the efficacy of dried plum in preventing and reversing bone loss associated with ovarian hormone deficiency in rodent models and in humans. We end with the results of a recent follow-up study demonstrating that postmenopausal women who previously consumed 100 g dried plum per day during our one-year clinical trial conducted five years earlier retained bone mineral density to a greater extent than those receiving a comparative control. Additionally, we highlight the possible mechanisms of action by which bioactive compounds in dried plum exert bone-protective effects. Overall, the findings of our studies and others strongly suggest that dried plum in its whole form is a promising and efficacious functional food therapy for preventing bone loss in postmenopausal women, with the potential for long-lasting bone-protective effects. PMID:28505102

Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization.

PubMed

Azuma, Kotaro; Shiba, Sachiko; Hasegawa, Tomoka; Ikeda, Kazuhiro; Urano, Tomohiko; Horie-Inoue, Kuniko; Ouchi, Yasuyoshi; Amizuka, Norio; Inoue, Satoshi

2015-07-01

Vitamin K is a fat-soluble vitamin that is necessary for blood coagulation. In addition, it has bone-protective effects. Vitamin K functions as a cofactor of γ-glutamyl carboxylase (GGCX), which activates its substrates by carboxylation. These substrates are found throughout the body and examples include hepatic blood coagulation factors. Furthermore, vitamin K functions as a ligand of the nuclear receptor known as steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR). We have previously reported on the bone-protective role of SXR/PXR signaling by demonstrating that systemic Pxr-knockout mice displayed osteopenia. Because systemic Ggcx-knockout mice die shortly after birth from severe hemorrhage, the GGCX-mediated effect of vitamin K on bone metabolism has been difficult to evaluate. In this work, we utilized Ggcx-floxed mice to generate osteoblast-specific GGCX-deficient (Ggcx(Δobl/Δobl)) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of Ggcx(Δobl/Δobl) mice was significantly higher than that of control Col1-Cre (Ggcx(+/+)) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in Ggcx(Δobl/Δobl) mice. The mechanical properties of bones from Ggcx(Δobl/Δobl) mice tended to be stronger than those from control Ggcx(+/+) mice. These results suggest that GGCX in osteoblasts functions to prevent abnormal mineralization in bone formation, although this function may not be a prerequisite for the bone-protective effect of vitamin K. © 2015 American Society for Bone and Mineral Research.

Protective Effects of Selected Botanical Agents on Bone

PubMed Central

Jolly, James Jam; Alias, Ekram; Chua, Kien Hui; Soelaiman, Ima Nirwana

2018-01-01

Osteoporosis is a serious health problem affecting more than 200 million elderly people worldwide. The early symptoms of this disease are hardly detectable. It causes progressive bone loss, which ultimately renders the patients susceptible to fractures. Osteoporosis must be prevented because the associated fragility fractures result in high morbidity, mortality, and healthcare costs. Many plants used in herbal medicine contain bioactive compounds possessing skeletal protective effects. This paper explores the anti-osteoporotic properties of selected herbal plants, including their actions on osteoblasts (bone forming cells), osteoclasts (bone resorbing cells), and bone remodelling. Some of the herbal plant families included in this review are Berberidaceae, Fabaceae, Arecaceae, Labiatae, Simaroubaceaea, and Myrsinaceae. Their active constituents, mechanisms of action, and pharmaceutical applications were discussed. The literature shows that very few herbal plants have undergone human clinical trials to evaluate their pharmacological effects on bone to date. Therefore, more intensive research should be performed on these plants to validate their anti-osteoporotic properties so that they can complement the currently available conventional drugs in the battle against osteoporosis. PMID:29751644

Protective effect of egg yolk peptide on bone metabolism.

PubMed

Kim, Hye Kyung; Lee, Sena; Leem, Kang-Hyun

2011-03-01

Osteoporosis is a major health problem worldwide, and most current therapy used in osteoporosis treatment acts by either increasing bone formation or decreasing bone resorption. However, the adverse effects of these therapies may preclude their long-term use. We examined the effects of egg yolk water-soluble peptide (YPEP) on bone metabolism as an alternative to current therapeutic agents in ovariectomized (OVX) rats. In the first step, the in vitro effects of YPEP on bone loss were determined. The proliferation, collagen content, and alkaline phosphatase activity of preosteoblastic MC3T3-E1 cells and osteoclastogenesis from bone marrow-derived precursor cells were measured. The in vivo experiment confirmed the positive effect of YPEP on bone tissue. Three-month-old female Sprague-Dawley rats were either sham operated or ovariectomized and fed commercial chow diet or 0.1% YPEP-supplemented diet for 3 month. YPEP increased preosteoblastic MC3T3-E1 cell proliferation and alkaline phosphatase activity in a dose-dependent manner. Collagen content was also increased by YPEP treatment. Furthermore, YPEP potently suppressed osteoclastogenesis from bone marrow-derived precursor cells. YPEP (100 μg/mL) abolished the formation of osteoclasts positive for tartrate-resistant acid phosphatase. OVX rats supplemented with YPEP showed an osteoprotective effect, as the bone mineral density and cortical thickness in the tibia were increased compared with the OVX controls. Moreover, histological data indicate that YPEP prevented the cancellous bone loss induced by ovariectomy. None of these protective effects were observed in casein-treated rats. The present study suggests that YPEP is a promising alternative to current therapeutic agents for the management of osteoporosis.

Protective effects of total saponins from stem and leaf of Panax ginseng against cyclophosphamide-induced genotoxicity and apoptosis in mouse bone marrow cells and peripheral lymphocyte cells.

PubMed

Zhang, Qiu Hua; Wu, Chun Fu; Duan, Lian; Yang, Jing Yu

2008-01-01

Cyclophosphamide (CP), commonly used anti-cancer, induces oxidative stress and is cytotoxic to normal cells. It is very important to choice the protective agent combined CP to reduce the side effects in cancer treatment. Ginsenosides are biological active constituents of Panax ginseng C.A. Meyer that acts as the tonic agent for the cancer patients to reduce the side effects in the clinic application. Because CP is a pro-oxidant agent and induces oxidative stress by the generation of free radicals to decrease the activities of anti-oxidant enzymes, the protective effects of the total saponins from stem and leaf of P. ginseng C.A. Meyer (TSPG) act as an anti-oxidant agent against the decreased anti-oxidant enzymes, the genotoxicity and apoptosis induced by CP was carried out. The alkaline single cell gel electrophoresis was employed to detect DNA damage; flow cytometry assay and AO/EB staining assay were employed to measure cell apoptosis; the enzymatic anti-oxidants (T-SOD, CAT and GPx) and non-enzymatic anti-oxidant (GSH) were measured by the various colorimetric methods. CP induced the significant DNA damage in mouse peripheral lymphocytes in time- and dose-dependent manners, inhibited the activities of T-SOD, GPx and CAT, and decreased the contents of GSH in mouse blood, triggered bone marrow cell apoptosis at 6 and 12h. TSPG significantly reduced CP-induced DNA damages in bone marrow cells and peripheral lymphocyte cells, antagonized CP-induced reduction of T-SOD, GPx, CAT activities and the GSH contents, decreased the bone marrow cell apoptosis induced by CP. TSPG, significantly reduced the genotoxicity of CP in bone marrow cells and peripheral lymphocyte cells, and decreased the apoptotic cell number induced by CP in bone marrow cells. The effects of TSPG on T-SOD, GPx, CAT activities and GSH contents might partially contribute to its protective effects on CP-induced cell toxicities.

Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy.

PubMed

Luo, D; Ren, H; Li, T; Lian, K; Lin, D

2016-03-01

Osteocyte is the orchestrator of bone remolding and decline in osteocyte autophagy is involved in senile osteoporosis. Our results suggested that rapamycin, at least in part by activating osteocyte autophagy, reduced the severity of age-related bone changes in trabecular bone of old male rats. Previous literatures have showed that osteocyte is the orchestrator of bone remolding and age-related decline in osteocyte number is associated with senile osteoporosis. Autophagy is an important cellular protective mechanism which can preserve osteocyte viability and failure of autophagy in osteocyte with age has been linked to senile osteoporosis. The purpose of this study was to explore whether rapamycin, one activator of autophagy, has protective effects on senile osteoporosis through inducing osteocyte autophagy. Fifty-two 24-month-old male Sprague-Dawley (SD) rats were randomly divided into two groups. Rapamycin (1 mg/kg weight/day) or DMSO vehicle control was administered intraperitoneally for 12 weeks. BMD and bone microstructure were determined by Micro-CT. Fluorochrome labeling of the bones was performed to measure the mineral apposition rate (MAR). TRAP staining was performed to evaluate osteoclast number. The plasma levels of bone turnover markers were also analyzed. The effects of rapamycin on osteocyte autophagy were determined by immunohistochemistry, Western blot, and q-PCR. TUNEL was used to determine the prevalence of osteocyte apoptosis. Micro-CT evaluation demonstrated that rapamycin had a protective effect on age-related bone loss in trabecular bone. Besides, rapamycin resulted in an obvious increase of MAR and a decrease of osteoclast number in contrast to the control group. Furthermore, rapamycin also induced autophagy in osteocyte demonstrated by increased LC3-positive osteocyte and increased LC3 turnover. In addition, rats treated with rapamycin exhibited decreased apoptosis of osteocyte determined by TUNEL. These results suggested that rapamycin, at least in part by activating osteocyte autophagy, reduced the severity of age-related bone changes in trabecular bone of old male rats. Therefore, rapamycin might be a feasible therapeutic approach for senile osteoporosis.

Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow.

PubMed

Shen, J C; Zhang, Y C; Zhao, M F

2017-10-19

Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.

The protective effect of platelet released growth factors and bone augmentation (Bio-Oss®) on ethanol impaired osteoblasts.

PubMed

Sönmez, Tolga Taha; Bayer, Andreas; Cremer, Tillman; Hock, Jennifer Vanessa Phi; Lethaus, Bernd; Kweider, Nisreen; Wruck, Christoph Jan; Drescher, Wolf; Jahr, Holger; Lippross, Sebastian; Pufe, Thomas; Tohidnezhad, Mersedeh

2017-11-01

Chronic alcohol consumption is a known limiting factor for bone healing. One promising strategy to improve bone augmentation techniques with Bio-Oss ® in oral and maxillofacial surgery might be the supportive application of platelet-concentrated biomaterials as platelet-released growth factor (PRGF). To address this matter, we performed an in vitro study investigating the protective effects of PRGF and Bio-Oss ® in ethanol (EtOH) treated osteoblasts. The SAOS-2 osteosarcoma cell line, with and without EtOH pretreatment was used. The cell viability, proliferation and alkali phosphatase activity (ALP) after application of 0%, 5% and 10% PRGF and Bio-Oss ® were assessed. The application of PRGF and Bio-Oss ® in EtOH impaired osteoblasts showed a significant beneficial influence increasing the viability of the osteoblasts in cell culture. The synergistic effect of Bio-Oss ® and 5% PRGF on the proliferation of osteoblasts was also demonstrated. Bio-Oss ® only in combination with PRGF increases the alkaline phosphatase (ALP) activity in EtOH pretreated cells. These results indicate that the simultaneous application of PRGF and Bio-Oss ® inhibits EtOH induced bone healing impairment. Furthermore, in the cells, PRGF induced a protective mechanism which might promote bone regeneration. Copyright © 2017 Elsevier GmbH. All rights reserved.

Effects of thirty elements on bone metabolism.

PubMed

Dermience, Michael; Lognay, Georges; Mathieu, Françoise; Goyens, Philippe

2015-10-01

The human skeleton, made of 206 bones, plays vital roles including supporting the body, protecting organs, enabling movement, and storing minerals. Bones are made of organic structures, intimately connected with an inorganic matrix produced by bone cells. Many elements are ubiquitous in our environment, and many impact bone metabolism. Most elements have antagonistic actions depending on concentration. Indeed, some elements are essential, others are deleterious, and many can be both. Several pathways mediate effects of element deficiencies or excesses on bone metabolism. This paper aims to identify all elements that impact bone health and explore the mechanisms by which they act. To date, this is the first time that the effects of thirty minerals on bone metabolism have been summarized. Copyright © 2015 Elsevier GmbH. All rights reserved.

Synergy of bone marrow transplantation and curcumin ensue protective effects at early onset of diabetes in mice.

PubMed

Arivazhagan, Arivarasan; Krishna, Soni; Yadav, Shivangi; Shah, Harshit Rajesh; Kumar, Pravir; Ambasta, Rashmi Kumar

2015-07-01

The aim of this study was to investigate the early onset effects of diabetes on pro-angiogenic signaling pathway, total number of bone marrow cells, organs (pancreas and kidney) damage and the reversal effect of diabetes by combinatorial treatment of curcumin and bone marrow transplantation in streptozotocin (STZ) induced diabetic mice. In the present study, Streptozotocin induced diabetic mice were transplanted with bone marrow cells (2 × 10(6) ) followed by the administration of curcumin (80 mg/kg bodyweight). Effect of diabetes on the different organs was studied by H&E, Western blotting and immunofluorescence using vascular endothelial growth factor (VEGF), platelet/endothelial cell adhesion molecule (PECAM), insulin, Caspase-9 and Caspase-3 antibodies. The effect of diabetes results in the reduction of the total cell number and viability of the bone marrow cells, organ degeneration and lower VEGF/PECAM expression. However, transplantation with normal bone marrow cells significantly reduced the blood glucose levels (above normal range) and initiated the organ regeneration via the VEGF/PECAM mediated manner. Curcumin treatment further reduced the blood glucose level (near normal); and accelerated the organ regeneration, enhanced VEGF/PECAM expression and decreased caspase expression level in the organs. Curcumin also had a protective role against the glucotoxicity test performed on the bone marrow cells. This study suggests that bone marrow transplantation and curcumin administration is an effective treatment in reversing the early onset effects of diabetes via the VEGF/PECAM signaling pathway. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects

USDA-ARS?s Scientific Manuscript database

The mutual interplay between energy homeostasis and bone metabolism is an important emerging concept. Ghrelin and leptin antagonize each other in regulating energy balance, but the role of this interaction in bone metabolism is unknown. Using ghrelin receptor and leptin-deficient mice, we show that ...

Vitamin D supplementation protects against bone loss associated with chronic alcohol administration in female mice

USDA-ARS?s Scientific Manuscript database

Chronic alcohol consumption is detrimental to bone by decreasing bone mineral density (BMD) resulting in increased risk of osteoporosis risk and fracture, particularly in women. In moderation, alcohol is positively associated with increased BMD and reduced fracture risk. Alcohol's toxic effects ha...

[Obesity and bone metabolism].

PubMed

Holecki, Michał; Zahorska-Markiewicz, Barbara; Wiecek, Andrzej; Nieszporek, Teresa; Zak-Gołab, Agnieszka

2008-01-01

Both bone and adipose tissue change their size, shape and distribution during the whole human being's life. Many factors, including genetic factors, hormones and activity of nervous system are responsible for these changes. It is generally accepted that obesity has a protective effect on bone tissue. On the other hand some authors present an opposite results--the lack of beneficial effect of obesity on development of osteoporosis fractures. The aim of this article was to present and discuss the relations between adipose tissue and bone metabolism.

The Estrogen Receptor-α in Osteoclasts Mediates the Protective Effects of Estrogens on Cancellous But Not Cortical Bone

PubMed Central

Martin-Millan, Marta; Almeida, Maria; Ambrogini, Elena; Han, Li; Zhao, Haibo; Weinstein, Robert S.; Jilka, Robert L.; O'Brien, Charles A.; Manolagas, Stavros C.

2010-01-01

Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)α from the monocyte/macrophage cell lineage in mice (ERαLysM−/−) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERαLysM−/− were resistant to the proapoptotic effect of 17β-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERα knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERα was as effective as 17β-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERα. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERα. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton. PMID:20053716

Tissue Specific Expression Of Sprouty1 In Mice Protects Against High Fat Diet Induced Fat Accumulation, Bone Loss, And Metabolic Dysfunction

PubMed Central

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J.; Liaw, Lucy

2012-01-01

We recently characterized Sprouty1 (Spry1), a growth factor signaling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue specific Spry1 expression in mice resulted in increased bone mass and reduced body fat while conditional knockout of Spry1 had the opposite effect with decreased bone and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high fat diet-induced obesity, bone loss, and associated lipid abnormalities and demonstrate that Spry1 has a long-term protective effect on mice fed a high caloric diet. We studied diet-induced obesity in mice with fatty acid binding promoter (aP2)-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1 null mice, high fat diet increased body fat by 40%, impaired glucose regulation, and led to liver steatosis. However, over-expression of Spry1 led to 35% lower body fat, reduced bone loss, and normal metabolic function compared to single transgenics. This protective phenotype was associated with decreased circulating insulin (70%) and leptin (54%) compared to controls on a high fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45%. We show that conditional Spry1 expression in adipose tissue protects against high fat diet-induced obesity and associated bone loss. PMID:22142492

Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction.

PubMed

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J; Liaw, Lucy

2012-09-28

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

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

PubMed

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

2014-10-01

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

Glycemic control protects against trabecular bone microarchitectural damage in a juvenile male rat model of streptozotocin-induced diabetes.

PubMed

de Oliveira, Guilherme José Pimentel Lopes; Basso, Túlio Luiz Durigan; Fontanari, Lucas Amaral; Faloni, Ana Paula de Souza; Marcantonio, Élcio; Orrico, Silvana Regina Perez

2017-08-01

To determine which features of the bone microarchitecture are affected by established diabetes mellitus (DM) and the effectiveness of glycemic control in the protection of bone tissue. Sixty juvenile Wistar male rats were divided into three groups of 20 animals: a control group (C) that included healthy animals, a diabetic group (D) that included animals with induced diabetes, and a controlled diabetic group (CD) that included animals with induced diabetes that were treated with insulin. The animals were euthanized at the periods of 6 and 8 weeks after the induction of diabetes (10 animals per group/period). Vertebral L4 specimens were submitted to μCT analysis to assess the following parameters of the bone microarchitecture: bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular spacing (Tb.Sp). The D group exhibited lower values of BV/TV (%) and numbers of trabeculae compared with the C group at 6 and 8 weeks and compared with the CD group at 8 weeks. The CD group exhibited higher trabecular thickness values compared with the D group at 8 weeks. There were no differences between the groups regarding the spaces between the trabeculae. Induced diabetes affected the microarchitecture of the trabecular bone of the vertebrae by reducing the values of the majority of the parameters in relation to those of the control group. Glycemic control with insulin appears to protect bones from the effects of the hyperglycemia.

Lithium attenuates lead induced toxicity on mouse non-adherent bone marrow cells.

PubMed

Banijamali, Mahsan; Rabbani-Chadegani, Azra; Shahhoseini, Maryam

2016-07-01

Lead is a poisonous heavy metal that occurs in all parts of environment and causes serious health problems in humans. The aim of the present study was to investigate the possible protective effect of lithium against lead nitrate induced toxicity in non-adherent bone marrow stem cells. Trypan blue and MTT assays represented that exposure of the cells to different concentrations of lead nitrate decreased viability in a dose dependent manner, whereas, pretreatment of the cells with lithium protected the cells against lead toxicity. Lead reduced the number and differentiation status of bone marrow-derived precursors when cultured in the presence of colony stimulating factor (CSF), while the effect was attenuated by lithium. The cells treated with lead nitrate exhibited cell shrinkage, DNA fragmentation, anion superoxide production, but lithium prevented lead action. Moreover, apoptotic indexes such as PARP cleavage and release of HMGB1 induced by lead, were protected by lithium, suggesting anti-apoptotic effect of lithium. Immunoblot analysis of histone H3K9 acetylation indicated that lithium overcame lead effect on acetylation. In conclusion, lithium efficiently reduces lead toxicity suggesting new insight into lithium action which may contribute to increased cell survival. It also provides a potentially new therapeutic strategy for lithium and a cost-effective approach to minimize destructive effects of lead on bone marrow stem cells. Copyright © 2016 Elsevier GmbH. All rights reserved.

The protective effect of calcium against genotoxicity of lead acetate administration on bone marrow and spermatocyte cells of mice in vivo.

PubMed

Aboul-Ela, Ezzat I

2002-04-26

The protective effect of calcium given orally by gavage with two doses (40 and 80mg/kg body weight) was evaluated against clastogenecity induced by lead acetate with two concentrations (200 and 400mg/kg diet) on bone marrow and spermatocyte cells of mice in vivo. The parameter screened was percentage of chromosomal aberrations with and without gaps and sperm abnormalities. Statistical analyses indicated the protection efficacy of calcium with the high dose rather than the other in both types of mouse cells. The observation from the laboratory tests, dealing that lead acetate can be considered as an environmental genotoxic material. We recommended that it must be administered of calcium (as calcium chloride) as a protective agent to reduce the genotoxic effect of lead in the somatic and germ cells.

Partial Protection by Dietary Antioxidants Against Ethanol-Induced Osteopenia and Changes in Bone Morphology in Female Mice.

PubMed

Alund, Alexander W; Mercer, Kelly E; Pulliam, Casey F; Suva, Larry J; Chen, Jin-Ran; Badger, Thomas M; Ronis, Martin J J

2017-01-01

Chronic alcohol consumption leads to increased fracture risk and an elevated risk of osteoporosis by decreasing bone accrual through increasing osteoclast activity and decreasing osteoblast activity. We have shown that this mechanism involves the generation of reactive oxygen species (ROS) produced by NADPH oxidases. It was hypothesized that different dietary antioxidants, N-acetyl cysteine (NAC; 1.2 mg/kg/d), and α-tocopherol (Vit.E; 60 mg/kg/d) would be able to attenuate the NADPH oxidase-mediated ROS effects on bone due to chronic alcohol intake. To study the effects of these antioxidants, female mice received a Lieber-DeCarli liquid diet containing ethanol (EtOH) with or without additional antioxidant for 8 weeks. Tibias displayed decreased cortical bone mineral density in both the EtOH and EtOH + antioxidant groups compared to pair-fed (PF) and PF + antioxidant groups (p < 0.05). However, there was significant protection from trabecular bone loss in mice fed either antioxidant (p < 0.05). Microcomputed tomography analysis demonstrated a significant decrease in bone volume (bone volume/tissue volume) and trabecular number (p < 0.05), along with a significant increase in trabecular separation in the EtOH compared to PF (p < 0.05). In contrast, the EtOH + NAC and EtOH + Vit.E did not statistically differ from their respective PF controls. Ex vivo histologic sections of tibias were stained for nitrotyrosine, an indicator of intracellular damage by ROS, and tibias from mice fed EtOH exhibited significantly more staining than PF controls. EtOH treatment significantly increased the number of marrow adipocytes per mm as well as mRNA expression of aP2, an adipocyte marker in bone. Only NAC was able to reduce the number of marrow adipocytes to PF levels. EtOH-fed mice exhibited reduced bone length (p < 0.05) and had a reduced number of proliferating chondrocytes within the growth plate. NAC and Vit.E prevented this (p < 0.05). These data show that alcohol's pathological effects on bone extend beyond decreasing bone mass and suggest a partial protective effect of the dietary antioxidants NAC and Vit.E at these doses with regard to alcohol effects on bone turnover and bone morphology. Copyright © 2016 by the Research Society on Alcoholism.

Radio protective effect of black mulberry extract on radiation-induced damage in bone marrow cells and liver in the rat

NASA Astrophysics Data System (ADS)

Ghasemnezhad Targhi, Reza; Homayoun, Mansour; Mansouri, Somaieh; Soukhtanloo, Mohammad; Soleymanifard, Shokouhozaman; Seghatoleslam, Masoumeh

2017-01-01

Ionizing radiation by producing free radicals induces tissue oxidative stress and has clastogenic and cytotoxic effects. The radio protective effect of black mulberry extract (BME) has been investigated on liver tissue and bone marrow cells in the rat. Intraperitoneal (ip) administration of 200 mg/kg BME three days before and three days after 3 Gy and 6 Gy gamma irradiation significantly reduced the frequencies of micro nucleated polychromatic erythrocytes (MnPCEs) and micro nucleated norm chromatic erythrocyte (MnNCEs) and increased PCE/PCE+NCE ratio in rat bone marrow compared to the non-treated irradiated groups. Moreover, this concentration of BME extract decreased the level of malondialdehyde (MDA) and superoxide dismutase (SOD), as well as enhanced the total thiol content and catalase activity in rat's liver compared to the non-treated irradiated groups. It seems that BME extract with antioxidant activity reduced the genotoxicity and cytotoxicity induced by gamma irradiation in bone marrow cells and liver in the rat.

Osteoporosis and body composition.

PubMed

Crepaldi, G; Romanato, G; Tonin, P; Maggi, S

2007-01-01

The Epidemiologic Study on the Prevalence of Osteoporosis in Italy showed that the prevalence of osteoporosis among women and men aged 60 yr and over is 22.8% and 14.5%, respectively, giving rise to about 80,000 new fractures a yr. Sarcopenia is considered to be one of the main features of the aging process. It is characterized by a reduction in muscle mass and muscle strength, and affects women more than men. It is associated with a increased risk of fractures consequent upon a greater predisposition to falls, but also to the lack of bone remodeling due to reduced muscle mechanical strength. Muscle strength determines quality bone modifications such as density, strength, and microarchitecture. Variations in the ratios of cortical and muscle areas give rise to various types of osteoporosis, with different risks of fracture. Bone mineral density increases with body fat mass, and obesity has a protective effect against osteoporosis. This protective effect is explained by a combination of hormonal (peripheral aromatization of androgens to estrogens in adipose tissue) and mechanical factors (on weight-bearing bone sites), but the hormone leptin also probably mediates fat and bone mass. Serum leptin levels are closely related to body fat mass, and some findings suggest the peripheral effect of leptin, which exerts estrogenic effects, enhancing osteoblastic differentiation and inhibiting late adipocytic differentiation. The overall effect of leptin on bone results from a balance between negative central effects and positive direct peripheral effects, according to serum leptin levels.

Diet versus jaw bones: Lessons from experimental models and potential clinical implications.

PubMed

Montalvany-Antonucci, Carina Cristina; Zicker, Marina C; Oliveira, Marina C; Macari, Soraia; Madeira, Mila Fernandes M; Andrade, Ildeu; Ferreira, Adaliene Versiani M; Silva, Tarcilia A

2018-01-01

The consumption of different types of diets influences not only body health but the bone remodeling process as well. Nutritional components can directly affect maxillary and mandibular alveolar bone microarchitecture. In this review, we focus on the current knowledge regarding the influence of diets and dietary supplementation on alveolar bone. Accumulating evidence from experimental models suggests that carbohydrate- and fat-rich diets are detrimental for alveolar bone, whereas protective effects are associated with consumption of calcium, ω-3, and bioactive compounds. Little is known about the effects of protein-free and protein-rich diets, boron, vitamin C, vitamin E, zinc, and caffeine on alveolar bone remodeling. Adipokines and direct effects of nutritional components on bone cells are proposed mechanisms linking diet and bone. Results from animal models substantiate the role of nutritional components on alveolar bone. It is a well-built starting point for clinical studies on nutritional monitoring and intervention for patients with alveolar bone disorders, especially those who are treatment refractory. Copyright © 2017 Elsevier Inc. All rights reserved.

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation.

PubMed

Gan, Xueqi; Zhang, Ling; Liu, Beilei; Zhu, Zhuoli; He, Yuting; Chen, Junsheng; Zhu, Junfei; Yu, Haiyang

2018-04-20

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-α (TNF-α) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

PubMed Central

Kwak, Kyung Min; Kim, Ju-Young; Yu, Seung Hee; Lee, Sihoon; Kim, Yeun Sun; Park, Ie Byung; Kim, Kwang-Won; Lee, Kiyoung

2016-01-01

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model. PMID:27997588

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

PubMed

Eom, Young Sil; Gwon, A-Ryeong; Kwak, Kyung Min; Kim, Ju-Young; Yu, Seung Hee; Lee, Sihoon; Kim, Yeun Sun; Park, Ie Byung; Kim, Kwang-Won; Lee, Kiyoung; Kim, Byung-Joon

2016-01-01

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

A Model for Assessing the Clinical and Economic Benefits of Bone-forming Agents for Reducing Fractures in Postmenopausal Women at High, Near-term Risk of Osteoporotic Fracture.

PubMed

O'Hanlon, Claire E; Parthan, Anju; Kruse, Morgan; Cartier, Shannon; Stollenwerk, Bjorn; Jiang, Yawen; Caloyeras, John P; Crittenden, Daria B; Barron, Richard

2017-07-01

The goal of this study was to assess and compare the potential clinical and economic value of emerging bone-forming agents using the only currently available agent, teriparatide, as a reference case in patients at high, near-term (imminent, 1- to 2-year) risk of osteoporotic fractures, extending to a lifetime horizon with sequenced antiresorptive agents for maintenance treatment. Analyses were performed by using a Markov cohort model accounting for time-specific fracture protection effects of bone-forming agents followed by antiresorptive treatment with denosumab. The alternative bone-forming agent profiles were defined by using assumptions regarding the onset and total magnitude of protection against fractures with teriparatide. The model cohort comprised 70-year-old female patients with T scores below -2.5 and a previous vertebral fracture. Outcomes included clinical fractures, direct costs, and quality-adjusted life years. The simulated treatment strategies were compared by calculating their incremental "value" (net monetary benefit). Improvements in the onset and magnitude of fracture protection (vs the teriparatide reference case) produced a net monetary benefit of $17,000,000 per 10,000 treated patients during the (1.5-year) bone-forming agent treatment period and $80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab. Incorporating time-specific fracture effects in the Markov cohort model allowed for estimation of a range of cost savings, quality-adjusted life years gained, and clinical fractures avoided at different levels of fracture protection onset and magnitude. Results provide a first estimate of the potential "value" new bone-forming agents (romosozumab and abaloparatide) may confer relative to teriparatide. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Bone curvature changes can predict the impact of treatment on cartilage volume loss in knee osteoarthritis: data from a 2-year clinical trial.

PubMed

Raynauld, Jean-Pierre; Pelletier, Jean-Pierre; Delorme, Philippe; Dodin, Pierre; Abram, François; Martel-Pelletier, Johanne

2017-06-01

Knee bone curvature assessed by MRI was associated with OA cartilage loss. A recent knee OA trial demonstrated the superiority of chondroitin sulfate over celecoxib (comparator) at reducing cartilage volume loss (CVL) in the medial compartment (condyle). The main objectives were to identify which baseline bone curvature regions of interest (BCROI) best associated with CVL and investigate whether baseline BCROI and 2-year change are correlated with the protective effect of chondroitin sulphate on CVL. This post hoc analysis of a clinical trial used the according-to-protocol population (chondroitin sulphate, n = 57; celecoxib, n = 63) baseline and 2-year MRI to assess bone curvature and CVL. Global optimum search identified the BCROI in the medial condyle using celecoxib as reference. Statistical analyses were performed with Pearson's correlation, Mann-Whitney U -test, Student's t -test and analysis of covariance. The BCROI including the medial posterior condyle and lateral central condyle was found to correlate best with medial condyle CVL at 2 years ( r = 0.33, P = 0.008). In patients with a baseline BCROI value less than the median (more flattened bone), chondroitin sulphate demonstrated a protective effect on CVL compared with celecoxib in the medial compartment (P = 0.037). In patients with 2-year BCROI changes greater than the median (greater severity of bone flattening), chondroitin sulphate protected against CVL in the medial compartment, condyle and central plateau (P ⩽ 0.030). This study is the first to demonstrate the feasibility and usefulness of bone curvature measurements to predict effectiveness of OA treatment on CVL. The results identify bone curvature as a potential novel biomarker for knee OA clinical trials. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss.

PubMed

Gautam, Jyoti; Khedgikar, Vikram; Kushwaha, Priyanka; Choudhary, Dharmendra; Nagar, Geet Kumar; Dev, Kapil; Dixit, Preety; Singh, Divya; Maurya, Rakesh; Trivedi, Ritu

2017-03-01

Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.

Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine

PubMed Central

Yilmaz, Mehmet; Isaoglu, Unal; Uslu, Turan; Yildirim, Kadir; Seven, Bedri; Akcay, Fatih; Hacimuftuoglu, Ahmet

2013-01-01

Objectives: In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate. Materials and Methods: Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement. Results: The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm2), while that with the lowest BMD was methylprednisolone (0.123 g/cm2). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm2), but not when used in combination with methylprednisolone (0.124 g/cm2). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group. Conclusions: Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine. PMID:24014908

The Effects of Obesity on Murine Cortical Bone

NASA Astrophysics Data System (ADS)

Martin, Sophi

This dissertation details the effects of obesity on the mechanical properties and structure of cortical bone. Obesity is associated with greater bone mineral content that might be expected to protect against fracture, which has been observed in adults. Paradoxically however, the incidence of bone fractures has been found to increase in overweight and obese children and adolescents. Femora from adolescent and adult mice fed a high-fat diet are investigated for changes in shape, tissue structure, as well as tissue-level and whole-bone mechanical properties. Results indicate increased bone size, reduced size-independent mechanical properties, but maintained size-dependent mechanical properties. Other changes in cortical bone response to obesity are observed with advancing age. This study indicates that bone quantity and bone quality play important compensatory roles in determining fracture risk, and that fracture risk may not be lessened for adults as previously thought.

Bone turnover in wild type and pleiotrophin-transgenic mice housed for three months in the International Space Station (ISS).

PubMed

Tavella, Sara; Ruggiu, Alessandra; Giuliani, Alessandra; Brun, Francesco; Canciani, Barbara; Manescu, Adrian; Marozzi, Katia; Cilli, Michele; Costa, Delfina; Liu, Yi; Piccardi, Federica; Tasso, Roberta; Tromba, Giuliana; Rustichelli, Franco; Cancedda, Ranieri

2012-01-01

Bone is a complex dynamic tissue undergoing a continuous remodeling process. Gravity is a physical force playing a role in the remodeling and contributing to the maintenance of bone integrity. This article reports an investigation on the alterations of the bone microarchitecture that occurred in wild type (Wt) and pleiotrophin-transgenic (PTN-Tg) mice exposed to a near-zero gravity on the International Space Station (ISS) during the Mice Drawer System (MDS) mission, to date, the longest mice permanence (91 days) in space. The transgenic mouse strain over-expressing pleiotrophin (PTN) in bone was selected because of the PTN positive effects on bone turnover. Wt and PTN-Tg control animals were maintained on Earth either in a MDS payload or in a standard vivarium cage. This study revealed a bone loss during spaceflight in the weight-bearing bones of both strains. For both Tg and Wt a decrease of the trabecular number as well as an increase of the mean trabecular separation was observed after flight, whereas trabecular thickness did not show any significant change. Non weight-bearing bones were not affected. The PTN-Tg mice exposed to normal gravity presented a poorer trabecular organization than Wt mice, but interestingly, the expression of the PTN transgene during the flight resulted in some protection against microgravity's negative effects. Moreover, osteocytes of the Wt mice, but not of Tg mice, acquired a round shape, thus showing for the first time osteocyte space-related morphological alterations in vivo. The analysis of specific bone formation and resorption marker expression suggested that the microgravity-induced bone loss was due to both an increased bone resorption and a decreased bone deposition. Apparently, the PTN transgene protection was the result of a higher osteoblast activity in the flight mice.

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

PubMed

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

2017-10-15

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

Effects of different varieties of Maca (Lepidium meyenii) on bone structure in ovariectomized rats.

PubMed

Gonzales, Carla; Cárdenas-Valencia, Isaias; Leiva-Revilla, Johanna; Anza-Ramirez, Cecilia; Rubio, Julio; Gonzales, Gustavo F

2010-01-01

This study was designed to determine the effect of different varieties of maca (Lepidium meyenii) on bone structure in ovariectomized (OVX) rats. 36 female rats were randomly divided into 6 groups: sham and OVX rats treated with vehicle, estradiol (40 microg/kg), black, yellow or red maca (63 mg/ml) for 4 weeks. At the end of the treatment, uterine weight, femoral bone and lumbar vertebra histomorphology were assessed. Ovariectomy reduced weight, diameter and width of the femoral bone. Estradiol, black and red maca treatment reduced the effect of ovariectomy on these variables. Histological analyses revealed that estradiol, black and red maca treatments reversed the effect of ovariectomy by increasing the trabecular bone area in the second lumbar vertebra. Uterine weight was reduced in OVX rats, and estradiol but neither black nor red maca increased uterine weight. Red and black maca have protective effects on bone architecture in OVX rats without showing estrogenic effects on uterine weight. 2010 S. Karger AG, Basel.

Alleviating anastrozole induced bone toxicity by selenium nanoparticles in SD rats

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

Vekariya, Kiritkumar K.; Kaur, Jasmine; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

Aromatase inhibitors like anastrozole play an undisputed key role in the treatment of breast cancer, but on the other hand, various side effects like osteoporosis and increased risk of bone fracture accompany the chronic administration of these drugs. Here we show for the first time that selenium nanoparticles, when given in conjugation to anastrozole, lower the bone toxicity caused by anastrozole and thus reduce the probable damage to the bone. Selenium nanoparticles at a dose of 5 μg/ml significantly reduced the cell death caused by anastrozole (1 μM) in HOS (human osteoblast) cells. In addition, our results also highlighted thatmore » in female SD rat model, SeNPs (0.25, 0.5, 1 mg/kg/day) significantly prevented the decrease in bone density and increase in biochemical markers of bone resorption induced by anastrozole (0.2 mg/kg/day) treatment. Histopathological examination of the femurs of SeNP treated group revealed ossification, mineralization, calcified cartilaginous deposits and a marginal osteoclastic activity, all of which indicate a marked restorative action, suggesting the protective action of the SeNPs. Interestingly, SeNPs (1 mg/kg/day) also exhibited protective effect in ovariectomized rat model, by preventing osteoporosis, which signifies that bone loss due to estrogen deficiency can be effectively overcome by using SeNPs. - Highlights: ► SeNPs significantly reduce bone toxicity in anastrozole treated rats. ► SeNPs successfully prevented osteoporosis in ovariectomized rats. ► SeNP treatment lowered the levels of TRAP and increased the levels of ALKP.« less

Delta-Tocotrienol: Radiation Protection and Effects on Signal Transduction Pathways

DTIC Science & Technology

2011-06-15

Delta- Tocotrienol : Radiation Protection and Effects on Signal Transduction Pathways Venkataraman Srinivasan, PhD Mang Xiao, MD Principal...2011 2. REPORT TYPE 3. DATES COVERED 00-00-2011 to 00-00-2011 4. TITLE AND SUBTITLE Delta- Tocotrienol : Radiation Protection And Effects On...Mechanisms? 17 Survival of γ-irradiated mouse bone marrow and primary human hematopoietic CD34+ cells was significantly enhanced by Delta- tocotrienol (DT3

Synergistic effects of green tea polyphenols and alphacalcidol on chronic inflammation-induced bone loss in female rats

PubMed Central

Yeh, J. K.; Cao, J. J.; Tatum, O. L.; Dagda, R. Y.; Wang, J.-S.

2010-01-01

Summary Studies suggest that green tea polyphenols (GTP) or alphacalcidol is promising agent for preventing bone loss. Findings that GTP supplementation plus alphacalcidol administration increased bone mass via a decrease of oxidative stress and inflammation suggest a significant role of GTP plus alphacalcidol in bone health of patients with chronic inflammation. Introduction Studies have suggested that green tea polyphenols (GTP) or alphacalcidol are promising dietary supplements for preventing bone loss in women. However, the mechanism(s) related to the possible osteo-protective role of GTP plus D3 in chronic inflammation-induced bone loss is not well understood. Methods This study evaluated bioavailability, efficacy, and related mechanisms of GTP in combination with alphacalcidol in conserving bone loss in rats with chronic inflammation. A 12-week study of 2 (no GTP vs. 0.5% GTP in drinking water) × 2 (no alphacalcidol vs. 0.05 μg/kg alphacalcidol, 5×/week) factorial design in lipopolysaccharide-administered female rats was performed. In addition, a group receiving placebo administration was used to compare with a group receiving lipopolysaccharide administration only to evaluate the effect of lipopolysaccharide. Results Lipopolysaccharide administration resulted in lower values for bone mass, but higher values for serum tartrate-resistant acid phosphatase (TRAP), urinary 8-hydroxy-2′-deoxyguanosine, and mRNA expression of tumor necrosis factor-α and cyclooxygenase-2 in spleen. GTP supplementation increased urinary epigallocatechin and epicatechin concentrations. Both GTP supplementation and alphacalcidol administration resulted in a significant increase in bone mass, but a significant decrease in serum TRAP levels, urinary 8-hydroxydeoxyguanosine levels, and mRNA expression of tumor necrosis factor-α and cyclooxygenase-2 in spleen. A synergistic effect of GTP and alphacalcidol was observed in these parameters. Neither GTP nor alphacalcidol affected femoral bone area or serum osteocalcin. Conclusion We conclude that a bone-protective role of GTP plus alphacalcidol during chronic inflammation bone loss may be due to a reduction of oxidative stress damage and inflammation. PMID:20069278

Naringin protects against bone loss in steroid-treated inflammatory bowel disease in a rat model.

PubMed

Li, Chengli; Zhang, Jun; Lv, Fang; Ge, Xingtao; Li, Gang

2018-07-15

We observed the effects of naringin on bone loss in glucocorticoid-treated inflammatory bowel disease (IBD) in a rat model. The IBD model was established in Sprague-Dawley rats by administering 5.0% dextran sodium sulfate. Dexamethasone (DEX) and naringin were given at the second week. Blood, colon and bone samples were collected for biomarker assay, histological analysis or microCT analysis. Superoxide dismutase, catalase and malonaldehyde were measured in bone. A significant decrease of procollagen type 1 N-terminal propeptide (P1NP) level was observed in DEX-treated IBD groups compared with the control (p < 0.05). P1NP levels were dose-dependently increased in the presence of naringin intervention. Bone loss and decreased bone biomechanical properties were observed in DEX-treated IBD rats compared with control rats (p < 0.01). Naringin intervention protected against bone loss and decreased bone biomechanical properties. Bone formation related gene mRNA expressions were significantly decreased in DEX-treated IBD rats compared with control rats. Naringin administration reversed the down-regulation of the expressions of those genes. Naringin treatment reduced the oxidative stress in bone from DEX-treated IBD rats. Our data indicated that naringin may have great potential for the treatment of bone loss in glucocorticoid-treated IBD patients via blocking oxidative stress and promoting bone formation. Copyright © 2018 Elsevier Inc. All rights reserved.

The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial.

PubMed

Atkinson, Charlotte; Compston, Juliet E; Day, Nicholas E; Dowsett, Mitch; Bingham, Sheila A

2004-02-01

Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone. The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied. Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo-controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo. Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type I, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant. These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.

Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

NASA Technical Reports Server (NTRS)

Globus, Ruth

2015-01-01

Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of sequential proton and iron, radiation species relevant to spaceflight. When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerts pro-osteogenic effects apart from its previously demonstrated anti-resorptive action, which may be one of the mechanisms underlying its radioprotective effect on bone. In conclusion, a diet enriched in certain types of antioxidants may be useful as an intervention for radiation-induced bone loss.

Oleuropein and hydroxytyrosol protect rats' pups against bisphenol A induced hypothyroidism.

PubMed

Mahmoudi, Asma; Ghorbel, Hèla; Feki, Ines; Bouallagui, Zouhaier; Guermazi, Fadhel; Ayadi, Lobna; Sayadi, Sami

2018-04-27

Bisphenol A (BPA) can disturb the endocrine system and the organs that respond to endocrine signals in organisms, indirectly exposed during prenatal and/or early postnatal life. The present study was designed to assess the protective effect of phenolic compounds from olive leaves against BPA induced thyroid dysfunction and growth perturbation in young rats during lactation. The BPA disrupting effect on thyroid function was investigated by measuring changes in plasma levels of thyroid hormones. Free triiodothyronine (FT3) and thyroxine (FT4) were decreased in young rats breast-fed from mothers treated with bisphenol A. This effect was associated with an increase in the plasma level of thyroid-stimulating hormone (TSH). The histological and immunohistochemical study of the thyroid gland revealed a disturbance in morphological structure and thyroid cells function. Thyroid dysfunction led to a disruption in the skeletal bone growth of young rats. In fact, the infrared microspectroscopic analysis and histological examination of femoral bone showed significant changes in their histoarchitecture associated with a perturbation in the mechanism of bone tissue mineralization. The administration of oleuropein or hydroxytyrosol in BPA treated lactating mothers improved the thyroid cells function by enhancing thyroid hormone levels. Moreover, these phenolics increased the body growth characterized by an amelioration in the structure and the microstructure of femoral bone tissue. HPLC analysis of rats-breast milk indicated the presence of oleuropein and hydroxytyrosol, which could contribute to the protective effect against bisphenol A induced hypothyroidism in pups rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

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

Lim Yiting; Hedayati, Mohammad; Merchant, Akil A.

2012-11-01

Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 {mu}g per 17 g of body weight, 24 hours and 4 hoursmore » before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection against the harmful effects of LDR radiation.« less

The influence of collagen membrane and autogenous bone chips on bone augmentation in the anterior maxilla: a preclinical study.

PubMed

Janner, Simone F M; Bosshardt, Dieter D; Cochran, David L; Chappuis, Vivianne; Huynh-Ba, Guy; Jones, Archie A; Buser, Daniel

2017-11-01

To evaluate the effect of a resorbable collagen membrane and autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) on the healing of buccal dehiscence-type defects. The second incisors and the first premolars were extracted in the maxilla of eight mongrels. Reduced diameter, bone-level implants were placed 5 weeks later. Standardized buccal dehiscence-type defects were created and grafted at implant surgery. According to an allocation algorithm, the graft composition of each of the four maxillary sites was DBBM + membrane (group D + M), autogenous bone chips + DBBM + membrane (group A + D + M), DBBM alone (group D) or autogenous bone chips + DBBM (group A + D). Four animals were sacrificed after 3 weeks of healing and four animals after 12 weeks. Histological and histomorphometric analyses were performed on oro-facial sections. The pattern of bone formation and resorption within the grafted area showed high variability among the same group and healing time. The histomorphometric analysis of the 3-week specimens showed a positive effect of autogenous bone chips on both implant osseointegration and bone formation into the grafted region (P < 0.05). The presence of the collagen membrane correlated with greater bone formation around the DBBM particles and greater bone formation in the grafted region after 12 weeks of healing (P < 0.05). The oro-facial width of the augmented region at the level of the implant shoulder was significantly reduced in cases where damage of the protection splints occurred in the first week of healing (P < 0.05). The addition of autogenous bone chips and the presence of the collagen membrane increased bone formation around DBBM particles. Wound protection from mechanical noxa during early healing may be critical for bone formation within the grafted area. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PTH prevents the adverse effects of focal radiation on bone architecture in young rats.

PubMed

Chandra, Abhishek; Lan, Shenghui; Zhu, Ji; Lin, Tiao; Zhang, Xianrong; Siclari, Valerie A; Altman, Allison R; Cengel, Keith A; Liu, X Sherry; Qin, Ling

2013-08-01

Radiation therapy is a common treatment regimen for cancer patients. However, its adverse effects on the neighboring bone could lead to fractures with a great impact on quality of life. The underlying mechanism is still elusive and there is no preventive or curative solution for this bone loss. Parathyroid hormone (PTH) is a current therapy for osteoporosis that has potent anabolic effects on bone. In this study, we found that focal radiation from frequent scans of the right tibiae in 1-month-old rats by micro-computed tomography severely decreased trabecular bone mass and deteriorated bone structure. Interestingly, PTH daily injections remarkably improved trabecular bone in the radiated tibiae with increases in trabecular number, thickness, connectivity, structure model index and stiffness, and a decrease in trabecular separation. Histomorphometric analysis revealed that radiation mainly decreased the number of osteoblasts and impaired their mineralization activity but had little effects on osteoclasts. PTH reversed these adverse effects and greatly increased bone formation to a similar level in both radiated and non-radiated bones. Furthermore, PTH protects bone marrow mesenchymal stem cells from radiation-induced damage, including a decrease in number and an increase in adipogenic differentiation. While radiation generated the same amount of free radicals in the bone marrow of vehicle-treated and PTH-treated animals, the percentage of apoptotic bone marrow cells was significantly attenuated in the PTH group. Taken together, our data demonstrate a radioprotective effect of PTH on bone structure and bone marrow and shed new light on a possible clinical application of anabolic treatment in radiotherapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Ablation of the pro-apoptotic protein Bax protects mice from glucocorticoid-induced bone growth impairment.

PubMed

Zaman, Farasat; Chrysis, Dionisios; Huntjens, Kirsten; Fadeel, Bengt; Sävendahl, Lars

2012-01-01

Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax.

Stable sulforaphane protects against gait anomalies and modifies bone microarchitecture in the spontaneous STR/Ort model of osteoarthritis.

PubMed

Javaheri, Behzad; Poulet, Blandine; Aljazzar, Ahmed; de Souza, Roberto; Piles, Miriam; Hopkinson, Mark; Shervill, Elaine; Pollard, Andrea; Chan, Boris; Chang, Yu-Mei; Orriss, Isabel R; Lee, Peter D; Pitsillides, Andrew A

2017-10-01

Osteoarthritis (OA), affecting joints and bone, causes physical gait disability with huge socio-economic burden; treatment remains palliative. Roles for antioxidants in protecting against such chronic disorders have been examined previously. Sulforaphane is a naturally occurring antioxidant. Herein, we explore whether SFX-01®, a stable synthetic form of sulforaphane, modifies gait, bone architecture and slows/reverses articular cartilage destruction in a spontaneous OA model in STR/Ort mice. Sixteen mice (n=8/group) were orally treated for 3months with either 100mg/kg SFX-01® or vehicle. Gait was recorded, tibiae were microCT scanned and analysed. OA lesion severity was graded histologically. The effect of SFX-01® on bone turnover markers in vivo was complemented by in vitro bone formation and resorption assays. Analysis revealed development of OA-related gait asymmetry in vehicle-treated STR/Ort mice, which did not emerge in SFX-01®-treated mice. We found significant improvements in trabecular and cortical bone. Despite these marked improvements, we found that histologically-graded OA severity in articular cartilage was unmodified in treated mice. These changes are also reflected in anabolic and anti-catabolic actions of SFX-01® treatment as reflected by alteration in serum markers as well as changes in primary osteoblast and osteoclast-like cells in vitro. We report that SFX-01® improves bone microarchitecture in vivo, produces corresponding changes in bone cell behaviour in vitro and leads to greater symmetry in gait, without marked effects on cartilage lesion severity in STR/Ort osteoarthritic mice. Our findings support both osteotrophic roles and novel beneficial gait effects for SFX-01® in this model of spontaneous OA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Protective Effect of Chokeberry (Aronia melanocarpa L.) Extract against Cadmium Impact on the Biomechanical Properties of the Femur: A Study in a Rat Model of Low and Moderate Lifetime Women Exposure to This Heavy Metal

PubMed Central

Brzóska, Małgorzata M.; Roszczenko, Alicja; Rogalska, Joanna; Gałażyn-Sidorczuk, Małgorzata; Mężyńska, Magdalena

2017-01-01

The hypothesis that the consumption of Aronia melanocarpa berries (chokeberries) extract, recently reported by us to improve bone metabolism in female rats at low-level and moderate chronic exposure to cadmium (1 and 5 mg Cd/kg diet for up to 24 months), may increase the bone resistance to fracture was investigated. Biomechanical properties of the neck (bending test with vertical head loading) and diaphysis (three-point bending test) of the femur of rats administered 0.1% aqueous chokeberry extract (65.74% of polyphenols) or/and Cd in the diet (1 and 5 mg Cd/kg) for 3, 10, 17, and 24 months were evaluated. Moreover, procollagen I was assayed in the bone tissue. The low-level and moderate exposure to Cd decreased the procollagen I concentration in the bone tissue and weakened the biomechanical properties of the femoral neck and diaphysis. Chokeberry extract administration under the exposure to Cd improved the bone collagen biosynthesis and femur biomechanical properties. The results allow for the conclusion that the consumption of chokeberry products under exposure to Cd may improve the bone biomechanical properties and protect from fracture. This study provides support for Aronia melanocarpa berries being a promising natural agent for skeletal protection under low-level and moderate chronic exposure to Cd. PMID:28587093

Protective Effect of Chokeberry (Aronia melanocarpa L.) Extract against Cadmium Impact on the Biomechanical Properties of the Femur: A Study in a Rat Model of Low and Moderate Lifetime Women Exposure to This Heavy Metal.

PubMed

Brzóska, Małgorzata M; Roszczenko, Alicja; Rogalska, Joanna; Gałażyn-Sidorczuk, Małgorzata; Mężyńska, Magdalena

2017-05-25

The hypothesis that the consumption of Aronia melanocarpa berries (chokeberries) extract, recently reported by us to improve bone metabolism in female rats at low-level and moderate chronic exposure to cadmium (1 and 5 mg Cd/kg diet for up to 24 months), may increase the bone resistance to fracture was investigated. Biomechanical properties of the neck (bending test with vertical head loading) and diaphysis (three-point bending test) of the femur of rats administered 0.1% aqueous chokeberry extract (65.74% of polyphenols) or/and Cd in the diet (1 and 5 mg Cd/kg) for 3, 10, 17, and 24 months were evaluated. Moreover, procollagen I was assayed in the bone tissue. The low-level and moderate exposure to Cd decreased the procollagen I concentration in the bone tissue and weakened the biomechanical properties of the femoral neck and diaphysis. Chokeberry extract administration under the exposure to Cd improved the bone collagen biosynthesis and femur biomechanical properties. The results allow for the conclusion that the consumption of chokeberry products under exposure to Cd may improve the bone biomechanical properties and protect from fracture. This study provides support for Aronia melanocarpa berries being a promising natural agent for skeletal protection under low-level and moderate chronic exposure to Cd.

The effects of visceral obesity and androgens on bone: trenbolone protects against loss of femoral bone mineral density and structural strength in viscerally obese and testosterone-deficient male rats.

PubMed

Donner, D G; Elliott, G E; Beck, B R; Forwood, M R; Du Toit, E F

2016-03-01

In males, visceral obesity and androgen deficiency often present together and result in harmful effects on bone. Our findings show that both factors are independently associated with adverse effects on femoral bone structure and strength, and trenbolone protects rats from diet-induced visceral obesity and consequently normalises femoral bone structural strength. In light of the rapidly increasing incidence of obesity and osteoporosis globally, and recent conjecture regarding the effects of visceral adiposity and testosterone deficiency on bone health, we investigated the effects of increased visceral adipose tissue (VAT) mass on femoral bone mineral density (BMD), structure and strength in normal weight rats with testosterone deficiency. Male Wistar rats (n = 50) were fed either standard rat chow (CTRL, n = 10) or a high-fat/high-sugar diet (HF/HS, n = 40). Following 8 weeks of feeding, rats underwent sham surgery (CTRL, n = 10; HF/HS, n = 10) or orchiectomy (HF/HS + ORX, n = 30). Following a 4-week recovery period, mini-osmotic pumps containing either vehicle (CTRL, n = 10; HF/HS, n = 10; HF/HS + ORX, n = 10), 2.0 mg kg day(-1), testosterone (HF/HS + ORX + TEST, n = 10) or 2.0 mg kg day(-1) trenbolone (HF/HS + ORX + TREN, n = 10) were implanted for 8 weeks of treatment. Dual-energy X-ray absorptiometry and three-point bending tests were used to assess bone mass, structure and strength of femora. Diet-induced visceral obesity resulted in decreased bone mineral area (BMA) and content (BMC) and impaired femoral stiffness and strength. Orchiectomy further impaired BMA, BMC and BMD and reduced energy to failure in viscerally obese animals. Both TEST and TREN treatment restored BMA, BMC, BMD and energy to failure. Only TREN reduced visceral adiposity and improved femoral stiffness and strength. Findings support a role for both visceral adiposity and testosterone deficiency as independent risk factors for femoral osteoporosis, adverse bone geometry and impaired bone strength in male rats. Trenbolone may be a more effective candidate for androgen replacement therapy than testosterone in viscerally obese testosterone-deficient males.

Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial

USDA-ARS?s Scientific Manuscript database

Isoflavones are naturally occurring plant estrogens that are abundant in soy. Although purported to protect against bone loss, the efficacy of soy isoflavone supplementation in the prevention of osteoporosis in postmenopausal women remains controversial. Our aim was to test the effect of soy isoflav...

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

PubMed

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

2018-01-20

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

Selenium- and Tellurium-Based Antioxidants for Modulating Inflammation and Effects on Osteoblastic Activity

PubMed Central

Lu, Xi; Mestres, Gemma; Singh, Vijay Pal; Effati, Pedram; Poon, Jia-Fei; Engman, Lars; Karlsson Ott, Marjam

2017-01-01

Increased oxidative stress plays a significant role in the etiology of bone diseases. Heightened levels of H2O2 disrupt bone homeostasis, leading to greater bone resorption than bone formation. Organochalcogen compounds could act as free radical trapping agents or glutathione peroxidase mimetics, reducing oxidative stress in inflammatory diseases. In this report, we synthesized and screened a library of organoselenium and organotellurium compounds for hydrogen peroxide scavenging activity, using macrophagic cell lines RAW264.7 and THP-1, as well as human mono- and poly-nuclear cells. These cells were stimulated to release H2O2, using phorbol 12-myristate 13-acetate, with and without organochalogens. Released H2O2 was then measured using a chemiluminescent assay over a period of 2 h. The screening identified an organoselenium compound which scavenged H2O2 more effectively than the vitamin E analog, Trolox. We also found that this organoselenium compound protected MC3T3 cells against H2O2-induced toxicity, whereas Trolox did not. The organoselenium compound exhibited no cytotoxicity to the cells and had no deleterious effects on cell proliferation, viability, or alkaline phosphatase activity. The rapidity of H2O2 scavenging and protection suggests that the mechanism of protection is due to the direct scavenging of extracellular H2O2. This compound is a promising modulators of inflammation and could potentially treat diseases involving high levels of oxidative stress. PMID:28216602

Serum leptin is correlated to high turnover in osteoporosis.

PubMed

Hipmair, Gunter; Böhler, Nikolaus; Maschek, Wilma; Soriguer, Federico; Rojo-Martínez, Gemma; Schimetta, Wolfgang; Pichler, Robert

2010-01-01

Clinical data have suggested that obesity protects against osteoporosis. Leptin, mainly secreted by white adipose tissue, might be involved by mediating an effect on bone metabolism. This study was conducted to investigate a possible relationship of leptin and bone turn-over in postmenopausal women with osteoporosis. We measured bone mineral density (BMD), serum leptin levels and markers of bone metabolism, including osteocalcin and cross-laps in 44 patients with osteoporosis. The main group consisted of 32 postmenopausal women. Mean serum leptin was 13.1 microg/L and showed no statistically significant difference to the levels measured in a collective of normal persons adjusted for age and BMI. When related to serum cross-laps as markers of bone resorption, a positive correlation (p<0.05) was observed, whereas no correlation with osteocalcin could be seen. A dual control of bone formation by leptin is assumed: This involves local mechanisms acting on osteoblasts and a central inhibitory effect on bone metabolism via a hypothalamic relay. Our data indicate that the net effect of circulating leptin may cause bone loss and is significantly related to high-turnover serum bone markers, at least in postmenopausal women with osteoporosis.

Effect of epimedium pubescen flavonoid on bone mineral status and bone turnover in male rats chronically exposed to cigarette smoke

PubMed Central

2012-01-01

Background Epimedii herba is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China and its main constituent is Epimedium pubescen flavonoid (EPF). However, it is unclear whether EPF during chronic exposure to cigarette smoke may have a protective influence on the skeleton. The present study investigated the effect of EPF on bone mineral status and bone turnover in a rat model of human relatively high exposure to cigarette smoke. Methods Fifty male Wistar rats were randomized into five groups: controls, passive smoking groups and passive smoking rats administered EPF at three dosage levels (75, 150 or 300 mg/kg/day) in drinking water for 4 months. A rat model of passive smoking was prepared by breeding male rats in a cigarette-smoking box. Bone mineral content (BMC), bone mineral density (BMD), bone turnover markers, bone histomorphometric parameters and biomechanical properties were examined. Results Smoke exposure decreased BMC and BMD, increased bone turnover (inhibited bone formation and stimulated its resorption), affected bone histomorphometry (increased trabecular separation and osteoclast surface per bone surface; decreased trabecular bone volume, trabecular thickness, trabecular number, cortical thickness, bone formation rate and osteoblast surface per bone surface), and reduced mechanical properties. EPF supplementation during cigarette smoke exposure prevented smoke-induced changes in bone mineral status and bone turnover. Conclusion The results suggest that EPF can prevent the adverse effects of smoke exposure on bone by stimulating bone formation and inhibiting bone turnover and bone resorption. PMID:22713117

Effect of epimedium pubescen flavonoid on bone mineral status and bone turnover in male rats chronically exposed to cigarette smoke.

PubMed

Gao, Shu-guang; Cheng, Ling; Li, Kang-hua; Liu, Wen-He; Xu, Mai; Jiang, Wei; Wei, Li-Cheng; Zhang, Fang-jie; Xiao, Wen-feng; Xiong, Yi-lin; Tian, Jian; Zeng, Chao; Sun, Jin-peng; Xie, Qiang; Lei, Guang-hua

2012-06-19

Epimedii herba is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China and its main constituent is Epimedium pubescen flavonoid (EPF). However, it is unclear whether EPF during chronic exposure to cigarette smoke may have a protective influence on the skeleton. The present study investigated the effect of EPF on bone mineral status and bone turnover in a rat model of human relatively high exposure to cigarette smoke. Fifty male Wistar rats were randomized into five groups: controls, passive smoking groups and passive smoking rats administered EPF at three dosage levels (75, 150 or 300 mg/kg/day) in drinking water for 4 months. A rat model of passive smoking was prepared by breeding male rats in a cigarette-smoking box. Bone mineral content (BMC), bone mineral density (BMD), bone turnover markers, bone histomorphometric parameters and biomechanical properties were examined. Smoke exposure decreased BMC and BMD, increased bone turnover (inhibited bone formation and stimulated its resorption), affected bone histomorphometry (increased trabecular separation and osteoclast surface per bone surface; decreased trabecular bone volume, trabecular thickness, trabecular number, cortical thickness, bone formation rate and osteoblast surface per bone surface), and reduced mechanical properties. EPF supplementation during cigarette smoke exposure prevented smoke-induced changes in bone mineral status and bone turnover. The results suggest that EPF can prevent the adverse effects of smoke exposure on bone by stimulating bone formation and inhibiting bone turnover and bone resorption.

New management options for osteoporosis with emphasis on SERMs.

PubMed

McClung, M R

2015-01-01

Albright was the first of many to show that loss of bone mass due to estrogen deficiency is an important part of the pathogenesis of postmenopausal osteoporosis. This led to the use of estrogen therapy which was shown to prevent bone loss at menopause and to reduce the risk of important fragility fractures. Selective estrogen receptor modulators (SERMs), with salutary estrogen-like skeletal effects and with protection from breast cancer, have important roles in the management of young postmenopausal women. New members of the SERM family may approach the effectiveness of estrogen in preventing bone loss and reducing fracture risk. When combined with estrogen, new SERMs prevent endometrial hyperplasia, and that combination reduces menopausal symptoms and prevents bone loss. Drugs that reduce bone turnover or stimulate bone formation by non-estrogen pathways have also been developed to treat osteoporosis. Emerging therapies, with unique mechanisms of action, may provide improved efficacy in treating women who already have osteoporosis.

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

PubMed Central

Takeda, Tsuyoshi; Sato, Yoshihiro

2006-01-01

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

Dietary Intake Can Predict and Protect Against Changes in Bone Metabolism during Spaceflight and Recovery (Pro K)

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Zwart, S. R.; Shackelford, L.; Heer, M.

2009-01-01

Bone loss is not only a well-documented effect of spaceflight on astronauts, but also a condition that affects millions of men and women on Earth each year. Many countermeasures aimed at preventing bone loss during spaceflight have been proposed, and many have been evaluated to some degree. To date, those showing potential have focused on either exercise or pharmacological interventions, but none have targeted dietary intake alone as a factor to predict or minimize bone loss during spaceflight. The "Dietary Intake Can Predict and Protect against Changes in Bone Metabolism during Spaceflight and Recovery" investigation ("Pro K") is one of the first inflight evaluations of a dietary countermeasure to lessen bone loss of astronauts. This protocol will test the hypothesis that the ratio of acid precursors to base precursors (specifically animal protein to potassium) in the diet can predict directional changes in bone mineral during spaceflight and recovery. The ratio of animal protein to potassium in the diet will be controlled for multiple short (4-day) periods before and during flight. Based on multiple sets of bed rest data, we hypothesize that a higher ratio of the intake of animal protein to the intake of potassium will yield higher concentrations of markers of bone resorption and urinary calcium excretion during flight and during recovery from bone mineral loss after long-duration spaceflight.

Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome

DTIC Science & Technology

2016-09-01

Syndrome of the Acute Radiation Syndrome PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome 5b. GRANT NUMBER W81XWH-15...protective role against hematopoietic syndrome of the acute radiation syndrome (H-ARS) and is able to attenuate the effect of residual bone marrow

The Effects of Tocotrienol and Lovastatin Co-Supplementation on Bone Dynamic Histomorphometry and Bone Morphogenetic Protein-2 Expression in Rats with Estrogen Deficiency.

PubMed

Chin, Kok-Yong; Abdul-Majeed, Saif; Mohamed, Norazlina; Ima-Nirwana, Soelaiman

2017-02-15

Both tocotrienol and statins are suppressors of the mevalonate pathway. Supplementation of tocotrienol among statin users could potentially protect them against osteoporosis. This study aimed to compare the effects of tocotrienol and lovastatin co-supplementation with individual treatments on bone dynamic histomorphometric indices and bone morphogenetic protein-2 (BMP-2) gene expression in ovariectomized rats. Forty-eight female Sprague-Dawley rats were randomized equally into six groups. The baseline was sacrificed upon receipt. All other groups were ovariectomized, except for the sham group. The ovariectomized groups were administered orally daily with (1) lovastatin 11 mg/kg/day alone; (2) tocotrienol derived from annatto bean (annatto tocotrienol) 60 mg/kg/day alone; (3) lovastatin 11 mg/kg/day, and annatto tocotrienol 60 mg/kg/day. The sham and ovariectomized control groups were treated with equal volume of vehicle. After eight weeks of treatment, the rats were sacrificed. Their bones were harvested for bone dynamic histomorphometry and BMP-2 gene expression. Rats supplemented with annatto tocotrienol and lovastatin concurrently demonstrated significantly lower single-labeled surface, but increased double-labeled surface, mineralizing surface, mineral apposition rate and bone formation rate compared to individual treatments ( p < 0.05). There was a parallel increase in BMP-2 gene expression in the rats receiving combined treatment ( p < 0.05). The combination of annatto tocotrienol and lovastatin exerted either additively or synergistically on selected bone parameters. In conclusion, tocotrienol can augment the bone formation and mineralization in rats receiving low-dose statins. Supplementation of tocotrienol in statin users can potentially protect them from osteoporosis.

The Effects of Tocotrienol and Lovastatin Co-Supplementation on Bone Dynamic Histomorphometry and Bone Morphogenetic Protein-2 Expression in Rats with Estrogen Deficiency

PubMed Central

Chin, Kok-Yong; Abdul-Majeed, Saif; Mohamed, Norazlina; Ima-Nirwana, Soelaiman

2017-01-01

Both tocotrienol and statins are suppressors of the mevalonate pathway. Supplementation of tocotrienol among statin users could potentially protect them against osteoporosis. This study aimed to compare the effects of tocotrienol and lovastatin co-supplementation with individual treatments on bone dynamic histomorphometric indices and bone morphogenetic protein-2 (BMP-2) gene expression in ovariectomized rats. Forty-eight female Sprague-Dawley rats were randomized equally into six groups. The baseline was sacrificed upon receipt. All other groups were ovariectomized, except for the sham group. The ovariectomized groups were administered orally daily with (1) lovastatin 11 mg/kg/day alone; (2) tocotrienol derived from annatto bean (annatto tocotrienol) 60 mg/kg/day alone; (3) lovastatin 11 mg/kg/day, and annatto tocotrienol 60 mg/kg/day. The sham and ovariectomized control groups were treated with equal volume of vehicle. After eight weeks of treatment, the rats were sacrificed. Their bones were harvested for bone dynamic histomorphometry and BMP-2 gene expression. Rats supplemented with annatto tocotrienol and lovastatin concurrently demonstrated significantly lower single-labeled surface, but increased double-labeled surface, mineralizing surface, mineral apposition rate and bone formation rate compared to individual treatments (p < 0.05). There was a parallel increase in BMP-2 gene expression in the rats receiving combined treatment (p < 0.05). The combination of annatto tocotrienol and lovastatin exerted either additively or synergistically on selected bone parameters. In conclusion, tocotrienol can augment the bone formation and mineralization in rats receiving low-dose statins. Supplementation of tocotrienol in statin users can potentially protect them from osteoporosis. PMID:28212283

Protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulation of IL-6/STAT3 signaling.

PubMed

Zhang, Zhi-Guo; Chen, Yan-Jing; Xiang, Li-Hua; Pan, Jing-Hua; Wang, Zhen; Xiao, Gary Guishan; Ju, Da-Hong

2017-11-01

The aim of the present study was to assess the effectiveness of Rhizoma Dioscoreae extract (RDE) on preventing rat alveolar bone loss induced by ovariectomy (OVX), and to determine the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in this effect. Female Wistar rats were subjected to OVX or sham surgery. The rats that had undergone OVX were treated with RDE (RDE group), vehicle (OVX group) or 17β-estradiol subcutaneous injection (E2 group). Subsequently, bone metabolic activity was assessed by analyzing 3-D alveolar bone construction, bone mineral density, as well as the plasma biomarkers of bone turnover. The gene expression of alveolar bone in the OVX and RDE groups was evaluated by IL-6/STAT3 signaling pathway polymerase chain reaction (PCR) arrays, and differentially expressed genes were determined through reverse transcription-quantitative PCR. The inhibitory effect of RDE on alveolar bone loss in the OVX group was demonstrated in the study. In comparison with the OVX group, the RDE group exhibited 19 downregulated genes and 1 upregulated gene associated with the IL-6/STAT3 signaling pathway in alveolar bone. Thus, RDE was shown to relieve OVX-induced alveolar bone loss in rats, an effect which was likely associated with decreased abnormal bone remodeling via regulation of the IL-6/STAT3 signaling pathway.

The effect of sensorineural hearing loss and tinnitus on speech recognition over air and bone conduction military communications headsets.

PubMed

Manning, Candice; Mermagen, Timothy; Scharine, Angelique

2017-06-01

Military personnel are at risk for hearing loss due to noise exposure during deployment (USACHPPM, 2008). Despite mandated use of hearing protection, hearing loss and tinnitus are prevalent due to reluctance to use hearing protection. Bone conduction headsets can offer good speech intelligibility for normal hearing (NH) listeners while allowing the ears to remain open in quiet environments and the use of hearing protection when needed. Those who suffer from tinnitus, the experience of perceiving a sound not produced by an external source, often show degraded speech recognition; however, it is unclear whether this is a result of decreased hearing sensitivity or increased distractibility (Moon et al., 2015). It has been suggested that the vibratory stimulation of a bone conduction headset might ameliorate the effects of tinnitus on speech perception; however, there is currently no research to support or refute this claim (Hoare et al., 2014). Speech recognition of words presented over air conduction and bone conduction headsets was measured for three groups of listeners: NH, sensorineural hearing impaired, and/or tinnitus sufferers. Three levels of speech-to-noise (SNR = 0, -6, -12 dB) were created by embedding speech items in pink noise. Better speech recognition performance was observed with the bone conduction headset regardless of hearing profile, and speech intelligibility was a function of SNR. Discussion will include study limitations and the implications of these findings for those serving in the military. Published by Elsevier B.V.

Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

2014-01-01

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma

PubMed Central

Labrinidis, Agatha; Diamond, Peter; Martin, Sally; Hay, Shelley; Liapis, Vasilios; Zinonos, Irene; Sims, Natalie A.; Atkins, Gerald J.; Vincent, Cristina; Ponomarev, Vladimir; Findlay, David M.; Zannettino, Andrew C.W.; Evdokiou, Andreas

2017-01-01

Purpose Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma. Experimental Design We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography. Results Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment. Conclusions This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma. PMID:19276263

Dried plum diet protects from bone loss caused by ionizing radiation

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

Schreurs, A. -S.; Shirazi-Fard, Y.; Shahnazari, M.

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or antiinflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss.more » Dried plum was most effective in reducing the expression of genes related to bone resorption ( Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Furthermore, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth.« less

Dried plum diet protects from bone loss caused by ionizing radiation

DOE PAGES

Schreurs, A. -S.; Shirazi-Fard, Y.; Shahnazari, M.; ...

2016-02-11

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or antiinflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss.more » Dried plum was most effective in reducing the expression of genes related to bone resorption ( Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Furthermore, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth.« less

Dried plum diet protects from bone loss caused by ionizing radiation

PubMed Central

Schreurs, A.-S.; Shirazi-Fard, Y.; Shahnazari, M.; Alwood, J. S.; Truong, T. A.; Tahimic, C. G. T.; Limoli, C. L.; Turner, N. D.; Halloran, B.; Globus, R. K.

2016-01-01

Bone loss caused by ionizing radiation is a potential health concern for radiotherapy patients, radiation workers and astronauts. In animal studies, exposure to ionizing radiation increases oxidative damage in skeletal tissues, and results in an imbalance in bone remodeling initiated by increased bone-resorbing osteoclasts. Therefore, we evaluated various candidate interventions with antioxidant or anti-inflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dried plum) both for their ability to blunt the expression of resorption-related genes in marrow cells after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy) and to prevent bone loss. Dried plum was most effective in reducing the expression of genes related to bone resorption (Nfe2l2, Rankl, Mcp1, Opg, TNF-α) and also preventing later cancellous bone decrements caused by irradiation with either photons or heavy ions. Thus, dietary supplementation with DP may prevent the skeletal effects of radiation exposures either in space or on Earth. PMID:26867002

Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence.

PubMed

Yang, Fan; Yang, Lei; Li, Yuan; Yan, Gege; Feng, Chao; Liu, Tianyi; Gong, Rui; Yuan, Ye; Wang, Ning; Idiiatullina, Elina; Bikkuzin, Timur; Pavlov, Valentin; Li, Yang; Dong, Chaorun; Wang, Dawei; Cao, Yang; Han, Zhenbo; Zhang, Lai; Huang, Qi; Ding, Fengzhi; Bi, Zhengang; Cai, Benzhi

2017-10-01

Bone marrow mesenchymal stem cells (BMSCs) are an expandable population of stem cells which can differentiate into osteoblasts, chondrocytes and adipocytes. Dysfunction of BMSCs in response to pathological stimuli contributes to bone diseases. Melatonin, a hormone secreted from pineal gland, has been proved to be an important mediator in bone formation and mineralization. The aim of this study was to investigate whether melatonin protected against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Here, we found that iron overload induced by ferric ammonium citrate (FAC) caused irregularly morphological changes and markedly reduced the viability in BMSCs. Consistently, osteogenic differentiation of BMSCs was significantly inhibited by iron overload, but melatonin treatment rescued osteogenic differentiation of BMSCs. Furthermore, exposure to FAC led to the senescence in BMSCs, which was attenuated by melatonin as well. Meanwhile, melatonin was able to counter the reduction in cell proliferation by iron overload in BMSCs. In addition, protective effects of melatonin on iron overload-induced dysfunction of BMSCs were abolished by its inhibitor luzindole. Also, melatonin protected BMSCs against iron overload-induced ROS accumulation and membrane potential depolarization. Further study uncovered that melatonin inhibited the upregulation of p53, ERK and p38 protein expressions in BMSCs with iron overload. Collectively, melatonin plays a protective role in iron overload-induced osteogenic differentiation dysfunction and senescence through blocking ROS accumulation and p53/ERK/p38 activation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

THE PROTECTIVE EFFECT OF LOCAL BONE MARROW ASPHYXIA IN ACUTE RADIATION SICKNESS IN ANIMALS (in Russian)

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

Zherebchenko, P.G.; Krasnykh, I.G.; Lebkova, N.P.

1960-10-01

In experiments on mice, rats, and dogs, a study was made of the effect of local bone marrow asphyxia on the course and outcome of radiation sickness. Asphyxia was induced by applying a hemostatic tourniquet on the extremity of animals during irradiation. It was established that local asphyxia of the bone marrow alleviates the severity of acute radiation sickness and increases the survival of animals. It is shown that at the basis of the radioprotective action lies the reduced degeneration of the bone marrow, subsequently facilitating the regeneration of hematopeiesis. Data are obtained relative to the intensification of the effectmore » of local asphyxia with the aid of prophylactic (mercamine) and curative (streptomycin) agents. (auth)« less

Development and characterization of a lung-protective method of bone marrow transplantation in the mouse.

PubMed

Janssen, William J; Muldrow, Alaina; Kearns, Mark T; Barthel, Lea; Henson, Peter M

2010-05-31

Allogeneic bone marrow transplantation is a common method used to study the contribution of myeloid and lymphoid cell populations in murine models of disease. The method requires lethal doses of radiation to ablate the bone marrow. Unintended consequences of radiation include organ injury and inflammatory cell activation. The goal of our study was to determine the degree to which bone marrow transplantation alters lungs and to develop a system to protect the lungs during radiation. C57BL/6 mice were subjected to total body irradiation with 900cGy and then transplanted with bone marrow from green fluorescent protein (GFP) expressing mice. Resultant chimeras exhibited a significant decline in alveolar macrophage numbers within 72h, modest influx of neutrophils in the lungs at 14days, and repopulation of the lungs by alveolar macrophages of bone marrow origin by 28days. Neutrophil influx and alveolar macrophage turnover were prevented when 1cm thick lead shields were used to protect the lungs during radiation, such that 8weeks after transplantation less than 30% of alveolar macrophages were of donor origin. Lung-shielded mice achieved a high level of bone marrow engraftment with greater than 95% of circulating leukocytes expressing GFP. In addition, their response to intratracheal lipopolysaccharide was similar to non-transplanted mice. We describe a model whereby lead shields protect resident cell populations in the lungs from radiation during bone marrow transplantation but permit full bone marrow engraftment. This system may be applicable to other organ systems in which protection from radiation during bone marrow transplantation is desired.

HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition

PubMed Central

Gao, Ling; Deng, Hongju; Zhao, Haibo; Hirbe, Angela; Harding, John; Ratner, Lee; Weilbaecher, Katherine

2005-01-01

One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis. PMID:16118323

Characterization of Microgravity Effects on Bone Structure and Strength Using Fractal Analysis

NASA Technical Reports Server (NTRS)

Acharya, Raj S.; Shackelford, Linda

1996-01-01

Protecting humans against extreme environmental conditions requires a thorough understanding of the pathophysiological changes resulting from the exposure to those extreme conditions. Knowledge of the degree of medical risk associated with the exposure is of paramount importance in the design of effective prophylactic and therapeutic measures for space exploration. Major health hazards due o musculoskeletal systems include the signs and symptoms of hypercalciuria, lengthy recovery of lost bone tissue after flight, the possibility of irreversible trabecular bone loss, the possible effect of calcification in the soft tissues, and the possible increase in fracture potential. In this research, we characterize the trabecular structure with the aid of fractal analysis. Our research to relate local trabecular structural information to microgravity conditions is an important initial step in understanding the effect of microgravity and countermeasures on bone condition and strength. The proposed research is also closely linked with Osteoporosis and will benefit the general population.

Protective effect of dietary long-chain n-3 polyunsaturated fatty acids on bone loss in gonad-intact middle-aged male rats.

PubMed

Shen, Chwan-Li; Yeh, James K; Rasty, Jahan; Li, Yong; Watkins, Bruce A

2006-03-01

This study evaluated the effect of a fat blend containing long-chain (LC) n-3 PUFA on bone mineral density (BMD) and bone metabolism in gonad-intact middle-aged male rats (12 months old, n 28). Seven rats were killed on day 0 of dietary intervention to determine the baseline BMD. The remaining rats (seven per group) were fed a diet with one of the following dietary lipid treatments (g/kg diet): 167 g safflower oil + 33 g menhaden oil (N6 + N3 diet, control), 200 g safflower oil (N6 diet, almost devoid of LC n-3 PUFA), or 190 g menhaden oil + 10 g corn oil (N3 diet, rich in LC n-3 PUFA) for 20 weeks. After 20 weeks, all dietary treatment groups had a lower BMD compared with the baseline reference. However, rats fed the N3 diet had the highest bone mineral content and cortical + subcortical BMD compared with those fed the N6 and control N6 + N3 diet. Compared with the control (N6 + N3) group, rats fed the N3 diet had higher values for serum insulin-like growth factor-I, parathyroid hormone, 1,25-(OH)2 vitamin D3 and bone-specific alkaline phosphatase activity, but lower bone NO production and urinary Ca, whereas rats fed the N6 diet had higher bone prostaglandin E2 production and serum pyridinoline. These findings indicate a protective action of LC n-3 PUFA on ageing-induced bone loss in gonad-intact middle-aged male rats through a modulation of local factors and systemic calcitrophic hormones.

Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation.

PubMed

Yamaguchi, Masayoshi; Weitzmann, M Neale

2011-01-01

Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans. However, the mechanisms of vitamin K action on the skeleton are poorly defined. Activation of the nuclear factor κB (NF-κB) signal transduction pathway is essential for osteoclast formation and resorption. By contrast, NF-κB signaling potently antagonizes osteoblast differentiation and function, prompting us to speculate that NF-κB antagonists may represent a novel class of dual anti-catabolic and pro-anabolic agents. We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-κB activation, by increasing IκB mRNA, in a γ-carboxylation-independent manner. Furthermore, vitamin K2 prevented repression by tumor necrosis factor α (TNFα) of SMAD signaling induced by either transforming growth factor ß (TGFß) or bone morphogenetic protein-2 (BMP-2). Vitamin K2 further antagonized receptor activator of NF-κB (RANK) ligand (RANKL)-induced NF-κB activation in osteoclast precursors. Our data provide a novel mechanism to explain the dual pro-anabolic and anti-catabolic activities of vitamin K2, and may further support the concept that pharmacological modulation of NF-κB signal transduction may constitute an effective mechanism for ameliorating pathological bone loss and for promoting bone health.

Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

NASA Technical Reports Server (NTRS)

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

2003-01-01

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

Knee loading inhibits osteoclast lineage in a mouse model of osteoarthritis

PubMed Central

Li, Xinle; Yang, Jing; Liu, Daquan; Li, Jie; Niu, Kaijun; Feng, Shiqing; Yokota, Hiroki; Zhang, Ping

2016-01-01

Osteoarthritis (OA) is a whole joint disorder that involves cartilage degradation and periarticular bone response. Changes of cartilage and subchondral bone are associated with development and activity of osteoclasts from subchondral bone. Knee loading promotes bone formation, but its effects on OA have not been well investigated. Here, we hypothesized that knee loading regulates subchondral bone remodeling by suppressing osteoclast development, and prevents degradation of cartilage through crosstalk of bone-cartilage in osteoarthritic mice. Surgery-induced mouse model of OA was used. Two weeks application of daily dynamic knee loading significantly reduced OARSI scores and CC/TAC (calcified cartilage to total articular cartilage), but increased SBP (subchondral bone plate) and B.Ar/T.Ar (trabecular bone area to total tissue area). Bone resorption of osteoclasts from subchondral bone and the differentiation of osteoclasts from bone marrow-derived cells were completely suppressed by knee loading. The osteoclast activity was positively correlated with OARSI scores and negatively correlated with SBP and B.Ar/T.Ar. Furthermore, knee loading exerted protective effects by suppressing osteoclastogenesis through Wnt signaling. Overall, osteoclast lineage is the hyper responsiveness of knee loading in osteoarthritic mice. Mechanical stimulation prevents OA-induced cartilage degeneration through crosstalk with subchondral bone. Knee loading might be a new potential therapy for osteoarthritis patients. PMID:27087498

Early consumption of blueberry diet protects against sex steroid deficiency-induced bone loss in adult female rats

USDA-ARS?s Scientific Manuscript database

We studied the effects of blueberry consumption in early development on bone loss in ovariectomized (OVX) female rats later in life. Weanling female rats were fed AIN-93G semi-purified diets supplemented with 10% whole blueberry powder from PND 21 to PND34 (short-term group), or PND21 to PND81 (chro...

Protective actions of green tea polyphenols and alfacalcidol on bone microstructure in female rats with chronic inflammation

USDA-ARS?s Scientific Manuscript database

This study investigated the effects of green tea polyphenols (GTP) and alfacalcidol on bone microstructure and strength along with possible mechanisms in rats with chronic inflammation. A 12-week study using a 2 (no GTP vs. 0.5%, w/v GTP in drinking water) × 2 (no alfacalcidol vs. 0.05 ug/kg alfacal...

Anti-osteopontin monoclonal antibody prevents ovariectomy-induced osteoporosis in mice by promotion of osteoclast apoptosis

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

Zhang, Bo; PLA General Hospital Cancer Center and PLA Cancer Research Institute, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing; Dai, Jianxin

Highlight: • We first report that anti-osteopontin mAb could protect osteoporosis in mice. • Anti-osteopontin mAb could promote the osteoclast apoptosis. • Targeting osteopontin might have therapeutic potentials for osteoporosis. - Abstract: Osteopontin (OPN) is abundant in mineralized tissues and has long been implicated in bone remodeling. However, the therapeutic effect of targeting OPN in bone loss diseases and the underlying molecular mechanism remain largely unknown. Here, we reported that anti-OPN mAb (23C3) could protect against ovariectomy-induced osteoporosis in mice, demonstrated by microcomputed tomography analysis and histopathology evaluation. In vitro assay showed that 23C3 mAb reduced osteoclasts (OCs)-mediated bone resorptionmore » through promotion of mature OC apoptosis. Thus, the study has important implications for understanding the role of OPN in OC bone resorption and survival, and OPN antagonists may have therapeutic potential for osteoporosis and other osteopenic diseases.« less

ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats.

PubMed

Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-08-01

The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40mgkg -1 d -1 ), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400ngkg -1 min -1 for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca 2+ and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R cascade and down-regulated OPG expression and ACE-2/Ang1-7/Mas pathway. In line with the clinical observations of the bone-preservative properties following ACE-1 inhibition, local activation of ACE-2/Ang1-7/Mas signaling and suppressed osteoclastogenesis seem responsible for the osteo-preservative effect of captopril, which could offers a potential therapeutic value in treatment of disabling bone and skeletal muscular diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Biologic therapies and bone loss in rheumatoid arthritis.

PubMed

Zerbini, C A F; Clark, P; Mendez-Sanchez, L; Pereira, R M R; Messina, O D; Uña, C R; Adachi, J D; Lems, W F; Cooper, C; Lane, N E

2017-02-01

Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis.

PubMed

Burgess, Stacey L; Buonomo, Erica; Carey, Maureen; Cowardin, Carrie; Naylor, Caitlin; Noor, Zannatun; Wills-Karp, Marsha; Petri, William A

2014-11-04

There is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection. Entamoeba histolytica is a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensal Clostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolytica infection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB(+) to an SFB(-) mouse was sufficient to provide protection against E. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells. Entamoeba histolytica is the causative agent of amebiasis, an infectious disease that contributes significantly to morbidity and mortality due to diarrhea in the developing world. We showed in a murine model that colonization with the commensal members of the Clostridia known as SFB provides protection against E. histolytica and that dendritic cells from SFB-colonized mice alone can recapitulate protection. Understanding interactions between enteropathogens, commensal intestinal bacteria, and the mucosal immune response, including dendritic cells, will help in the development of effective treatments for this disease and other infectious and inflammatory diseases. The demonstration of immune-mediated protection due to communication from the microbiome to the bone marrow represents an emerging field of study that will yield unique approaches to the development of these treatments. Copyright © 2014 Burgess et al.

Injectable Reactive Biocomposites For Bone Healing In Critical-Size Rabbit Calvarial Defects

DTIC Science & Technology

2012-03-29

defects (i.e. be conformable), provide temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of...temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of biologics. In this study, we evaluated the...complex defects (i.e. be conformable), harden to provide temporary protection until tissue remodels (i.e. be settable), and enhance tissue regeneration

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

PubMed Central

Jin, Linhua; Tabe, Yoko; Lu, Hongbo; Borthakur, Gautam; Miida, Takashi; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina

2013-01-01

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. PMID:23036488

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment.

PubMed

Jin, Linhua; Tabe, Yoko; Lu, Hongbo; Borthakur, Gautam; Miida, Takashi; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina

2013-02-01

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. Copyright © 2012 Elsevier Ltd. All rights reserved.

Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-κB signaling pathways in osteoblasts.

PubMed

Wu, Chi-Ming; Chen, Po-Chun; Li, Te-Mao; Fong, Yi-Chin; Tang, Chih-Hsin

2013-10-24

Si-Wu-Tang (SWT), a Traditional Chinese Medicine (TCM) formula, is widely used for the treatment of gynopathies diseases such as menstrual discomfort, climacteric syndrome, dysmenorrhea, and other estrogen-related diseases. Recent studies have shown that SWT can treat primary dysmenorrhea, have anti-pruritic anti-inflammatory effects, and protect against radiation-induced bone marrow damage in an animal model. It has been reported that anti-inflammatory and anti-oxidant agents have the potential to treat osteoporosis by increasing bone formation and/or suppressing bone resorption. However, the effect of SWT on bone cell function has not yet been reported. Alkaline phosphatase (ALP), bone morphogenetic proteins (BMP)-2, and osteopontin (OPN) mRNA expression was analyzed by qPCR. The mechanism of action of SWT extract was investigated using western blotting. The in vivo anti-osteoporotic effect of SWT extract was assessed in ovariectomized mice. Here, we report that SWT increases ALP, BMP-2, and OPN expression as well as bone mineralization. In addition, we show that the PI3K, Akt, and NF-κB signaling pathways may be involved in the SWT-mediated increase in gene expression and bone mineralization. Notably, treatment of mice with SWT extract prevented bone loss induced by ovariectomy in vivo. SWT may be used to stimulate bone formation for the treatment of osteoporosis.

Potential medicinal benefits of Cosmos caudatus (Ulam Raja): A scoping review

PubMed Central

Cheng, Shi-Hui; Barakatun-Nisak, Mohd Yusof; Anthony, Joseph; Ismail, Amin

2015-01-01

Cosmos caudatus is widely used as a traditional medicine in Southeast Asia. C. caudatus has been reported as a rich source of bioactive compounds such as ascorbic acid, quercetin, and chlorogenic acid. Studies have shown that C. caudatus exhibits high anti-oxidant capacity and various medicinal properties, including anti-diabetic activity, anti-hypertensive properties, anti-inflammatory responses, bone-protective effect, and anti-microbial activity. This review aims to present the potential medicinal benefits of C. caudatus from the available scientific literature. We searched PubMed and ScienceDirect database for articles published from 1995 to January 2015. Overall, 15 articles related to C. caudatus and its medicinal benefits are reviewed. All these studies demonstrated that C. caudatus is effective, having demonstrated its anti-diabetic, anti-hypertensive, anti-inflammatory, bone-protective, anti-microbial, and anti-fungal activity in both in vitro and animal studies. None of the studies showed any negative effect of C. caudatus related to medicinal use. Currently available evidence suggests that C. caudatus has beneficial effects such as reducing blood glucose, reducing blood pressure, promoting healthy bone formation, and demonstrating anti-inflammatory and anti-microbial properties. However, human clinical trial is warranted. PMID:26929767

Potential medicinal benefits of Cosmos caudatus (Ulam Raja): A scoping review.

PubMed

Cheng, Shi-Hui; Barakatun-Nisak, Mohd Yusof; Anthony, Joseph; Ismail, Amin

2015-10-01

Cosmos caudatus is widely used as a traditional medicine in Southeast Asia. C. caudatus has been reported as a rich source of bioactive compounds such as ascorbic acid, quercetin, and chlorogenic acid. Studies have shown that C. caudatus exhibits high anti-oxidant capacity and various medicinal properties, including anti-diabetic activity, anti-hypertensive properties, anti-inflammatory responses, bone-protective effect, and anti-microbial activity. This review aims to present the potential medicinal benefits of C. caudatus from the available scientific literature. We searched PubMed and ScienceDirect database for articles published from 1995 to January 2015. Overall, 15 articles related to C. caudatus and its medicinal benefits are reviewed. All these studies demonstrated that C. caudatus is effective, having demonstrated its anti-diabetic, anti-hypertensive, anti-inflammatory, bone-protective, anti-microbial, and anti-fungal activity in both in vitro and animal studies. None of the studies showed any negative effect of C. caudatus related to medicinal use. Currently available evidence suggests that C. caudatus has beneficial effects such as reducing blood glucose, reducing blood pressure, promoting healthy bone formation, and demonstrating anti-inflammatory and anti-microbial properties. However, human clinical trial is warranted.

Endocrine Regulation of Bone and Energy Metabolism in Hibernating Mammals

PubMed Central

Doherty, Alison H.; Florant, Gregory L.; Donahue, Seth W.

2014-01-01

Precise coordination among organs is required to maintain homeostasis throughout hibernation. This is particularly true in balancing bone remodeling processes (bone formation and resorption) in hibernators experiencing nutritional deprivation and extreme physical inactivity, two factors normally leading to pronounced bone loss in non-hibernating mammals. In recent years, important relationships between bone, fat, reproductive, and brain tissues have come to light. These systems share interconnected regulatory mechanisms of energy metabolism that potentially protect the skeleton during hibernation. This review focuses on the endocrine and neuroendocrine regulation of bone/fat/energy metabolism in hibernators. Hibernators appear to have unique mechanisms that protect musculoskeletal tissues while catabolizing their abundant stores of fat. Furthermore, the bone remodeling processes that normally cause disuse-induced bone loss in non-hibernators are compared to bone remodeling processes in hibernators, and possible adaptations of the bone signaling pathways that protect the skeleton during hibernation are discussed. Understanding the biological mechanisms that allow hibernators to survive the prolonged disuse and fasting associated with extreme environmental challenges will provide critical information regarding the limit of convergence in mammalian systems and of skeletal plasticity, and may contribute valuable insight into the etiology and treatment of human diseases. PMID:24556365

Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine

PubMed Central

Sterner, Rosalie M.; Kremer, Kimberly N.; Al-Kali, Aref; Patnaik, Mrinal M.; Gangat, Naseema; Litzow, Mark R.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2017-01-01

The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts. Moreover, pretreating differentiating osteoblasts with the histone deacetylase inhibitors (HDACi) vorinostat and panobinostat abrogated the ability of the differentiating osteoblasts to protect AML cells. Together, our results indicate that differentiating osteoblasts have the potential to promote residual AML in the bone marrow following standard chemotherapy and act via a mechanism requiring HDACi-sensitive gene expression. Using HDACi to target the leukemic microenvironment in combination with Ara-C could potentially improve treatment of AML. Moreover, other strategies for manipulating bone marrow osteoblasts may also help eradicate AML cells and reduce relapse. PMID:29212250

Naringin improves bone properties in ovariectomized mice and exerts oestrogen-like activities in rat osteoblast-like (UMR-106) cells

PubMed Central

Pang, Wai-Yin; Wang, Xin-Lun; Mok, Sau-Keng; Lai, Wan-Ping; Chow, Hung-Kay; Leung, Ping-Chung; Yao, Xin-Sheng; Wong, Man-Sau

2010-01-01

Background and purpose: Naringin, a flavanone glycoside in citrus fruits, has been recently reported to stimulate bone formation in vitro and in vivo. The present study was designed to determine if naringin could exert oestrogen-like protective actions in bone. Experimental approach: Young C57/BL6J mice were ovariectomized (OVX) and treated orally with naringin (0.2 or 0.4 mg·g−1·day−1), 17β-oestradiol (2 µg·g−1·day−1) or its vehicle for 6 weeks. Bone mineral densities (BMD) and polar stress-strain index (SSI) were measured by peripheral quantitative computed tomography. Rat osteoblast-like UMR-106 cells were co-incubated with the oestrogen receptor (ER) antagonist ICI 182780 to determine if the effects of naringin on osteoblastic functions were ER dependent. Functional transactivation of ERα and ERβ as well as ERα phosphorylation by naringin were also studied. Key results: Naringin at 0.4 mg·g−1·day−1 increased BMD at trabecular-rich bone in OVX mice. Naringin (at both doses) significantly increased SSI at distal femur and lumbar spine and increased biomechanical strength (ultimate load and energy for breaking) at tibia diaphysis in OVX mice. The stimulatory effects of naringin on osteoblastic functions could be abolished by co-incubation with ICI 182780 in UMR-106 cells. Naringin failed to stimulate ERα- or ERβ-mediated oestrogen response element-dependent luciferase activity but could significantly induce ERα phosphorylation at serine 118, in UMR-106 cells. Conclusions and implications: Naringin was effective in protecting against OVX-induced bone loss in mice and its actions might be mediated through ligand-independent activation of ER in osteoblastic cells. PMID:20397301

Integrated Resistance and Aerobic Training Study - Sprint

NASA Technical Reports Server (NTRS)

Ploutz-Snyder, Lori; Moore, Alan; Ryder, Jeffrey; Everett, Meg; Bloomberg, Jacob; Sibonga, Jean; Shackelford, Linda; Platts, Steven; Martin, David; Ploutz-Snyder, Robert;

Impact of obesity on bone metabolism.

PubMed

López-Gómez, Juan J; Pérez Castrillón, José L; de Luis Román, Daniel A

2016-12-01

High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention. Copyright © 2016. Publicado por Elsevier España, S.L.U.

Dietary coral calcium and zeolite protects bone in a mouse model for postmenopausal bone loss.

PubMed

Banu, Jameela; Varela, Erika; Guerra, Juan M; Halade, Ganesh; Williams, Paul J; Bahadur, Ali N; Hanaoka, Kokichi; Fernandes, Gabriel

2012-12-01

In patients diagnosed with osteoporosis, calcium is lost from bones making them weaker and easily susceptible to fractures. Supplementation of calcium is highly recommended for such conditions. However, the source of calcium plays an important role in the amount of calcium that is assimilated into bone. We hypothesize that naturally occurring coral calcium and zeolite may prevent ovariectomy-induced bone loss. We have measured bone loss in ovariectomized mice supplemented with coral calcium and Zeolite. Female C57BL/6 mice were either sham-operated or ovariectomized and fed diets containing coral calcium or zeolite for 6 months. Serum was analyzed for bone biochemical markers and cytokines. Bones were analyzed using dual x-ray absorbtiometry, peripheral quantitative computed tomography, and micro-computed tomography densitometry. In the distal femoral metaphysis, total bone and cortical bone mass was restored and the endocortical surface was significantly decreased in coral calcium and zeolite fed ovariectomized (OVX) mice. Trabecular number and the ratio of bone volume to total volume was higher in OVX mice after coral calcium and zeolite feeding, while trabecular separation decreased in the different treatment OVX groups. Coral calcium protected bone to a lesser extent in the proximal tibia and lumbar vertebrae. Overall, coral calcium and zeolite may protect postmenopausal bone loss. Copyright © 2012 Elsevier Inc. All rights reserved.

The role of estrogen and androgen receptors in bone health and disease

PubMed Central

2014-01-01

Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis. PMID:24042328

Tocotrienols for bone health: a translational approach.

PubMed

Shen, Chwan-Li; Klein, Annika; Chin, Kok-Yong; Mo, Huanbiao; Tsai, Peihsuan; Yang, Rong-Sen; Chyu, Ming-Chien; Ima-Nirwana, Soelaiman

2017-08-01

Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research. © 2017 New York Academy of Sciences.

Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro.

PubMed

Torisawa, Yu-suke; Spina, Catherine S; Mammoto, Tadanori; Mammoto, Akiko; Weaver, James C; Tat, Tracy; Collins, James J; Ingber, Donald E

2014-06-01

Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow-on-a-chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro.

The effect of bone growth onto massive prostheses collars in protecting the implant from fracture.

PubMed

Fromme, Paul; Blunn, Gordon W; Aston, William J; Abdoola, Tasneem; Koris, Jacob; Coathup, Melanie J

2017-03-01

Limb-sparing distal femoral endoprotheses used in cancer patients have a high risk of aseptic loosening. It had been reported that young adolescent patients have a higher rate of loosening and fatigue fracture of intramedullary stems because the implant becomes undersized as patients grow. Extracortical bone growth into the grooved hydroxyapatite-coated collar had been shown to reduce failure rates. The stresses in the implant and femur have been calculated from Finite Element models for different stages of bone growth onto the collar. For a small diameter stem without any bone growth, a large stress concentration at the implant shoulder was found, leading to a significant fracture risk under normal walking loads. Bone growth and osseointergration onto the implant collar reduced the stress level in the implant to safe levels. For small bone bridges a risk of bone fracture was observed. Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.

Vitamin D supplementation protects against bone loss associated with chronic alcohol administration in female mice.

PubMed

Mercer, Kelly E; Wynne, Rebecca A; Lazarenko, Oxana P; Lumpkin, Charles K; Hogue, William R; Suva, Larry J; Chen, Jin-Ran; Mason, Andrew Z; Badger, Thomas M; Ronis, Martin J J

2012-11-01

Chronic alcohol abuse results in decreased bone mineral density (BMD), which can lead to increased fracture risk. In contrast, low levels of alcohol have been associated with increased BMD in epidemiological studies. Alcohol's toxic skeletal effects have been suggested to involve impaired vitamin D/calcium homeostasis. Therefore, dietary vitamin D supplementation may be beneficial in reducing bone loss associated with chronic alcohol consumption. Six-week-old female C57BL/6J mice were pair-fed ethanol (EtOH)-containing liquid diets (10 or 36% total calories) for 78 days. EtOH exposure at 10% calories had no effects on any measured bone or serum parameter. EtOH consumption at 36% of calories reduced BMD and bone strength (P<0.05), decreased osteoblastogenesis, increased osteoclastogenesis, suppressed 1,25-hydroxyvitamin D3 [1,25(OH)2D3] serum concentrations (P<0.05), and increased apoptosis in bone cells compared with pair-fed controls. In a second study, female mice were pair-fed 30% EtOH diets with or without dietary supplementation with vitamin D3 (cholecalciferol; VitD) for 40 days. VitD supplementation in the EtOH diet protected against cortical bone loss, normalized alcohol-induced hypocalcaemia, and suppressed EtOH-induced expression of receptor of nuclear factor-κB ligand mRNA in bone. In vitro, pretreatment of 1,25(OH)2D3 in osteoblastic cells inhibited EtOH-induced apoptosis. In EtOH/VitD mice circulating 1,25(OH)2D3 was lower compared with mice receiving EtOH alone (P<0.05), suggesting increased sensitivity to feedback control of VitD metabolism in the kidney. These findings suggest dietary VitD supplementation may prevent skeletal toxicity in chronic drinkers by normalizing calcium homeostasis, preventing apoptosis, and suppressing EtOH-induced increases in bone resorption.

Protective effect of Aronia melanocarpa polyphenols against cadmium-induced disorders in bone metabolism: a study in a rat model of lifetime human exposure to this heavy metal.

PubMed

Brzóska, Malgorzata M; Rogalska, Joanna; Galazyn-Sidorczuk, Malgorzata; Jurczuk, Maria; Roszczenko, Alicja; Tomczyk, Michal

2015-03-05

It was investigated, in a female rat model of low and moderate lifetime human exposure to cadmium (Cd), whether polyphenols from Aronia melanocarpa berries (chokeberry; AMP) may offer protection from this heavy metal-induced disorders in bone metabolism. For this purpose, numerous indices of bone formation (osteocalcin, alkaline phosphatase, osteoprotegerin) and resorption (carboxy-terminal cross-linking telopeptides of type I collagen, soluble receptor activator of nuclear factor-κB ligand) in the serum and/or distal femur epiphysis (trabecular bone region), as well as bone mineral status (volumetric bone mineral density of the femur and content of mineral components, including calcium, in the bone tissue at the distal femur epiphysis) were evaluated in female Wistar rats that received a 0.1% aqueous extract of AMP, as the only drinking fluid (prepared from lyophilized extract by Adamed Consumer Healthcare), and/or Cd in diet (1 and 5mg/kg) for 3, 10, 17, and 24 months. Examination of the phytochemical profile of the aronia extract revealed high content of polyphenols (612.40 ± 3.33 mg/g), including anthocyanins, proanthocyanidins, phenolic acids, and flavonoids. Among detected compounds anthocyanins were identified as dominating. The exposure to Cd, dose- and duration-dependently, enhanced resorption and inhibited formation of the bone tissue resulting in its decreased mineralization. The administration of AMP under the exposure to 1 and 5 mgCd/kg diet provided important protection from this heavy metal-induced disturbances in the bone turnover and changes in the bone mineral status, and the beneficial impact of polyphenols resulted from their independent action and interaction with Cd. These findings suggest that consumption of Aronia melanocarpa polyphenols may play a role in prevention against female skeleton damage due to chronic exposure to Cd and that chokeberry represents the good natural plant candidate for further investigations of its prophylactic use under environmental exposure to this heavy metal. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Mechanism of the Osteoprotective Action of a Polyphenol-Rich Aronia melanocarpa Extract during Chronic Exposure to Cadmium is Mediated by the Oxidative Defense System.

PubMed

Brzóska, Malgorzata M; Rogalska, Joanna; Roszczenko, Alicja; Galazyn-Sidorczuk, Malgorzata; Tomczyk, Michal

2016-05-01

Recently, we demonstrated in a rat model that consumption of a polyphenol-rich extract obtained from the berries of Aronia melanocarpa could protect from cadmium-induced disorders in bone turnover and changes in bone mineral status. The aim of this study was to investigate whether the osteoprotective effect of this extract is mediated by the oxidative defense system. Enzymatic and nonenzymatic antioxidants, total antioxidative and oxidative status, hydrogen peroxide, and markers of oxidative protein, lipid, and DNA damage were determined in bone tissue at the distal femoral epiphysis of female Wistar rats receiving 0.1 % aqueous A. melanocarpa extract (prepared from the lyophilized commercial extract containing 65.74 % of polyphenols) as the only drinking fluid and/or cadmium in the diet (1 and 5 mg/kg) for 3, 10, 17, and 24 months. The total oxidative and antioxidative status of the serum was also evaluated. The administration of A. melanocarpa extract provided significant protection from cadmium-induced oxidative stress in the bone and serum, and from lipid peroxidation and oxidative damage to the protein and DNA in the bone tissue. Numerous correlations were noted between indices of the oxidative/antioxidative bone status and markers of bone metabolism previously assayed in the animals receiving A. melanocarpa extract. The results allow the conclusion that the ability of A. melanocarpa extract to mediate the oxidative defense system and prevent oxidative modifications of protein, lipid, and DNA in the bone tissue plays an important role in its osteoprotective action under exposure to cadmium. The findings provide further evidence supporting our suggestion that chokeberry may be a promising natural agent for protection against the toxic action of cadmium in women chronically exposed to this metal. Georg Thieme Verlag KG Stuttgart · New York.

The protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulating Wnt and p38 MAPK signaling.

PubMed

Zhang, Zhiguo; Xiang, Lihua; Bai, Dong; Wang, Wenlai; Li, Yan; Pan, Jinghua; Liu, Hong; Wang, Shaojun; Xiao, Gary Guishan; Ju, Dahong

2014-12-12

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17β-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/β-catenin and the p38 MAPK signaling pathways via gene regulation.

Aesculin modulates bone metabolism by suppressing receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and transduction signals.

PubMed

Zhao, Xiao-Li; Chen, Lin-Feng; Wang, Zhen

2017-06-17

Aesculin (AES), a coumarin compound derived from Aesculus hippocasanum L, is reported to exert protective role against inflammatory diseases, gastric disease and cancer. However, direct effect of AES in bone metabolism is deficient. In this study, we examined the effects of AES on osteoclast (OC) differentiation in receptor activator of NF-κB ligand (RANKL)-induced RAW264.7 cells. AES inhibits the OC differentiation in both dose- and time-dependent manner within non-toxic concentrations, as analyzed by Tartrate Resistant Acid Phosphatase (TRAP) staining. The actin ring formation manifesting OC function is also decreased by AES. Moreover, expressions of osteoclastogenesis related genes Trap, Atp6v0d2, Cathepsin K and Mmp-9 are decreased upon AES treatment. Mechanistically, AES attenuates the activation of MAPKs and NF-κB activity upon RANKL induction, thus leading to the reduction of Nfatc1 mRNA expression. Moreover, AES inhibits Rank expression, and RANK overexpression markedly decreases AES's effect on OC differentiation and NF-κB activity. Consistently, AES protects against bone mass loss in the ovariectomized and dexamethasone treated rat osteoporosis model. Taken together, our data demonstrate that AES can modulate bone metabolism by suppressing osteoclastogenesis and related transduction signals. AES therefore could be a promising agent for the treatment of osteoporosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Nutrition for Space Exploration

NASA Technical Reports Server (NTRS)

Smith, Scott M.

2005-01-01

Nutrition has proven to be critical throughout the history of human exploration, on both land and water. The importance of nutrition during long-duration space exploration is no different. Maintaining optimal nutritional status is critical for all bodily systems, especially in light of the fact that that many are also affected by space flight itself. Major systems of concern are bone, muscle, the cardiovascular system, the immune system, protection against radiation damage, and others. The task ahead includes defining the nutritional requirements for space travelers, ensuring adequacy of the food system, and assessing crew nutritional status before, during, and after flight. Accomplishing these tasks will provide significant contributions to ensuring crew health on long-duration missions. In addition, development and testing of nutritional countermeasures to effects of space flight is required, and assessment of the impact of other countermeasures (such as exercise and pharmaceuticals) on nutrition is also critical for maintaining overall crew health. Vitamin D stores of crew members are routinely low after long-duration space flight. This occurs even when crew members take vitamin D supplements, suggesting that vitamin D metabolism may be altered during space flight. Vitamin D is essential for efficient absorption of calcium, and has numerous other benefits for other tissues with vitamin D receptors. Protein is a macronutrient that requires additional study to define the optimal intake for space travelers. Administration of protein to bed rest subjects can effectively mitigate muscle loss associated with disuse, but too much or too little protein can also have negative effects on bone. In another bed rest study, we found that the ratio of protein to potassium was correlated with the level of bone resorption: the higher the ratio, the more bone resorption. These relationships warrant further study to optimize the beneficial effect of protein on both bone and muscle during space flight. Omega3 fatty acids are currently being studied as a means of protecting against radiation-induced cancer. They have also recently been implicated as having a role in mitigating the physical wasting, or cachexia, caused by cancer. The mechanism of muscle loss associated with this type of cachexia is similar to the mechanism of muscle loss during disuse or space flight. Omega3 fatty acids have already been shown to have protective effects on bone and cardiovascular function. Omega3 fatty acids could be an ideal countermeasure for space flight because they have protective effects on multiple systems. A definition of optimal nutrient intake requirements for long-duration space travel should also include antioxidants. Astronauts are exposed to numerous sources of oxidative stress, including radiation, elevated oxygen exposure during extravehicular activity, and physical and psychological stress. Elevated levels of oxidative damage are related to increased risk for cataracts, cardiovascular disease, and cancer. Many groundbased studies show the protective effects of antioxidants against oxidative damage induced by radiation or oxygen. Balancing the diet with foods that have high levels of antioxidants would be another ideal countermeasure because it should have minimal side effects on crew health. Antioxidant supplements, however, are often used without having data on their effectiveness or side effects. High doses of supplements have been associated with bone and cardiovascular problems, but research on antioxidant effects during space flight has not been conducted. Much work must be done before we can send crews on exploration missions. Nutrition is often assumed to be the simple provision of food items that will be stable throughout the mission. As outlined briefly above, the situation is much more complex than food provision. As explorers throughout history have found, failure to truly understand the role of nutrition can be catastrophic. When huns are in environments unlike any they have seen before, this is more true than ever.

Effects of water extract of Cajanus cajan leaves on the osteogenic and adipogenic differentiation of mouse primary bone marrow stromal cells and the adipocytic trans-differentiation of mouse primary osteoblasts.

PubMed

Zhang, Jinchao; Liu, Cuilian; Sun, Jing; Liu, Dandan; Wang, Peng

2010-01-01

The effects of water extract of Cajanus cajan (Linn.) Millsp. (Leguminosae) leaves (WECML) on the osteogenic and adipogenic differentiation of mouse primary bone marrow stromal cells (BMSCs) and the adipocytic trans-differentiation of mouse primary osteoblasts (OBs) were studied. The results indicated that WECML promoted the proliferation of BMSCs and OBs at most concentrations. WECML promoted the osteogenic differentiation and formation of mineralized matrix nodules of BMSCs at concentrations of 0.1, 1, and 10 microg/mL, but inhibited the osteogenic differentiation and formation of mineralized matrix nodules of BMSCs at concentration of 0.01 microg/mL. WECML inhibited the adipogenic differentiation of BMSCs and adipocytic trans-differentiation of OBs at concentrations of 0.001, 0.1, 1, 10, and 100 microg/mL, but had no effects at concentration of 0.01 microg/mL. The results suggest that WECML has protective effects on bone and these protective effects may be mediated by decreasing adipocytic cell formation from BMSCs, which may promote the proliferation, differentiation, and mineralization function of OBs. The defined active ingredients in the WECML and the active mechanism need to be further studied.

Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones, and prophylactic vitamin D treatment protects against these changes in rats

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

Pal, Subhashis; Khan, Kainat; China, Shyamsundar Pal

The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks)more » bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH){sub 2} vitamin D{sub 3} (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective. - Highlights: • Theophylline induced osteoblast apoptosis by cAMP-induced ROS generation. • Theophylline levels in bone marrow were much higher than blood. • Theophylline diminished bone regeneration at the fracture site and caused osteopenia. • Theophylline caused hypo-vitaminosis D, and altered calciotropic hormones. • Vitamin D treatment prevented theophylline-induced changes in bone metabolism.« less

Superoxide Dismutase Protects Osteoprogenitors from Irradiation with Low-LET but Not High-LET Species

NASA Technical Reports Server (NTRS)

Schreurs, A.-S.; Tran, L.; Alwood, J. S.; Tahimic, C. G.; Globus, R. K.

2016-01-01

Ionizing radiation-induced bone loss appears to be a two-stage process: first an early increase in pro-resorption cytokines and increased bone resorption by osteoclasts, followed by a decrease in bone formation by osteoblasts. This results in a net loss of mass in mineralized bone tissue. The molecular mechanisms underlying the imbalance in bone remodeling caused by exposure to radiation are not fully understood. We hypothesized that the radiation-induced rise in reactive oxygen species (ROS) damages osteoblast progenitors, leading to a decrease in number and activity of differentiated progeny. We have shown that a diet high in antioxidant capacity prevents radiation-induced bone loss in adult mice (Schreurs et al. 2016) by reducing the early increase in pro-resotption cytokines. Here, we investigated the damaging effects of radiation exposure on cells in the osteoblast lineage, testing if addition of the exogenous antioxidant enzyme, superoxide dismutase (SOD) can mitigate radiation damage. Osteoprogenitors were grown in vitro from the marrow of 16wk old, male C57Bl/6 mice. Cells were irradiated 3 days after plating (day 0) with either gamma (Cs-137, 0.1-5Gy) or iron (Fe-56, 600 MeV/n, 0.5-2Gy), and then grown until day 10. SOD or vehicle was added 2 hours before irradiation (SOD at 200U/ml), twice a day and up to day 5, for a total of 2 days treatment. Cell behavior was assessed by: (a) colony number (counted on day 7), (b) DNA content (surrogate for cell number) to assess cell growth (percent change between day 3 and day 10) and (c) alkaline phosphatase activity (osteoblast differentiation marker). Results show that SOD protected cells from the adverse effects of low-LET ionizing radiation, but not high-LET radiation. These novel results provide an interesting platform to explore further diverse effects and damages caused by low-LET and high-LET, pointing toward different mechanisms and possible intervention strategies for radiation-induced bone loss.

Carvedilol protects bone marrow stem cells against hydrogen peroxide-induced cell death via PI3K-AKT pathway.

PubMed

Chen, Meihui; Chen, Shudong; Lin, Dingkun

2016-03-01

Carvedilol, a nonselective β-adrenergic receptor blocker, has been reported to exert potent anti-oxidative activities. In the present study, we aimed to investigate the effects of carvedilol against hydrogen peroxide (H2O2)-induced bone marrow-derived mesenchymal stem cells (BMSCs) death, which imitate the microenvironment surrounding transplanted cells in the injured spinal cord in vitro. Carvedilol significantly reduced H2O2-induced reactive oxygen species production, apoptosis and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protective effects and up-regulation of Akt phosphorylation of carvedilol. Together, our results showed that carvedilol protects H2O2-induced BMSCs cell death partly through PI3K-Akt pathway, suggesting carvedilol could be used in combination with BMSCs for the treatment of spinal cord injury by improving the cell survival and oxidative stress microenvironments. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

In vitro simulation of pathological bone conditions to predict clinical outcome of bone tissue engineered materials

NASA Astrophysics Data System (ADS)

Nguyen, Duong Thuy Thi

According to the Centers for Disease Control, the geriatric population of ≥65 years of age will increase to 51.5 million in 2020; 40% of white women and 13% of white men will be at risk for fragility fractures or fractures sustained under normal stress and loading conditions due to bone disease, leading to hospitalization and surgical treatment. Fracture management strategies can be divided into pharmaceutical therapy, surgical intervention, and tissue regeneration for fracture prevention, fracture stabilization, and fracture site regeneration, respectively. However, these strategies fail to accommodate the pathological nature of fragility fractures, leading to unwanted side effects, implant failures, and non-unions. Compromised innate bone healing reactions of patients with bone diseases are exacerbated with protective bone therapy. Once these patients sustain a fracture, bone healing is a challenge, especially when fracture stabilization is unsuccessful. Traditional stabilizing screw and plate systems were designed with emphasis on bone mechanics rather than biology. Bone grafts are often used with fixation devices to provide skeletal continuity at the fracture gap. Current bone grafts include autologous bone tissue and donor bone tissue; however, the quality and quantity demanded by fragility fractures sustained by high-risk geriatric patients and patients with bone diseases are not met. Consequently, bone tissue engineering strategies are advancing towards functionalized bone substitutes to provide fracture reconstruction while effectively mediating bone healing in normal and diseased fracture environments. In order to target fragility fractures, fracture management strategies should be tailored to allow bone regeneration and fracture stabilization with bioactive bone substitutes designed for the pathological environment. The clinical outcome of these materials must be predictable within various disease environments. Initial development of a targeted treatment strategy should focus on simulating, in vitro, a physiological bone environment to predict clinical effectiveness of engineered bone and understand cellular responses due to the proposed agents and bioactive scaffolds. An in vitro test system can be the necessary catalyst to reduce implant failures and non-unions in fragility fractures.

Sex Steroid Actions in Male Bone

PubMed Central

Laurent, Michaël R.; Claessens, Frank; Gielen, Evelien; Lagerquist, Marie K.; Vandenput, Liesbeth; Börjesson, Anna E.; Ohlsson, Claes

2014-01-01

Sex steroids are chief regulators of gender differences in the skeleton, and male gender is one of the strongest protective factors against osteoporotic fractures. This advantage in bone strength relies mainly on greater cortical bone expansion during pubertal peak bone mass acquisition and superior skeletal maintenance during aging. During both these phases, estrogens acting via estrogen receptor-α in osteoblast lineage cells are crucial for male cortical and trabecular bone, as evident from conditional genetic mouse models, epidemiological studies, rare genetic conditions, genome-wide meta-analyses, and recent interventional trials. Genetic mouse models have also demonstrated a direct role for androgens independent of aromatization on trabecular bone via the androgen receptor in osteoblasts and osteocytes, although the target cell for their key effects on periosteal bone formation remains elusive. Low serum estradiol predicts incident fractures, but the highest risk occurs in men with additionally low T and high SHBG. Still, the possible clinical utility of serum sex steroids for fracture prediction is unknown. It is likely that sex steroid actions on male bone metabolism rely also on extraskeletal mechanisms and cross talk with other signaling pathways. We propose that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall. Given the demographic trends of increased longevity and consequent rise of osteoporosis, an increased understanding of how sex steroids influence male bone health remains a high research priority. PMID:25202834

In vivo and in vitro anti-tumor and anti-metastasis effects of Coriolus versicolor aqueous extract on mouse mammary 4T1 carcinoma.

PubMed

Luo, Ke-Wang; Yue, Grace Gar-Lee; Ko, Chun-Hay; Lee, Julia Kin-Ming; Gao, Si; Li, Long-Fei; Li, Gang; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara Bik-San

2014-01-01

Coriolus versicolor (CV), a medicinal mushroom widely consumed in Asian countries, has been demonstrated to be effective in stimulation of immune system and inhibition of tumor growth. The present study aimed to investigate the anti-tumor and anti-metastasis effects of CV aqueous extract in mouse mammary carcinoma 4T1 cells and in 4T1-tumor bearing mouse model. Our results showed that CV aqueous extract (0.125-2 mg/ml) did not inhibit 4T1 cell proliferation while the non-cytotoxic dose of CV extract (1-2 mg/ml) significantly inhibited cell migration and invasion (p<0.05). Besides, the enzyme activities and protein levels of MMP-9 were suppressed by CV extract significantly. Animal studies showed that CV aqueous extract (1 g/kg, orally-fed daily for 4 weeks) was effective in decreasing the tumor weight by 36%, and decreased the lung metastasis by 70.8% against untreated control. Besides, micro-CT analysis of the tumor-bearing mice tibias indicated that CV extract was effective in bone protection against breast cancer-induced bone destruction as the bone volume was significantly increased. On the other hand, CV aqueous extract treatments resulted in remarkable immunomodulatory effects, which was reflected by the augmentation of IL-2, 6, 12, TNF-α and IFN-γ productions from the spleen lymphocytes of CV-treated tumor-bearing mice. In conclusion, our results demonstrated for the first time that the CV aqueous extract exhibited anti-tumor, anti-metastasis and immunomodulation effects in metastatic breast cancer mouse model, and could protect the bone from breast cancer-induced bone destruction. These findings provided scientific evidences for the clinical application of CV aqueous extract in breast cancer patients. Copyright © 2014 Elsevier GmbH. All rights reserved.

Suppression of bone resorption by miR-141 in aged rhesus monkeys.

PubMed

Yang, Shihua; Zhang, Wenhui; Cai, Mingxiang; Zhang, Yuanxu; Jin, Fujun; Yan, Sen; Baloch, Zulqurain; Fang, Zhihao; Xue, Senren; Tang, Rongping; Xiao, Jia; Huang, Qunshan; Sun, Yao; Wang, Xiaogang

2018-05-31

Aging-related osteoporosis is considered as serious public health concern. Approximately 30% of postmenopausal women suffer from osteoporosis, and more than 40% of them risk fragility fractures. Multiple types of drugs have been applied to treat osteoporosis, but they are not ideal due to insufficient curing and adverse side effects. miRNA-based gene therapy is a rapidly developed strategy in disease treatment that presents certain advantages, such as large-scale production, genetic safety and rapid effects. Until now, miRNA drugs have been used in investigations of cancer treatments. However, in primates, miRNA drugs have not yet been reported as candidates for osteoclast-targeting osteoporosis treatment. In addition, the therapeutic efficacy was limited by several shortcomings, such as low efficiency of selective delivery, insufficient expression levels in targeting cells, and unexpected side effects. Here, we identify miR-141 as a critical suppressor of osteoclastogenesis and bone resorption. The expression levels of miR-141 are positively correlated with bone mineral density and negatively correlated with aging of bones in both aged rhesus monkeys (Macaca mulatta) and osteoporotic patients. Selective delivery of miR-141 into osteoclasts of aged rhesus monkeys via a nucleic acid delivery system allowed for a gradual increase in bone mass without significant effects on health behavior and function of primary organs. Furthermore, we found that the functional mechanism of miR-141 is targeting two osteoclast differentiation players, Calcr (calcitonin receptors) and EphA2 (Ephrin type-A receptor 2 precursor). Our study suggests that miRNAs such as miR-141 could play a crucial role in suppressing bone resorption in primates and provide reliable experimental evidence for the clinical application of miRNA in osteoporosis treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Nutlin-3 Treatment Spares Cisplatin-Induced Inhibition of Bone Healing While Maintaining Osteosarcoma Toxicity

PubMed Central

Stine, Kimo C.; Wahl, Elizabeth C.; Liu, Lichu; Skinner, Robert A.; VanderSchilden, Jaclyn; Bunn, Robert C.; Montgomery, Corey O.; Aronson, James; Becton, David L.; Nicholas, Richard W.; Swearingen, Christopher J.; Suva, Larry J.; Lumpkin, Charles K.

2017-01-01

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01–0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. PMID:26867804

Synergistic Phytochemicals Fail to Protect Against Ovariectomy Induced Bone Loss in Rats.

PubMed

Ambati, Suresh; Miller, Colette N; Bass, Erica F; Hohos, Natalie M; Hartzell, Diane L; Kelso, Emily W; Trunnell, Emily R; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A; Rayalam, Srujana

2018-05-24

Menopause induces a loss of bone as a result of estrogen deficiency. Despite pharmaceutical options for the treatment of osteopenia and osteoporosis, many aging women use dietary supplements with estrogenic activity to prevent bone loss and other menopausal-related symptoms. Such supplements are yet to be tested for efficacy against a Food and Drug Administration (FDA) approved medication for menopausal bone loss such as zoledronic acid (ZA). The postmenopausal rat model was used to investigate the efficacy of various synergistic phytochemical blends mixed into the diet for 16 weeks. Retired-breeder, Fischer 344 rats were randomly assigned to sham or ovariectomy surgery and 4 treatment groups: ZA; genistein supplementation; and a low dose and high dose blend of genistein, resveratrol, and quercetin. Ovariectomy resulted in a loss of both trabecular and cortical bone which was prevented with ZA. The phytochemical blends tested were unable to reverse these losses. Despite the lack of effectiveness in preventing bone loss, a significant dose-response trend was observed in the phytochemical-rich diets in bone adipocyte number compared to ovariectomized control rats. Data from this study indicate that estrogenic phytochemicals are not as efficacious as ZA in preventing menopausal-related bone loss but may have beneficial effects on bone marrow adiposity in rats.

The Effects of Cosmos caudatus on Structural Bone Histomorphometry in Ovariectomized Rats

PubMed Central

Mohamed, Norazlina; Gwee Sian Khee, Sharon; Shuid, Ahmad Nazrun; Muhammad, Norliza; Suhaimi, Farihah; Othman, Faizah; Babji, Abdul Salam; Soelaiman, Ima-Nirwana

2012-01-01

Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women. PMID:22924056

The Effects of Cosmos caudatus on Structural Bone Histomorphometry in Ovariectomized Rats.

PubMed

Mohamed, Norazlina; Gwee Sian Khee, Sharon; Shuid, Ahmad Nazrun; Muhammad, Norliza; Suhaimi, Farihah; Othman, Faizah; Babji, Abdul Salam; Soelaiman, Ima-Nirwana

2012-01-01

Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women.

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

PubMed

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

2017-03-15

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

Biomedical research publications, 1982 - 1983

NASA Technical Reports Server (NTRS)

Bolcik, C.; Pleasant, L. G.

1983-01-01

Cardiovascular deconditioning, motion sickness, bone alterations, muscle atrophy, blood cell alterations, fluid and electrolyte changes, radiation effects and protection, behavior and performance, and general biomedical research are covered in a bibliography of 444 items.

Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome

DTIC Science & Technology

2017-05-01

AWARD NUMBER: W81XWH-15-1-0207 TITLE: “Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome ...SUBTITLE Protective Role of Angiogenin Against Hematopoietic Syndrome 5a. CONTRACT NUMBER of the Acute Radiation Syndrome 5b. GRANT NUMBER 5c...hematopoietic syndrome of the acute radiation syndrome (H-ARS) and is able to attenuate the effect of residual bone marrow damage (RBMD) after

Rhizoma Dioscoreae extract protects against alveolar bone loss by regulating the cell cycle: A predictive study based on the protein‑protein interaction network.

PubMed

Zhang, Zhi-Guo; Song, Chang-Heng; Zhang, Fang-Zhen; Chen, Yan-Jing; Xiang, Li-Hua; Xiao, Gary Guishan; Ju, Da-Hong

2016-06-01

Rhizoma Dioscoreae extract (RDE) exhibits a protective effect on alveolar bone loss in ovariectomized (OVX) rats. The aim of this study was to predict the pathways or targets that are regulated by RDE, by re‑assessing our previously reported data and conducting a protein‑protein interaction (PPI) network analysis. In total, 383 differentially expressed genes (≥3‑fold) between alveolar bone samples from the RDE and OVX group rats were identified, and a PPI network was constructed based on these genes. Furthermore, four molecular clusters (A‑D) in the PPI network with the smallest P‑values were detected by molecular complex detection (MCODE) algorithm. Using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA) tools, two molecular clusters (A and B) were enriched for biological process in Gene Ontology (GO). Only cluster A was associated with biological pathways in the IPA database. GO and pathway analysis results showed that cluster A, associated with cell cycle regulation, was the most important molecular cluster in the PPI network. In addition, cyclin‑dependent kinase 1 (CDK1) may be a key molecule achieving the cell‑cycle‑regulatory function of cluster A. From the PPI network analysis, it was predicted that delayed cell cycle progression in excessive alveolar bone remodeling via downregulation of CDK1 may be another mechanism underling the anti‑osteopenic effect of RDE on alveolar bone.

Effect of an estrogen-deficient state and alendronate therapy on bone loss resulting from experimental periapical lesions in rats.

PubMed

Xiong, Haofei; Peng, Bin; Wei, Lili; Zhang, Xiaolei; Wang, Li

2007-11-01

The aim of the research was to evaluate the impact of an estrogen-deficient state and alendronate (ALD) therapy on bone loss resulting from experimental periapical lesions in rats. Periapical lesions were induced on ovariectomized (OVX) and sham-ovariectomized (Sham) rats. After sample preparation, histologic and radiographic examination for periapical bone loss area and an enzyme histochemical test for tartrate-resistant acid phosphatase (TRAP) were performed. The results showed that OVX significantly increased bone loss resulting from periradicular lesions. After daily subcutaneous injection of ALD, the bone loss area and the number of TRAP-positive cells (osteoclasts) were reduced. These findings suggested that alendronate may protect against increased bone loss from experimental periapical lesions in estrogen-deficient rats. Given recent recognition of adverse effects of bisphosphonates, including an increased risk for osteonecrosis, the findings from this study should not be interpreted as a new indication for ALD treatment. However, they may offer insight into understanding and predicting outcomes in female postmenopausal patients already on ALD therapy for medical indications.

Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells.

PubMed

Ma, Zhong-ping; Liao, Jia-cheng; Zhao, Chang; Cai, Dao-zhang

2015-08-01

Osteoporosis (OP) often increases the risk of bone fracture and other complications and is a major clinical problem. Previous studies have found that high blood pressure is associated with bone formation abnormalities, resulting in increased calcium loss. We have investigated the effect of the antihypertensive drug benidipine on bone marrow stromal cell (BMSC) differentiation into osteoblasts and bone formation under osteoporotic conditions. We used a combination of in vitro and in vivo approaches to test the hypothesis that benidipine promotes murine BMSC differentiation into osteoblasts. Alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), β-catenin, and low-density lipoprotein receptor-related protein 5 (LRP5) protein expression was evaluated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of benidipine. An ovariectomized (OVX) mouse model was used to investigate the effect of benidipine treatment for 3 months in vivo. We found that ALP, OCN, and RUNX2 expression was up-regulated and WNT/β-catenin signaling was enhanced in vitro and in vivo. In OVX mice that were intragastrically administered benidipine, bone parameters (trabecular thickness, bone mineral density, and trabecular number) in the distal femoral metaphysis were significantly increased compared with control OVX mice. Consistently, benidipine promoted BMSC differentiation into osteoblasts and protected against bone loss in OVX mice. Therefore, benidipine might be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and hypertension.

The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

PubMed Central

Léotoing, Laurent; Wauquier, Fabien; Guicheux, Jérôme; Miot-Noirault, Elisabeth; Wittrant, Yohann; Coxam, Véronique

2013-01-01

Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-κB, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent. PMID:23861901

Role of Oxidative Damage in Radiation-Induced Bone Loss

NASA Technical Reports Server (NTRS)

Schreurs, Ann-Sofie; Alwood, Joshua S.; Limoli, Charles L.; Globus, Ruth K.

2014-01-01

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation, and are at risk for increased skeletal fragility due to bone loss. Evidence from rodent experiments demonstrates that both microgravity and ionizing radiation can cause bone loss due to increased bone-resorbing osteoclasts and decreased bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fully understood. We hypothesized that excess reactive oxidative species (ROS), produced by conditions that simulate spaceflight, alter the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletal remodeling and culminating in bone loss. To test this, we used the MCAT mouse model; these transgenic mice over-express the human catalase gene targeted to mitochondria, the major organelle contributing free radicals. Catalase is an anti-oxidant that converts reactive species, hydrogen peroxide into water and oxygen. This animal model was selected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous system radio-sensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that mice overexpressing catalase in mitochondria of osteoblast and osteoclast lineage cells would be protected from the bone loss caused by simulated spaceflight. Over-expression of human catalase localized to mitochondria caused various skeletal phenotypic changes compared to WT mice; this includes greater bone length, decreased cortical bone area and moment of inertia, and indications of altered microarchitecture. These findings indicate mitochondrial ROS are important for normal bone-remodeling and skeletal integrity. Catalase over-expression did not fully protect skeletal tissue from structural decrements caused by simulated spaceflight; however there was significant protection in terms of cellular oxidative damage (MDA levels) to the skeletal tissue. Furthermore, we used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

Kaempferol stimulates bone sialoprotein gene transcription and new bone formation.

PubMed

Yang, Li; Takai, Hideki; Utsunomiya, Tadahiko; Li, Xinyue; Li, Zhengyang; Wang, Zhitao; Wang, Shuang; Sasaki, Yoko; Yamamoto, Hirotsugu; Ogata, Yorimasa

2010-08-15

Kaempferol is a typical flavonol-type flavonoid that is present in a variety of vegetables and fruits, and has a protective effect on postmenopausal bone loss. Bone sialoprotein (BSP) is thought to function in the initial mineralization of bone and could be crucial for osteoblast differentiation, bone matrix mineralization and tumor metastasis. In the present study we investigated the regulation of BSP transcription by kaempferol in rat osteoblast-like UMR106 cells, and the effect of kaempferol on new bone formation. Kaempferol (5 microM) increased BSP and Osterix mRNA levels at 12 h and up-regulated Runx2 mRNA expression at 6 h. Kaempferol increased luciferase activity of the construct pLUC3, which including the promoter sequence between nucleotides -116 to +60. Transcriptional stimulation by kaempferol abrogated in constructs included 2 bp mutations in the inverted CCAAT, CRE, and FRE elements. Gel shift analyses showed that kaempferol increased nuclear protein binding to CRE and FRE elements, whereas the CCAAT-protein complex did not change after kaempferol stimulation. Twelve daily injections of 5 microM kaempferol directly into the periosteum of parietal bones of newborn rats increased new bone formation. These data suggest that kaempferol increased BSP gene transcription mediated through inverted CCAAT, CRE, and FRE elements in the rat BSP gene promoter, and could induce osteoblast activities in the early stage of bone formation. (c) 2010 Wiley-Liss, Inc.

Effect of gallium nitrate on the expression of osteoprotegerin and receptor activator of nuclear factor‑κB ligand in osteoblasts in vivo and in vitro.

PubMed

Li, Jingwu; Wang, Guang-Bin; Feng, Xue; Zhang, Jing; Fu, Qin

2016-01-01

Osteoporosis is characterized by the progressive loss of bone mass and the micro‑architectural deterioration of bone tissue, leading to bone fragility and an increased risk of fracture. Gallium has demonstrated efficacy in the treatment of several diverse disorders that are characterized by accelerated bone loss. Osteoblasts orchestrate bone degradation by expressing the receptor activator of NF‑κB ligand (RANKL), however they additionally protect the skeleton by secreting osteoprotegerin (OPG). Therefore, the relative concentration of RANKL and OPG in bone is a key determinant of bone mass and strength. The current study demonstrated that gallium nitrate (GaN) is able to counteract bone loss in an experimental model of established osteoporosis. Ovariectomized (OVX) rats exhibited significantly increased bone mineral density following GaN treatment for 4 and 8 weeks by 19.3 and 37.3%, respectively (P<0.05). The bone volume of the OVX + GaN group was increased by 40.9% (P<0.05) compared with the OVX group. In addition, the current study demonstrated that GaN stimulates the synthesis of OPG however has no effect on the expression of RANKL in osteoblasts, as demonstrated by RT‑qPCR, western blotting and ELISA, resulting in an increase in the OPG/RANKL ratio and a reduction in osteoclast differentiation in vivo and in vitro.

Effect of gallium nitrate on the expression of osteoprotegerin and receptor activator of nuclear factor-κB ligand in osteoblasts in vivo and in vitro

PubMed Central

LI, JINGWU; WANG, GUANG-BIN; FENG, XUE; ZHANG, JING; FU, QIN

2016-01-01

Osteoporosis is characterized by the progressive loss of bone mass and the micro-architectural deterioration of bone tissue, leading to bone fragility and an increased risk of fracture. Gallium has demonstrated efficacy in the treatment of several diverse disorders that are characterized by accelerated bone loss. Osteoblasts orchestrate bone degradation by expressing the receptor activator of NF-κB ligand (RANKL), however they additionally protect the skeleton by secreting osteoprotegerin (OPG). Therefore, the relative concentration of RANKL and OPG in bone is a key determinant of bone mass and strength. The current study demonstrated that gallium nitrate (GaN) is able to counteract bone loss in an experimental model of established osteoporosis. Ovariectomized (OVX) rats exhibited significantly increased bone mineral density following GaN treatment for 4 and 8 weeks by 19.3 and 37.3%, respectively (P<0.05). The bone volume of the OVX + GaN group was increased by 40.9% (P<0.05) compared with the OVX group. In addition, the current study demonstrated that GaN stimulates the synthesis of OPG however has no effect on the expression of RANKL in osteoblasts, as demonstrated by RT-qPCR, western blotting and ELISA, resulting in an increase in the OPG/RANKL ratio and a reduction in osteoclast differentiation in vivo and in vitro. PMID:26647856

Bone as a source of organism vitality and regeneration.

PubMed

Mackiewicz, Zygmunt; Niklińska, Wiesława Ewa; Kowalewska, Jolanta; Chyczewski, Lech

2011-01-01

The most important features that determine the vital role of bone include: a) a continuous supply of calcium, which is indispensible for every cell of the entire organism at all times, and b) the delivery of circulating blood cells and some adult stem cells to keep the body vigorous, ready for self-reparation, and continuously rebuilding throughout life. These functions of bones are no less important than protecting the body cavities, serving as mechanical levers connected to the muscles, and determining the shape and dimensions of the entire organism. The aim of this review was to address some basic cellular and molecular knowledge to better understand the complex interactions of bone structural components. The apprehension of osteoblast differentiation and its local regulation has substantially increased in recent years. It has been suggested that osteocytes, cells within the bone matrix, act as regulatory mechanosensors. Therefore immobility as well as limited activity has a dramatic effect on bone structure and influences a broad spectrum of bone physiology-related functions as well as the functions of many other organs. Lifelong bone rebuilding is modulated through several pathways, including the Wnt pathway that regulates bone formation and resorption. In the adult skeleton, bone is continuously renewed in response to a variety of stimuli, such as the specific process of remodeling dependent on RANK/ /RANKL/OPG interactions. Better understanding of bone biology provides opportunities for the development of more effective prevention and treatment modalities for a variety of bone diseases, including new approaches to adult stem cell-based therapies.

Physical activity effects on bone metabolism.

PubMed

Smith, E L; Gilligan, C

1991-01-01

The incidence of osteoporotic fractures rises exponentially with age and is increasing faster than the demographic increase in the aging population. Physical activity has great potential to reduce the risk for osteoporotic fractures. Three independent but interactive factors contribute to the risk of fractures: bone strength, the risk of falling, and the effectiveness of neuromuscular response that protects the skeleton from injury. Exercise can reduce fracture risk not only by preventing bone loss, but by decreasing the risk of falling and the force of impact by improving strength, flexibility, balance, and reaction time. Extreme inactivity causes rapid bone loss of up to 40%, while athletic activity results in bone hypertrophy of up to 40%. Exercise intervention programs have reduced bone loss or increased bone mass in both men and women of various ages and initial bone status. These benefits have been shown for arm bone mineral content, total body calcium, spine, calcium bone index, tibia, and calcaneus. In both middle-aged and elderly women, physical activity intervention reduced bone loss or increased bone mass. The mechanisms for maintenance of skeletal integrity rely on a cellular response to hormonal and mechanical load stimuli. Studies in animal models show that training affects cellular activity. In osteoporotics, cellular erosion is increased and mineral apposition rate (MAR) decreased compared with normal age-matched controls. In contrast to this, sows trained on a treadmill 20 min per day for 20 weeks had greater active periosteal surface, periosteal MAR, and osteonal MAR than untrained sows.

TSG-6 Regulates Bone Remodeling through Inhibition of Osteoblastogenesis and Osteoclast Activation*S⃞

PubMed Central

Mahoney, David J.; Mikecz, Katalin; Ali, Tariq; Mabilleau, Guillaume; Benayahu, Dafna; Plaas, Anna; Milner, Caroline M.; Day, Anthony J.; Sabokbar, Afsaneh

2008-01-01

TSG-6 is an inflammation-induced protein that is produced at pathological sites, including arthritic joints. In animal models of arthritis, TSG-6 protects against joint damage; this has been attributed to its inhibitory effects on neutrophil migration and plasmin activity. Here we investigated whether TSG-6 can directly influence bone erosion. Our data reveal that TSG-6 inhibits RANKL-induced osteoclast differentiation/activation from human and murine precursor cells, where elevated dentine erosion by osteoclasts derived from TSG-6-/- mice is consistent with the very severe arthritis seen in these animals. However, the long bones from unchallenged TSG-6-/- mice were found to have higher trabecular mass than controls, suggesting that in the absence of inflammation TSG-6 has a role in bone homeostasis; we have detected expression of the TSG-6 protein in the bone marrow of unchallenged wild type mice. Furthermore, we have observed that TSG-6 can inhibit bone morphogenetic protein-2 (BMP-2)-mediated osteoblast differentiation. Interaction analysis revealed that TSG-6 binds directly to RANKL and to BMP-2 (as well as other osteogenic BMPs but not BMP-3) via composite surfaces involving its Link and CUB modules. Consistent with this, the full-length protein is required for maximal inhibition of osteoblast differentiation and osteoclast activation, although the isolated Link module retains significant activity in the latter case. We hypothesize that TSG-6 has dual roles in bone remodeling; one protective, where it inhibits RANKL-induced bone erosion in inflammatory diseases such as arthritis, and the other homeostatic, where its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts. PMID:18586671

Simulated weightlessness and synbiotic diet effects on rat bone mechanical strength

NASA Astrophysics Data System (ADS)

Sarper, Hüseyin; Blanton, Cynthia; DePalma, Jude; Melnykov, Igor V.; Gabaldón, Annette M.

2014-10-01

This paper reports results on exposure to simulated weightlessness that leads to a rapid decrease in bone mineral density known as spaceflight osteopenia by evaluating the effectiveness of dietary supplementation with synbiotics to counteract the effects of skeletal unloading. Forty adult male rats were studied under four different conditions in a 2 × 2 factorial design with main effects of diet (synbiotic and control) and weight condition (unloaded and control). Hindlimb unloading was performed at all times for 14 days followed by 14 days of recovery (reambulation). The synbiotic diet contained probiotic strains Lactobacillus acidophilus and Lactococcus lactis lactis and prebiotic fructooligosaccharide. This paper also reports on the development of a desktop three-point bending device to measure the mechanical strength of bones from rats subjected to simulated weightlessness. The importance of quantifying bone resistance to breakage is critical when examining the effectiveness of interventions against osteopenia resulting from skeletal unloading, such as astronauts experience, disuse or disease. Mechanical strength indices provide information beyond measures of bone density and microarchitecture that enhance the overall assessment of a treatment's potency. In this study we used a newly constructed three-point bending device to measure the mechanical strength of femur and tibia bones from hindlimb-unloaded rats fed an experimental synbiotic diet enriched with probiotics and fermentable fiber. Two calculated outputs for each sample were Young's modulus of elasticity and fracture stress. Bone major elements (calcium, magnesium, and phosphorous) were quantified using ICP-MS analysis. Hindlimb unloading was associated with a significant loss of strength in the femur, and with significant reductions in major bone elements. The synbiotic diet did not protect against these unloading effects. Tibia strength and major elements were not reduced by hindlimb unloading, as was the case for femur, but tibia bone strength was negatively affected by the synbiotic diet. Thus, unexpectedly, the synbiotic diet was associated with null or detrimental effects on bone strength.

Role of carbonic anhydrase in bone - Partial inhibition of disuse atrophy of bone by parenteral acetazolamide

NASA Technical Reports Server (NTRS)

Kenny, A. D.

1985-01-01

The effectiveness of orally and subcutaneously administered acetazolamide sodium in preventing denervation-induced bone loss in rats is examined. Male Sprague-Dawley rats were treated with acetazolamide either orally by incorporation of 0.2, 0.5, or 1.5 percent concentrations in their diet for 15 days, or subcutaneously by either injection of 0.5 ml/rat of a solution containing either 20 or 100 mg/ml of the drug twice daily for 15 days or by continuous infusion of 5, 50, 500, or 1000 mg/ml of acetazolamide sodium for 8 days using an osmotic minipump. The effects of acetazolamide on body weight, food consumption, and plasma calcium content are evaluated. It is observed that parenteral administration is equally effective as oral administration in partially preventing denervation-induced bone mass changes. The data reveal that approximately 50 percent protection occurs with daily doses of 1094, 129, and 8 mg/kg body weight for the oral, subcutaneous injection, and subcutaneous infusion methods, respectively.

Water extract of the fruits of Alpinia oxyphylla inhibits osteoclast differentiation and bone loss.

PubMed

Ha, Hyunil; Shim, Ki-Shuk; Kim, Taesoo; Lee, Chung-Jo; Park, Ji Hyung; Kim, Han Sung; Ma, Jin Yeul

2014-09-23

Excessive bone resorption by osteoclasts causes pathological bone destruction, seen in various bone diseases. There is accumulating evidence that certain herbal extracts have beneficial effects on bone metabolism. The fruits of Alpinia oxyphylla has been traditionally used for the treatment of diarrhea and enuresis. In this study, we investigated the effects of water extract of the fruits of Alpinia oxyphylla (WEAO) on osteoclast differentiation and osteoclast-mediated bone destruction. For osteoclast differentiation assay, mouse bone marrow-derived macrophages (BMMs) were cultured in the presence of RANKL and M-CSF. RANKL signaling pathways and gene expression of transcription factors regulating osteoclast differentiation were investigated by real-time PCR and Western blotting. A constitutively active form of NFATc1 was retrovirally transduced into BMMs. Bone resorbing activity of mature osteoclast was examined on a plate coated with an inorganic crystalline calcium phosphate. The in vivo effect against bone destruction was assessed in a murine model of RANKL-induced osteoporosis by micro-computed tomography and bone metabolism marker analyses. WEAO dose-dependently inhibited RANKL-induced osteoclast differentiation from BMMs by targeting the early stages of osteoclast differentiation. WEAO inhibited RANKL-induced expression of NFATc1, the master regulator of osteoclast differentiation. Overexpression of a constitutively active form of NFATc1 blunted the inhibitory effect of WEAO on osteoclast differentiation, suggesting that NFATc1 is a critical target of the inhibitory action of WEAO. WEAO inhibited RANKL-induced expression of c-Fos, an upstream activator of NFATc1, by suppressing the classical NF-κB signaling pathway. WEAO also inhibited RANKL-induced down-regulation of Id2 and MafB, negative regulators of NFATc1. WEAO does not directly affect bone resorbing activity of mature osteoclasts. In accordance with the in vitro results, WEAO attenuated RANKL-induced bone destruction in mice by inhibiting osteoclast differentiation. This study demonstrates that WEAO exhibits a protective effect against bone loss by inhibiting RANKL-induced osteoclast differentiation. These findings suggest that WEAO might be useful for the prevention and treatment of bone diseases associated with excessive bone resorption.

Olive Oil and Vitamin D Synergistically Prevent Bone Loss in Mice

PubMed Central

Tagliaferri, Camille; Davicco, Marie-Jeanne; Lebecque, Patrice; Georgé, Stéphane; Amiot, Marie-Jo; Mercier, Sylvie; Dhaussy, Amélie; Huertas, Alain; Walrand, Stéphane; Wittrant, Yohann; Coxam, Véronique

2014-01-01

As the Mediterranean diet (and particularly olive oil) has been associated with bone health, we investigated the impact of extra virgin oil as a source of polyphenols on bone metabolism. In that purpose sham-operated (SH) or ovariectomized (OVX) mice were subjected to refined or virgin olive oil. Two supplementary OVX groups were given either refined or virgin olive oil fortified with vitamin D3, to assess the possible synergistic effects with another liposoluble nutrient. After 30 days of exposure, bone mineral density and gene expression were evaluated. Consistent with previous data, ovariectomy was associated with increased bone turnover and led to impaired bone mass and micro-architecture. The expression of oxidative stress markers were enhanced as well. Virgin olive oil fortified with vitamin D3 prevented such changes in terms of both bone remodeling and bone mineral density. The expression of inflammation and oxidative stress mRNA was also lower in this group. Overall, our data suggest a protective impact of virgin olive oil as a source of polyphenols in addition to vitamin D3 on bone metabolism through improvement of oxidative stress and inflammation. PMID:25551374

The effects of simulated bone loss on the implant-abutment assembly and likelihood of fracture: an in vitro study.

PubMed

Manzoor, Behzad; Suleiman, Mahmood; Palmer, Richard M

2013-01-01

The crestal bone level around a dental implant may influence its strength characteristics by offering protection against mechanical failures. Therefore, the present study investigated the effect of simulated bone loss on modes, loads, and cycles to failure in an in vitro model. Different amounts of bone loss were simulated: 0, 1.5, 3.0, and 4.5 mm from the implant head. Forty narrow-diameter (3.0-mm) implant-abutment assemblies were tested using compressive bending and cyclic fatigue testing. Weibull and accelerated life testing analysis were used to assess reliability and functional life. Statistical analyses were performed using the Fisher-Exact test and the Spearman ranked correlation. Compressive bending tests showed that the level of bone loss influenced the load-bearing capacity of implant-abutment assemblies. Fatigue testing showed that the modes, loads, and cycles to failure had a statistically significant relationship with the level of bone loss. All 16 samples with bone loss of 3.0 mm or more experienced horizontal implant body fractures. In contrast, 14 of 16 samples with 0 and 1.5 mm of bone loss showed abutment and screw fractures. Weibull and accelerated life testing analysis indicated a two-group distribution: the 0- and 1.5-mm bone loss samples had better functional life and reliability than the 3.0- and 4.5-mm samples. Progressive bone loss had a significant effect on modes, loads, and cycles to failure. In addition, bone loss influenced the functional life and reliability of the implant-abutment assemblies. Maintaining crestal bone levels is important in ensuring biomechanical sustainability and predictable long-term function of dental implant assemblies.

Antibiotic-loaded bone void filler accelerates healing in a femoral condylar rat model.

PubMed

Shiels, S M; Cobb, R R; Bedigrew, K M; Ritter, G; Kirk, J F; Kimbler, A; Finger Baker, I; Wenke, J C

2016-08-01

Demineralised bone matrix (DBM) is rarely used for the local delivery of prophylactic antibiotics. Our aim, in this study, was to show that a graft with a bioactive glass and DBM combination, which is currently available for clinical use, can be loaded with tobramycin and release levels of antibiotic greater than the minimum inhibitory concentration for Staphylococcus aureus without interfering with the bone healing properties of the graft, thus protecting the graft and surrounding tissues from infection. Antibiotic was loaded into a graft and subsequently evaluated for drug elution kinetics and the inhibition of bacterial growth. A rat femoral condylar plug model was used to determine the effect of the graft, loaded with antibiotic, on bone healing. We found that tobramycin loaded into a graft composed of bioglass and DBM eluted antibiotic above the minimum inhibitory concentration for three days in vitro. It was also found that the antibiotic loaded into the graft produced no adverse effects on the bone healing properties of the DBM at a lower level of antibiotic. This antibiotic-loaded bone void filler may represent a promising option for the delivery of local antibiotics in orthopaedic surgery. Cite this article: Bone Joint J 2016;98-B:1126-31. ©2016 The British Editorial Society of Bone & Joint Surgery.

[Fetal bone and joint disorders].

PubMed

Jakobovits, Akos

2008-12-21

The article discusses the physiology and pathology of fetal bone and joint development and functions. The bones provide static support for the body. The skull and the bones of spinal column encase the central and part of the peripheral nervous system. The ribs and the sternum shield the heart and the lungs, while the bones of the pelvis protect the intraabdominal organs. Pathological changes of these bony structures may impair the functions of the respective systems or internal organs. Movements of the bones are brought about by muscles. The deriving motions are facilitated by joints. Bony anomalies of the extremities limit their effective functions. Apart from skeletal and joint abnormalities, akinesia may also be caused by neurological, muscular and skin diseases that secondarily affect the functions of bones and joints. Such pathological changes may lead to various degrees of physical disability and even to death. Some of the mentioned anomalies are recognizable in utero by ultrasound. The diagnosis may serve as medical indication for abortion in those instances when the identified abnormality is incompatible with independent life.

Selenium in bone health: roles in antioxidant protection and cell proliferation.

PubMed

Zeng, Huawei; Cao, Jay J; Combs, Gerald F

2013-01-10

Selenium (Se) is an essential trace element for humans and animals, and several findings suggest that dietary Se intake may be necessary for bone health. Such findings may relate to roles of Se in antioxidant protection, enhanced immune surveillance and modulation of cell proliferation. Elucidation of the mechanisms by which Se supports these cellular processes can lead to a better understanding of the role of this nutrient in normal bone metabolism. This article reviews the current knowledge concerning the molecular functions of Se relevant to bone health.

Selenium in Bone Health: Roles in Antioxidant Protection and Cell Proliferation

PubMed Central

Zeng, Huawei; Cao, Jay J.; Combs, Gerald F.

2013-01-01

Selenium (Se) is an essential trace element for humans and animals, and several findings suggest that dietary Se intake may be necessary for bone health. Such findings may relate to roles of Se in antioxidant protection, enhanced immune surveillance and modulation of cell proliferation. Elucidation of the mechanisms by which Se supports these cellular processes can lead to a better understanding of the role of this nutrient in normal bone metabolism. This article reviews the current knowledge concerning the molecular functions of Se relevant to bone health. PMID:23306191

Protective effects of the angiotensin type 1 receptor antagonist losartan in infection-induced and arthritis-associated alveolar bone loss.

PubMed

Queiroz-Junior, C M; Silveira, K D; de Oliveira, C R; Moura, A P; Madeira, M F M; Soriani, F M; Ferreira, A J; Fukada, S Y; Teixeira, M M; Souza, D G; da Silva, T A

2015-12-01

The angiotensin type 1 (AT1) receptor has been implicated in the pathogenesis of inflammatory bone disorders. This study aimed to investigate the effect of an AT1 receptor antagonist in infection-induced and arthritis-associated alveolar bone loss in mice. Mice were subjected to Aggregatibacter actinomycetemcomitans oral infection or antigen-induced arthritis and treated daily with 10 mg/kg of the prototype AT1 antagonist, losartan. Treatment was conducted for 30 d in the infectious condition and for 17 d and 11 d in the preventive or therapeutic regimens in the arthritic model, respectively. The mice were then killed, and the maxillae, serum and knee joints were collected for histomorphometric and immunoenzymatic assays. In vitro osteoclast assays were performed using RAW 264.7 cells stimulated with A. actinomycetemcomitans lipopolysacharide (LPS). Arthritis and A. actinomycetemcomitans infection triggered significant alveolar bone loss in mice and increased the levels of myeloperoxidase and of TRAP(+) osteoclasts in periodontal tissues. Losartan abolished such a phenotype, as well as the arthritis joint inflammation. Both arthritis and A. actinomycetemcomitans conditions were associated with the release of tumor necrosis factor alpha (TNF-α), interferon-gamma, interleukin-17 and chemokine (C-X-C motif) ligand 1 and an increased RANKL/osteoprotegerin ratio in periodontal tissues, but such expression decreased after losartan treatment, except for TNF-α. The therapeutic approach was as beneficial as the preventive one. In vitro, losartan prevented LPS-induced osteoclast differentiation and activity. The blockade of AT1 receptor exerts anti-inflammatory and anti-osteoclastic effects, thus protecting periodontal tissues in distinct pathophysiological conditions of alveolar bone loss. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Osteoprotective effect of combination therapy of low-dose oestradiol with G15, a specific antagonist of GPR30/GPER in ovariectomy-induced osteoporotic rats.

PubMed

Kang, Wen-Bo; Cong, Yu; Ru, Jiang-Ying; Ying, Si-Qi; Zhu, Ting; Wang, Dong-Sheng; Liu, Xiao-Wei; Liu, Gang; Zhao, Jian-Ning

2015-07-03

Identified and cloned in 1996 for the first time, G protein-coupled oestrogen receptor (ER) 30 (GPR30/GPER) has been a hot spot in the field of sex hormone research till now. In the present study, we examined the effects of low-dose oestradiol (E2) combined with G15, a specific antagonist of GPR30 on ovariectomy (OVX)-induced osteoporosis in rats. Female Sprague-Dawley (SD) rats undergoing OVX were used to evaluate the osteoprotective effect of the drugs. Administration of E2 [35 μg/kg, intraperitoneally (ip), three times/week) combining G15 (160 μg/kg, ip, three times/week) for 6 weeks was found to have prevented OVX-induced effects, including increase in bone turnover rate, decrease in bone mineral content (BMC) and bone mineral density (BMD), damage of bone structure and the aggravation in biomechanical properties of bone. The therapeutic effect of these two drugs in combination was better than that of E2 alone. Meanwhile, the administration of G15 prevented body weight increase or endometrium proliferation in the rats. In conclusion, administration of low-dose E2 combining G15 had a satisfactory bone protective effect for OVX rats, without significant influence on body weight or the uterus. This combination therapy may be an effective supplement of drugs in prevention and treatment for postmenopausal osteoporosis. © 2015 Authors.

Influence of obesity on bone mineral density in postmenopausal asthma patients undergoing treatment with inhaled corticosteroids.

PubMed

Yanik, Burcu; Ayrim, Aylin; Ozol, Duygu; Koktener, Asli; Gokmen, Derya

2009-01-01

The etiology of osteoporosis in asthma is complex as various factors contribute to its pathogenesis. The purpose of our study was to investigate the effects of obesity and inhaled steroids, as well as the severity and duration of asthma, on osteoporosis in postmenopausal asthma patients as compared to healthy controls. A total of 46 patients with asthma and 60 healthy female controls, all postmenopausal, were enrolled in our study. Bone mineral density was assessed at the lumbar spine and hip using a Lunar DPX-L densitometer. Bone mineral density (BMD) scores were comparable between the asthmatic and control groups, with average scores of 0.95 +/- 0.29 and 0.88 +/- 0.14 g/cm(2), respectively. Likewise, osteoporosis was diagnosed in a similar percentage of patients in the asthmatic (39.1%) and control (43.3%) groups. Bone fracture was identified in four patients with asthma (8.6%) and in six patients from the control group (10%). We could not detect any relationship between BMD and duration of asthma, asthma severity, inhaled steroids or body mass index (BMI). There was no difference between the two groups with respect to age or years since menopause. Although asthma patients were more likely to be overweight and presented higher BMD scores on average than the control subjects, these differences were not statistically significant. There is a slight positive protective effect of high BMI against osteoporosis in asthma patients, but this effect is overcome by time and menopause status. Therefore, the protective effect of obesity against osteoporosis in asthma patients seems to not be significant.

Bisphosphonates Improve Trabecular Bone Mass and Normalize Cortical Thickness in Ovariectomized, Osteoblast Connexin43 Deficient Mice

PubMed Central

Watkins, Marcus P.; Norris, Jin Yi; Grimston, Susan K.; Zhang, Xiaowen; Phipps, Roger J.; Ebetino, Frank H.; Civitelli, Roberto

2012-01-01

The gap junction protein, connexin43 (Cx43) controls both bone formation and osteoclastogenesis via osteoblasts and/or osteocytes. Cx43 has also been proposed to mediate an anti-apoptotic effect of bisphosphonates, potent inhibitors of bone resorption. We studied whether bisphosphonates are effective in protecting mice with a conditional Cx43 gene deletion in osteoblasts and osteocytes (cKO) from the consequences of ovariectomy on bone mass and strength. Ovariectomy resulted in rapid loss of trabecular bone followed by a slight recovery in wild type (WT) mice, and a similar degree of trabecular bone loss, albeit slightly delayed, occurred in cKO mice. Treatment with either risedronate (20µg/kg) or alendronate (40µg/kg) prevented ovariectomy-induced bone loss in both genotypes. In basal conditions, bones of cKO mice have larger marrow area, higher endocortical osteoclast number, and lower cortical thickness and strength relative to WT. Ovariectomy increased endocortical osteoclast number in WT but not in cKO mice. Both bisphosphonates prevented these increases in WT mice, and normalized endocortical osteoclast number, cortical thickness and bone strength in cKO mice. Thus, lack of osteoblast/osteocyte Cx43 does not alter bisphosphonate action on bone mass and strength in estrogen deficiency. These results support the notion that one of the main functions of Cx43 in cortical bone is to restrain osteoblast and/or osteocytes from inducing osteoclastogenesis at the endocortical surface. PMID:22750450

Increased Bone Mass in Female Mice Lacking Mast Cell Chymase

PubMed Central

Lind, Thomas; Gustafson, Ann-Marie; Calounova, Gabriela; Hu, Lijuan; Rasmusson, Annica; Jonsson, Kenneth B.; Wernersson, Sara; Åbrink, Magnus; Andersson, Göran; Larsson, Sune; Melhus, Håkan; Pejler, Gunnar

2016-01-01

Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age. Mcpt4-/- mice also showed increased levels of a bone anabolic serum marker and higher periosteal bone formation rate. However, they were not protected from experimental osteoporosis, suggesting that chymase regulates normal bone homeostasis rather than the course of osteoporosis. Further, the absence of Mcpt4 resulted in age-dependent upregulation of numerous genes important for bone formation but no effects on osteoclast activity. In spite of the latter, Mcpt4-/- bones had increased cortical porosity and reduced endocortical mineralization. Mast cells were found periosteally and, notably, bone-proximal mast cells in Mcpt4-/- mice were degranulated to a larger extent than in wild type mice. Hence, chymase regulates degranulation of bone mast cells, which could affect the release of mast cell-derived factors influencing bone remodelling. Together, these findings reveal a functional impact of mast cell chymase on bone. Further studies exploring the possibility of using chymase inhibitors as a strategy to increase bone volume may be warranted. PMID:27936149

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

PubMed

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

2013-05-10

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

The Protective Effect of Rhizoma Dioscoreae Extract against Alveolar Bone Loss in Ovariectomized Rats via Regulating Wnt and p38 MAPK Signaling

PubMed Central

Zhang, Zhiguo; Xiang, Lihua; Bai, Dong; Wang, Wenlai; Li, Yan; Pan, Jinghua; Liu, Hong; Wang, Shaojun; Xiao, Gary Guishan; Ju, Dahong

2014-01-01

Aim: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Methods: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17β-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). Results: Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). Conclusion: These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/β-catenin and the p38 MAPK signaling pathways via gene regulation. PMID:25514564

Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis.

PubMed

Hayami, Tadashi; Zhuo, Ya; Wesolowski, Gregg A; Pickarski, Maureen; Duong, Le T

2012-06-01

To investigate the disease modifying effects of cathepsin K (CatK) inhibitor L-006235 compared to alendronate (ALN) in two preclinical models of osteoarthritis (OA). Skeletally mature rabbits underwent sham or anterior cruciate ligament transection (ACLT)-surgery and were treated with L-006235 (L-235, 10 mg/kg or 50 mg/kg, p.o., daily) or ALN (0.6 mg/kg, s.c., weekly) for 8-weeks. ACLT joint instability was also induced in CatK(-/-) versus wild type (wt) mice and treated for 16-weeks. Changes in cartilage degeneration, subchondral bone volume and osteophyte area were determined by histology and μ-CT. Collagen type I helical peptide (HP-I), a bone resorption marker and collagen type II C-telopeptide (CTX-II), a cartilage degradation marker were measured. L-235 (50 mg/kg) and ALN treatment resulted in significant chondroprotective effects, reducing CTX-II by 60% and the histological Mankin score for cartilage damage by 46% in the ACLT-rabbits. Both doses of L-235 were more potent than ALN in protecting against focal subchondral bone loss, and reducing HP-I by 70% compared to vehicle. L-235 (50 mg/kg) and ALN significantly reduced osteophyte formation in histomorphometric analysis by 55%. The Mankin score in ACLT-CatK(-/-) mice was ~2.5-fold lower than the ACLT-wt mice and was not different from sham-CatK(-/-). Osteophyte development was not different among the groups. Inhibition of CatK provides significant benefits in ACLT-model of OA, including: 1) protection of subchondral bone integrity, 2) protection against cartilage degradation and 3) reduced osteophytosis. Preclinical evidence supports the role of CatK as a potential therapeutic target for the treatment of OA. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of exemestane, anastrozole and tamoxifen on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: results of N-SAS BC 04, the TEAM Japan substudy.

PubMed

Aihara, T; Suemasu, K; Takei, H; Hozumi, Y; Takehara, M; Saito, T; Ohsumi, S; Masuda, N; Ohashi, Y

2010-01-01

Use of aromatase inhibitors in women with postmenopausal breast cancer accompanies risks of bone loss. We evaluated changes in bone mineral density (BMD) and bone turnover markers in patients treated with exemestane, anastrozole or tamoxifen for hormone-sensitive postmenopausal early breast cancer. Sixty-eight patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational Japan bone substudy were randomly assigned to receive tamoxifen, exemestane or anastrozole. During a 2-year study period, lumbar spine BMD was measured using dual-energy X-ray absorptiometry, and urinary type I collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP) were also measured. BMD at 2 years of treatment was higher in tamoxifen patients compared with exemestane and anastrozole patients; however, the intergroup difference was not significant (p = 0.2521 and p = 0.0753, respectively). BMD was higher in exemestane patients compared with anastrozole patients; however, the intergroup difference was not significant (p = 0.7059 and p = 0.8134, respectively). NTX and BAP were significantly lower in tamoxifen patients compared with exemestane and anastrozole patients at 1 and 2 years of treatment (p < 0.05). Tamoxifen may provide better bone protection compared with exemestane or anastrozole. The effect of exemestane and anastrozole on bone loss may be comparable in Japanese postmenopausal women. Copyright © 2011 S. Karger AG, Basel.

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts*

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; Hess, Allan D.; Smith, B. Douglas; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2015-01-01

Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently up-regulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1α (PP1α) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1α or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1α-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis. PMID:26491017

[Optimizing staff radiation protection in radiology by minimizing the effective dose].

PubMed

von Boetticher, H; Lachmund, J; Hoffmann, W; Luska, G

2006-03-01

In the present study the optimization of radiation protection devices is achieved by minimizing the effective dose of the staff members since the stochastic radiation effects correlate to the effective dose. Radiation exposure dosimetry was performed with TLD measurements using one Alderson Phantom in the patient position and a second phantom in the typical position of the personnel. Various types of protective clothing as well as fixed shields were considered in the calculations. It was shown that the doses of the unshielded organs (thyroid, parts of the active bone marrow) contribute significantly to the effective dose of the staff. Therefore, there is no linear relationship between the shielding factors for protective garments and the effective dose. An additional thyroid protection collar reduces the effective dose by a factor of 1.7 - 3.0. X-ray protective clothing with a 0.35 mm lead equivalent and an additional thyroid protection collar provides better protection against radiation than an apron with a 0.5 mm lead equivalent but no collar. The use of thyroid protection collars is an effective preventive measure against exceeding occupational organ dose limits, and a thyroid shield also considerably reduces the effective dose. Therefore, thyroid protection collars should be a required component of anti-X protection.

Bone mass regulation of leptin and postmenopausal osteoporosis with obesity.

PubMed

Legiran, Siswo; Brandi, Maria Luisa

2012-09-01

Leptin has been known to play a role in weight regulation through food intake and energy expenditure. Leptin also has an important role in bone metabolism. The role of leptin is determined by leptin receptors, either central or peripheral to the bones. We discuss the role of leptin on bone and molecular genetics of osteoporosis in postmenopausal obese women. The role of leptin in bone preserves bone mineral density (BMD) through increased OPG levels leading to bind RANKL, resulting in reducing osteoclast activity. The estrogen role on bone is also mediated by RANKL and OPG. In postmenopausal women who have estrogen deficiency, it increases the rate of RANKL, which increases osteoclastogenesis. Obese individuals who have a high level of leptin will be effected by bone protection. There are similarities in the mechanism between estrogen and leptin in influencing the process of bone remodeling. It may be considered that the role of estrogen can be replaced by leptin. Molecular genetic aspects that play a role in bone remodeling, such as leptin, leptin receptors, cytokines (e.g. RANK, RANKL, and OPG), require further study to be useful, especially regarding osteoporosis therapy based on genetic analysis.

p53-Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan

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

Su, Hang, E-mail: suh3@uthscsa.edu; Ganapathy, Suthakar; Li, Xiaolei

Purpose: The main drawbacks of radioimmunotherapy have been severe hematological toxicity and potential development of myelodysplastic syndrome and secondary leukemia. Activation of p53 follows a major pathway by which normal tissues respond to DNA-damaging agents, such as chemotherapy and radiation therapy, that result in injuries and pathological consequences. This pathway is separate from the tumor suppressor pathway of p53. We have previously reported that use of low-dose arsenic (LDA) temporarily and reversibly suppresses p53 activation, thereby ameliorating normal tissue toxicity from exposure to 5-fluorouracil and X rays. We have also demonstrated that LDA-mediated protection requires functional p53 and thus ismore » selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Here we tested the protective efficacy of LDA for bone marrow tissue against radioimmunotherapy through animal experiments. Methods and Materials: Mice were subjected to LDA pretreatment for 3 days, followed by treatment with Y-90 ibritumomab tiuxetan. Both dose course (10, 25, 50, 100, and 200 μCi) and time course (6, 24, and 72 hours and 1 and 2 weeks) experiments were performed. The response of bone marrow cells to LDA was determined by examining the expression of NFκB, Glut1, and Glut3. Staining with hematoxylin and eosin, γ-H2AX, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to examine morphology, DNA damage response, and apoptotic cell populations. Results: Elevated levels of NFκB, Glut1, and Glut3 were observed in bone marrow cells after LDA treatment. Bone marrow damage levels induced by Y-90 ibritumomab tiuxetan were greatly reduced by LDA pretreatment. Consistent with this observation, significantly less DNA damage and fewer apoptotic cells were accumulated after Y-90 ibritumomab tiuxetan treatment in LDA-pretreated mice. Furthermore, in the mouse xenograft model implanted with human Karpas-422 lymphoma cells, LDA pretreatment did not have any detectable effect on either tumor growth or Y-90 ibritumomab tiuxetan (200 μCi)-induced tumor suppression. Conclusions: LDA pretreatment protected bone marrow without compromising tumor control caused by Y-90 ibritumomab tiuxetan.« less

Effects of Arbutin on Radiation-Induced Micronuclei in Mice Bone Marrow Cells and Its Definite Dose Reduction Factor

PubMed Central

Nadi, Saba; Monfared, Ali Shabestani; Mozdarani, Hossein; Mahmodzade, Aziz; Pouramir, Mahdi

2016-01-01

Background: Interactions of free radicals from ionizing radiation with DNA can induce DNA damage and lead to mutagenesis and carsinogenesis. With respect to radiation damage to human, it is important to protect humans from side effects induced by ionizing radiation. In the present study, the effects of arbutin were investigated by using the micronucleus test for anti-clastogenic activity, to calculate the ratio of polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte (PCE/PCE+NCE) in order to show cell proliferation activity. Methods: Arbutin (50, 100, and 200 mg/kg) was intraperitoneally (ip)administered to NMRI mice two hours before gamma radiation at 2 and 4 gray (Gy). The frequency of micronuclei in 1000 PCEs (MnPCEs) and the ratio of PCE/PCE+NCE were calculated for each sample. Data were statistically evaluated using one-way ANOVA, Tukey HSD test, and t-test. Results: The findings indicated that gamma radiation at 2 and 4 Gy extremely increased the frequencies of MnPCE (P<0.001) while reducing PCE/PCE+NCE (P<0.001) compared to the control group. All three doses of arbutin before irradiation significantly reduced the frequencies of MnPCEs and increased the ratio of PCE/PCE+NCE in mice bone marrow compared to the non-drug-treated irradiated control (P<0.001). All three doses of arbutin had no toxicity effect on bone marrow cells. The calculated dose reduction factor (DRF) showed DRF=1.93 for 2Gy and DRF=2.22 for 4 Gy. Conclusion: Our results demonstrated that arbutin gives significant protection to rat bone against the clastogenic and cytotoxic effects of gamma irradiation. PMID:27217601

Artificial Gravity: Will it Preserve Bone Health on Long-Duration Missions?

NASA Technical Reports Server (NTRS)

Davis-Street, Janis; Paloski, William H.

2005-01-01

Prolonged microgravity exposure disrupts bone, muscle, and cardiovascular homeostasis, sensory-motor coordination, immune function, and behavioral performance. Bone loss, in particular, remains a serious impediment to the success of exploration-class missions by increasing the risks of bone fracture and renal stone formation for crew members. Current countermeasures, consisting primarily of resistive and aerobic exercise, have not yet proven fully successful for preventing bone loss during long-duration spaceflight. While other bone-specific countermeasures, such as pharmacological therapy and dietary modifications, are under consideration, countermeasure approaches that simultaneously address multiple physiologic systems may be more desirable for exploration-class missions, particularly if they can provide effective protection at reduced mission resource requirements (up-mass, power, crew time, etc). The most robust of the multi-system approaches under consideration, artificial gravity (AG), could prevent all of the microgravity-related physiological changes from occurring. The potential methods for realizing an artificial gravity countermeasure are reviewed, as well as selected animal and human studies evaluating the effects of artificial gravity on bone function. Future plans for the study of the multi-system effects of artificial gravity include a joint, cooperative international effort that will systematically seek an optimal prescription for intermittent AG to preserve bone, muscle, and cardiovascular function in human subjects deconditioned by 6 degree head-down-tilt-bed rest. It is concluded that AG has great promise as a multi-system countermeasure, but that further research is required to determine the appropriate parameters for implementation of such a countermeasure for exploration-class missions.

Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis

PubMed Central

Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

2016-01-01

Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

Black rice (Oryza sativa L.) extracts induce osteoblast differentiation and protect against bone loss in ovariectomized rats.

PubMed

Jang, Woo-Seok; Seo, Cho-Rong; Jang, Hwan Hee; Song, No-Joon; Kim, Jong-Keun; Ahn, Jee-Yin; Han, Jaejoon; Seo, Woo Duck; Lee, Young Min; Park, Kye Won

2015-01-01

Osteoporosis, an age associated skeletal disease, exhibits increased adipogenesis at the expense of osteogenesis from common osteoporotic bone marrow cells. In this study, black rice (Oryza sativa L.) extracts (BRE) were identified as osteogenic inducers. BRE stimulated the alkaline phosphatase (ALP) activity in both C3H10T1/2 and primary bone marrow cells. Similarly, BRE increased mRNA expression of ALP and osterix. Oral administration of BRE in OVX rats prevented decreases in bone density and strength. By contrast, BRE inhibited adipocyte differentiation of mesenchymal C3H10T1/2 cells and prevented increases in body weight and fat mass in high fat diet fed obese mice, further suggesting the dual effects of BRE on anti-adipogenesis and pro-osteogenesis. UPLC analysis identified cyanidin-3-O-glucoside and peonidin-3-O-glucoside as main anti-adipogenic effectors but not for pro-osteogenic induction. In mechanism studies, BRE selectively stimulated Wnt-driven luciferase activities. BRE treatment also induced Wnt-specific target genes such as Axin2, WISP2, and Cyclin D1. Taken together, these data suggest that BRE is a potentially useful ingredient to protect against age related osteoporosis and diet induced obesity.

The fast track to canonical Wnt signaling in MC3T3-E1 cells protected by substance P against serum deprivation-induced apoptosis.

PubMed

Yang, Jianguo; Nie, Jiping; Fu, Su; Liu, Song; Wu, Jianqun; Cui, Liang; Zhang, Yongtao; Yu, Bin

2017-01-01

The canonical Wnt pathway is vital to bone physiology by increasing bone mass through elevated osteoblast survival. Although investigated extensively in stem cells, its role in osteoblastic MC3T3-E1 cells has not been completely determined. To explore how this pathway is regulated by different conditions, we assessed the anti-apoptotic effects of substance P on the canonical Wnt pathway in MC3T3-E1 cells by treating cells with serum deprivation or serum starving with "substance P," a neuropeptide demonstrated to promote bone growth and stimulate Wnt signaling. The results showed that serum deprivation both induced apoptosis and activated Wnt signal transduction while substance P further stimulated the Wnt pathway via the NK-1 receptor but protected the cells from apoptotic death. Fast-tracking of Wnt signaling by substance P was also noted. These results indicate that nutritional deprivation and substance P synergistically activated the canonical Wnt pathway, a finding that helps to reveal the role of Wnt signaling in bone physiology affected by nutritional deprivation and neuropeptide substance P. © 2016 International Federation for Cell Biology.

Efficacy of anti-IL-23 monotherapy versus combination therapy with anti-IL-17 in estrogen deficiency induced bone loss conditions.

PubMed

Shukla, Priyanka; Mansoori, Mohd Nizam; Singh, Divya

2018-05-01

Recent studies have identified that Interleukin (IL)-23/IL-17 axis plays crucial role in pathogenesis of inflammation and bone destruction. IL-23 is thought to promote joint destruction in arthritis by stimulating Th17 cells. IL-23 directly mediates bone loss by inducing osteoclastogenesis and receptor activator of kappa B ligand (RANKL) expression in T cells. IL-23 also promotes tartrate-resistant acid phosphatase (TRAP) activity of osteoclast in osteoblast-osteoclast co-culture. The role of IL-23 has not been studied in estrogen deficiency induced bone loss. Here, we study the effect of IL-23 neutralization in ovariectomized (Ovx) estrogen deficient mice on various immune and skeletal parameters. We also determine whether the combination of anti-IL-23 and anti-IL17 has enhanced osteoprotective effects compared to monotherapies. Treatment of anti-IL-23 and its combination with anti-IL-17 suppressed Th17 cell differentiation and promoted development of T regulatory cells. Anti-IL-23 and its combination with anti-IL-17 prevented bone loss. However, the individual monotherapies of anti-IL-23 and anti-IL-17 were more effective than combination therapy. Treatment of IL-17 and IL-23 cytokines to bone marrow stromal cells led to increased differentiation towards osteoblast lineage. Double neutralization of IL-23 and IL-17 might be inhibiting this phenomenon thus producing less potent effects. Our studies thus support bone protective effects of anti-IL-23 and that the monotherapies of neutralizing antibodies against IL-17 and IL-23 may be a more accepted mode of treatment in management of post-menopausal bone loss rather than combination therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Complex association between body weight and fracture risk in postmenopausal women.

PubMed

Mpalaris, V; Anagnostis, P; Goulis, D G; Iakovou, I

2015-03-01

Osteoporosis is a common disease, characterized by low bone mass with micro-architectural disruption and skeletal fragility, resulting in an increased risk of fracture. A substantial number of studies has examined the possible relationship between body weight, bone mineral density and fracture risk in post-menopausal women, with the majority of them concluding that low body weight correlates with increased risk of fracture, especially hip fracture. Controversies about the potential protective effect of obesity on osteoporosis and consequent fracture risk still exist. Several recent studies question the concept that obesity exerts a protective effect against fractures, suggesting that it stands as a risk factor for fractures at specific skeletal sites, such as upper arm. The association between body weight and fracture risk is complex, differs across skeletal sites and body mass index, and is modified by the interaction between body weight and bone mineral density. Some potential explanations that link obesity with increased fracture risk may be the pattern of falls and impaired mobility in obese individuals, comorbidities, such as asthma, diabetes and early menopause, as well as, increased parathyroid hormone and reduced 25-hydroxy-vitamin D concentrations. © 2015 World Obesity.

Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

DTIC Science & Technology

2015-10-01

several recently identified small molecules can protect hematopoietic stem cells (HSCs) from damage or killing by endogenous aldehydes . Proof-of-concept...anemia bone marrow failure CD34+ hematopoietic stem cells aldehydes formaldehyde DNA damage DNA base adduct DNA-protein crosslink mass...below. Revised Specific Aim 1: Small molecule protection of human cells from aldehyde - induced killing (in vitro studies - no mice or human subjects

Soy Components vs. Whole Soy: Are We Betting Our Bones on a Long Shot?123

PubMed Central

Reinwald, Susan; Weaver, Connie M.

2010-01-01

Soybeans are a good source of bone-healthy nutrients. Epidemiological studies in Asia evaluating diets containing traditional whole soy foods show a positive association with bone mineral density and fracture protection. Smaller scale intervention studies in Western nations mainly feature isolated soy protein (SP) and purified or concentrated soy isoflavones (SI) rather than whole soy foods and they have produced inconsistent results. Consumption of SP does not alter calcium (Ca) retention even though urinary Ca excretion is less in diets with SP compared with proteins higher in sulfur-containing amino acids. SI, often consumed at higher concentrations than would be available in traditional Asian diets, are not yielding the type of incontrovertible evidence that might be expected in support of their benefit to bone health. This forces one to ask whether whole soy might provide a superior effect on bone. PMID:20980647

Does selective beta-1 blockade provide bone marrow protection after trauma/hemorrhagic shock?

PubMed

Pasupuleti, Latha V; Cook, Kristin M; Sifri, Ziad C; Kotamarti, Srinath; Calderon, Gabriel M; Alzate, Walter D; Livingston, David H; Mohr, Alicia M

2012-09-01

Previously, nonselective beta-blockade (BB) with propranolol demonstrated protection of the bone marrow (BM) after trauma and hemorrhagic shock (HS). Because selective beta-1 blockers are used commonly for their cardiac protection, the aim of this study was to more clearly define the role of specific beta adrenergic receptors in BM protection after trauma and HS. Male Sprague-Dawley rats underwent unilateral lung contusion (LC) followed by HS for 45 minutes. After resuscitation, animals were injected with a selective beta-blocker, atenolol (B1B), butoxamine (B2B), or SR59230A (B3B). Animals were killed at 3 hours or 7 days. Heart rate and blood pressure were measured throughout the study period. BM cellularity, growth of hematopoietic progenitor cells (HPCs) in BM, and hemoglobin levels (Hb) were assessed. Treatment with a B2B or B3B after LCHS restored both BM cellularity and BM HPC colony growth at 3 hours and 7 days. In contrast, treatment with a B1B had no effect on BM cellularity or HPC growth but did decrease heart effectively rate throughout the study. Treatment with a B3B after LCHS increased Hb as compared with LCHS alone. After trauma and HS, protection of BM for 7 days was seen with use of either a selective beta-2 or beta-3 blocker. Use of a selective beta-1 blocker was ineffective in protecting the BM despite a physiologic decrease in heart rate. Therefore, the protection of BM is via the beta-2 and beta-3 receptors and it is not via a direct cardiovascular effect. Published by Mosby, Inc.

Lysophosphatidic acid rescues bone mesenchymal stem cells from hydrogen peroxide-induced apoptosis.

PubMed

Wang, Xian-Yun; Fan, Xue-Song; Cai, Lin; Liu, Si; Cong, Xiang-Feng; Chen, Xi

2015-03-01

The increase of reactive oxygen species in infracted heart significantly reduces the survival of donor mesenchymal stem cells, thereby attenuating the therapeutic efficacy for myocardial infarction. In our previous study, we demonstrated that lysophosphatidic acid (LPA) protects bone marrow-derived mesenchymal stem cells (BMSCs) against hypoxia and serum deprivation-induced apoptosis. However, whether LPA protects BMSCs from H2O2-induced apoptosis was not examined. In this study, we report that H2O2 induces rat BMSC apoptosis whereas LPA pre-treatment effectively protects BMSCs from H2O2-induced apoptosis. LPA protection of BMSC from the induced apoptosis is mediated mostly through LPA3 receptor. Furthermore, we found that membrane G protein Gi2 and Gi3 are involved in LPA-elicited anti-apoptotic effects through activation of ERK1/2- and PI3 K-pathways. Additionally, H2O2 increases levels of type II of light chain 3B (LC3B II), an autophagy marker, and H2O2-induced autophagy thus protected BMSCs from apoptosis. LPA further increases the expression of LC3B II in the presence of H2O2. In contrast, autophagy flux inhibitor bafilomycin A1 has no effect on LPA's protection of BMSC from H2O2-induced apoptosis. Taken together, our data suggest that LPA rescues H2O2-induced apoptosis mainly by interacting with Gi-coupled LPA3, resulting activation of the ERK1/2- and PI3 K/AKT-pathways and inhibition caspase-3 cleavage, and LPA protection of BMSCs against the apoptosis is independent of it induced autophagy.

The impact of diabetes and diabetes medications on bone health.

PubMed

Gilbert, Matthew P; Pratley, Richard E

2015-04-01

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women. In contrast, metformin and sulfonylureas do not appear to have a negative effect on bone health and may, in fact, protect against fragility fracture. Animal models indicate a potential role for incretin hormones in bone metabolism, but there are only limited data on the impact of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists on bone health in humans. Animal models also have demonstrated a role for amylin in bone metabolism, but clinical trials in patients with type 1 diabetes with an amylin analog (pramlintide) have not shown a significant impact on bone metabolism. The effects of insulin treatment on fracture risk are inconsistent with some studies showing an increased risk and others showing no effect. Finally, although there is limited information on the latest class of medications for the treatment of T2DM, the sodium-glucose co-transporter-2 inhibitors, these drugs do not seem to increase fracture risk. Because diabetes is an increasingly common chronic condition that can affect patients for many decades, further research into the effects of agents for the treatment of T2DM on bone metabolism is warranted. In this review, the physiological mechanisms and clinical impact of diabetes treatments on bone health and fracture risk in patients with T2DM are described.

The mechanical and morphological properties of bone beneath internal fixation plates of differing rigidity.

PubMed

Claes, L

1989-01-01

The internal fixation of diaphyseal fractures by bone plates is a well recognized treatment. The normal physiological stress of bone is reduced by plates that cause a negative balance of bone-remodeling processes. Many investigators have shown that the degree of stress protection is dependent on the rigidity of the plates. It was the aim of this study to quantify mechanical and morphological changes at different locations in a plated diaphyseal bone as a function of differing plate rigidity. Two types of plates with the same size but different materials were used. The stainless steel plates had a modulus of elasticity and bending stiffness 3.2 times higher than the carbon fiber reinforced carbon plates. Both types of plates were applied to the intact right and left femora of six foxhounds for 6 months. The stiffer stainless steel plates led to a significantly higher bone loss and correspondingly greater loss of mechanical properties. These effects were greatest directly beneath the plate and less with increasing distance from the plate.

Effects of honey supplementation combined with different jumping exercise intensities on bone mass, serum bone metabolism markers and gonadotropins in female rats

PubMed Central

2014-01-01

Background The effects of high and low jumping exercise intensities combined with honey on bone and gonadotrophins were investigated in eighty four 9 week-old female rats. Methods The experimental groups were 20 or 80 jumps per day combined with or without honey supplementation (HJ20, HJ80, J20 and J80), honey supplementation (H), sedentary without supplementation control (C), and baseline control (C0) groups. Results Study results showed that HJ80 elicited greatest beneficial effects on tibial and femoral mass, serum total calcium and alkaline phosphatase concentrations. There were significantly (p < 0.05) lower levels of serum follicle stimulating hormone concentrations in H, J20, J80 compared to C, with exception of HJ20 and HJ80. Serum luteinizing hormone concentrations were significantly (p < 0.05) greater in HJ20, HJ80 and J20 compared to J80. Conclusions It appears that high intensity jumping exercise combined with honey supplementation resulted more discernable effects on bone. Meanwhile, honey may protect against the adverse effects induced by jumping exercise on gonadotropins in female rats. PMID:24708608

Epigallocatechin-3-Gallate Ameliorates Glucocorticoid-Induced Osteoporosis of Rats in Vivo and in Vitro.

PubMed

Liu, Shengye; Yang, Liyu; Mu, Shuai; Fu, Qin

2018-01-01

Background: Prolonged administration of overdoses of glucocorticoids results in increased bone remodeling, leading to glucocorticoid-induced osteoporosis (GIO), which is primarily due to the dysfunction and apoptosis of osteoblasts. The present study investigated the therapeutic effect and molecular mechanism of action of epigallocatechin-3-gallate (EGCG), a bioactive catechin in green tea, in high-dose dexamethasone-induced osteoblast differentiation in vivo and in vitro . Methods: The anti-dexamethasone (DEX) effects of EGCG on primary osteoblasts were determined on the basis of cell viability and alkaline phosphatase (ALP) and total cellular superoxide dismutase (SOD) activities. Flow cytometry and Western blot analysis were also used to evaluate the expression of related biomarkers in vitro , and bone microarchitecture was also extensively examined in a rat model in vivo . Results: The results showed that EGCG pretreatment significantly increased osteoblast viability and ALP and SOD activities when cells were exposed to DEX. Alizarin red staining indicated that there was more mineralization with EGCG pretreatment, countering DEX effects. EGCG reduced DEX-induced reactive oxygen species at both the mitochondrial and cellular levels in osteoblasts by activating the nuclear factor erythroid-derived 2-like-2 (Nrf2) pathway. In addition, EGCG protected osteoblasts from apoptosis. EGCG also regulated the formation of active glucocorticoid by 11β-hydroxysteroid dehydrogenase activity. Furthermore, femoral micro-computed tomography scans revealed that EGCG improved bone microstructure and mitigated DEX-induced deterioration of bone quality. Conclusion: These findings suggested that EGCG reversed GIO in rats by protecting osteoblasts by activating the Nrf2 signaling pathway.

Probiotics Protect Mice from Ovariectomy-Induced Cortical Bone Loss

PubMed Central

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

2014-01-01

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

Probiotics protect mice from ovariectomy-induced cortical bone loss.

PubMed

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

2014-01-01

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

Genistein treatment increases bone mass in obese, hyperglycemic mice.

PubMed

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.

Pilot Study: Unique Response of Bone Tissue During an Investigation of Radio-Adaptive Effects in Mice

NASA Technical Reports Server (NTRS)

Sibonga, J. D.; Iwaniec, U.; Wu, H.

2011-01-01

PURPOSE: We obtained bone tissue to evaluate the collateral effects of experiments designed to investigate molecular mechanisms of radio-adaptation in a mouse model. Radio-adaptation describes a process by which the prior exposure to low dose radiation can protect against the toxic effect of a subsequent high dose exposure. In the radio-adaptation experiments, C57Bl/6 mice were exposed to either a Sham or a priming Low Dose (5 cGy) of Cs-137 gamma rays before being exposed to either a Sham or High Dose (6 Gy) 24 hours later. ANALYSIS: Bone tissue were obtained from two experiments where mice were sacrificed at 3 days (n=3/group, 12 total) and at 14 days (n=6/group, 24 total) following high dose exposure. Tissues were analyzed to 1) evaluate a radio-adaptive response in bone tissue and 2) describe cellular and microstructural effects for two skeletal sites with different rates of bone turnover. One tibia and one lumbar vertebrae (LV2), collected at the 3-day time-point, were analyzed by bone histomorphometry and micro-CT to evaluate the cellular response and any evidence of microarchitectural impact. Likewise, tibia and LV2, collected at the 14-day time-point, were analyzed by micro-CT alone to evaluate resulting changes to bone structure and microarchitecture. The data were analyzed by 2-way ANOVA to evaluate the effects of the priming low dose radiation, of the high dose radiation, and of any interaction between the priming low and high doses of radiation. Bone histomorphometry was performed in the cancellous bone (aka trabecular bone) compartments of the proximal tibial metaphysis and of LV2. RESULTS: Cellular Response @ 3 Days The priming Low Dose radiation decreased osteoblast-covered bone perimeter in the proximal tibia and the total cell density in the bone marrow in the LV2. High Dose radiation, regardless of prior exposure to priming dose, dramatically reduced total cell density in bone marrow of both the long bone and vertebra. However, in the proximal tibia, High Dose radiation increased the osteoclast-covered bone perimeters, the density of adipocytes in bone marrow, and the area of bone marrow occupied by fat cells -- while in the LV2, adipocytes were rare and not stimulated by High Dose radiation. In an unexpected response, High Dose radiation dramatically increased (10-fold) osteoblast-covered bone perimeter in the LV2.

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

PubMed

Misiorowski, Waldemar

2011-01-01

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

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

PubMed

Misiorowski, Waldemar

2011-01-01

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

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

PubMed

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

2017-12-01

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

A modified cementing technique using BoneSource to augment fixation of the acetabulum in a sheep model.

PubMed

Timperley, A John; Nusem, Iulian; Wilson, Kathy; Whitehouse, Sarah L; Buma, Pieter; Crawford, Ross W

2010-08-01

Our aim was to assess in an animal model whether the use of HA paste at the cement-bone interface in the acetabulum improves fixation. We examined, in sheep, the effect of interposing a layer of hydroxyapatite cement around the periphery of a polyethylene socket prior to fixing it using polymethylmethacrylate (PMMA). We performed a randomized study involving 22 sheep that had BoneSource hydroxyapatite material applied to the surface of the acetabulum before cementing a polyethylene cup at arthroplasty. We studied the gross radiographic appearance of the implant-bone interface and the histological appearance at the interface. There were more radiolucencies evident in the control group. Histologically, only sheep randomized into the BoneSource group exhibited a fully osseointegrated interface. Use of the hydroxyapatite material did not give any detrimental effects. In some cases, the material appeared to have been fully resorbed. When the material was evident in histological sections, it was incorporated into an osseointegrated interface. There was no giant cell reaction present. There was no evidence of migration of BoneSource to the articulation. The application of HA material prior to cementation of a socket produced an improved interface. The technique may be useful in humans, to extend the longevity of the cemented implant by protecting the socket interface from the effect of hydrodynamic fluid flow and particulate debris.

S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte–Renal Cell Interactions

PubMed Central

Pepper, Ruth J.; Wang, Hsu-Han; Rajakaruna, Gayathri K.; Papakrivopoulou, Eugenia; Vogl, Thomas; Pusey, Charles D.; Cook, H. Terence; Salama, Alan D.

2015-01-01

Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9−/−), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow–derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14−/− cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow–derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14−/− bone marrow–derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow–derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis. PMID:25759267

Treatment with Rhizoma Dioscoreae Extract Has Protective Effect on Osteopenia in Ovariectomized Rats

PubMed Central

Xiang, Lihua; Bai, Dong; Fu, Xiaowei; Wang, Wenlai; Li, Yan; Liu, Hong; Pan, Jinghua; Li, Ya'nan; Xiao, Gary Guishan; Ju, Dahong

2014-01-01

The aims of this study were to evaluate the osteoprotective effect of aqueous extract from Rhizoma Dioscoreae (RDE) on rats with ovariectomy- (OVX-) induced osteopenia. Our results show that RDE could inhibit bone loss of OVX rats after a 12-week treatment. The microarray analysis showed that 68 genes were upregulated and that 100 genes were downregulated in femurs of the RDE group rats compared to those in the OVX group. The Ingenuity Pathway Analysis (IPA) showed that several downregulated genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Sost, Lrp6, Tcf7l2, and Alpl) and the RANKL/RANK signaling pathway (Map2k6 and Nfatc4). These results revealed that the mechanism for an antiosteopenic effect of RDE might lie in the synchronous inhibitory effects on both the bone formation and the bone resorption, which is associated with modulating the Wnt/β-catenin signaling and the RANKL/RANK signaling. PMID:24526913

Treatment with Rhizoma Dioscoreae extract has protective effect on osteopenia in ovariectomized rats.

PubMed

Zhang, Zhiguo; Xiang, Lihua; Bai, Dong; Fu, Xiaowei; Wang, Wenlai; Li, Yan; Liu, Hong; Pan, Jinghua; Li, Ya'nan; Xiao, Gary Guishan; Ju, Dahong

2014-01-01

The aims of this study were to evaluate the osteoprotective effect of aqueous extract from Rhizoma Dioscoreae (RDE) on rats with ovariectomy- (OVX-) induced osteopenia. Our results show that RDE could inhibit bone loss of OVX rats after a 12-week treatment. The microarray analysis showed that 68 genes were upregulated and that 100 genes were downregulated in femurs of the RDE group rats compared to those in the OVX group. The Ingenuity Pathway Analysis (IPA) showed that several downregulated genes had the potential to code for proteins that were involved in the Wnt/ β -catenin signaling pathway (Sost, Lrp6, Tcf7l2, and Alpl) and the RANKL/RANK signaling pathway (Map2k6 and Nfatc4). These results revealed that the mechanism for an antiosteopenic effect of RDE might lie in the synchronous inhibitory effects on both the bone formation and the bone resorption, which is associated with modulating the Wnt/ β -catenin signaling and the RANKL/RANK signaling.

Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury

PubMed Central

Miao, Ming-san; Guo, Lin; Li, Rui-qi; Ma, Xiao

2016-01-01

Previous studies have shown that Radix Ilicis Pubescentis total flavonoids have a neuroprotective effect, but it remains unclear whether Radix Ilicis Pubescentis total flavonoids have a synergistic effect with the recombinant human granulocyte colony stimulating factor-mobilized bone marrow stem cell transplantation on cerebral ischemia/reperfusion injury. Rat ischemia models were administered 0.3, 0.15 and 0.075 g/kg Radix Ilicis Pubescentis total flavonoids from 3 days before modeling to 2 days after injury. Results showed that Radix Ilicis Pubescentis total flavonoids could reduce pathological injury in rats with cerebral ischemia/reperfusion injury. The number of Nissl bodies increased, Bax protein expression decreased, Bcl-2 protein expression increased and the number of CD34-positive cells increased. Therefore, Radix Ilicis Pubescentis total flavonoids can improve the bone marrow stem cell mobilization effect, enhance the anti-apoptotic ability of nerve cells, and have a neuroprotective effect on cerebral ischemia/reperfusion injury in rats. PMID:27073381

Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway

PubMed Central

Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

2016-01-01

Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

Acute immunosuppression and syngeneic bone marrow transplantation in ocular autoimmunity abort disease, but do not result in induction of long-term protection.

PubMed

Savion, S; Silver, P B; Chan, C C; Caspi, R R

1998-09-01

Acute immunosuppression induced by total body irradiation (TBI) or cyclophosphamide (Cy) treatment, followed by syngeneic bone marrow transplantation (SBMT), was reported to be effective in inducing long-term tolerance in some autoimmune disease models. We examined the efficacy of this approach in the mouse model of experimental autoimmune uveoretinitis (EAU). Development of EAU induced by the interphotoreceptor retinoid binding protein (IRBP) was abolished almost completely by either TBI or Cy treatment, followed by SBMT, instituted one week after priming. In parallel, IRBP-specific delayed-type hypersensitivity (DTH) responses and lymph node cell proliferation were strongly suppressed or abolished. However, when these IRBP-immunized, lymphoablated and BM reconstituted mice were rechallenged with the immunizing antigen seven weeks after the primary immunization, they were not protected from developing disease, despite the fact that DTH and lymph node cell proliferation to the antigen were suppressed relative to controls. TBI treatment appeared somewhat more effective than Cy treatment as judged by its more profound effect on immunological responses. These results demonstrate the ability of acute immunosuppression followed by reconstitution of the immune system to inhibit the development of EAU, although long-term protection from disease was not achieved.

[Protective effects of astaxanthin against oxidative damage induced by 60Co gamma-ray irradiation].

PubMed

Zhao, Wei; Jing, Xuejun; Chen, Chen; Cui, Jie; Yang, Mo; Zhang, Zunzhen

2011-09-01

To investigate the protection effect of haematococcus pluvialis (containing astaxanthin) against the impairment of anti-oxidative system and DNA damage in mice induced by 60Co gamma-rays. Fifty mice were randomly divided into five groups, i.e. three haematococcus pluvialis groups (41.7, 83.3 and 166.7 mg/kg in vegetable oil, respectively), control group and model group (vegetable oil only). All mice except control group were irradiated by 8 Gy 60Co gamma-rays 30 days later, and executed in the 4th day after irradiation. Liver cells were collected for the analysis of the integrity of DNA by comet assay, as well as MDA contents, SOD and GSH-Px activities in liver by commercial kits. Peripheral granulocyte and bone marrow nucleated cells were counted by hematocyte counter. MDA contents of model group were higher than those of control group (P < 0.01), and SOD, GSH-Px activities of model group were lower than those of control group (P < 0.01). Compared with the model group, MDA contents were decreased (P < 0.01), and SOD and GSH-Px activities were increased (P < 0.01) in all haematococcus pluvialis groups, especially in the high haematococcus pluvialis group, and the more haematococcus pluvialis in the diet of mice, the lower rate of comet tail and OTM value were shown (P < 0.01). Furthermore, the counts of peripheral granulocyte and bone marrow nucleated cells of model group were lower than those of the control group, while the counts of peripheral granulocyte and bone marrow nucleated cells of medium and high haematococcus pluvialis groups were increased significantly when compared with the model group (P < 0.01). Astaxanthin might have some protective effect against oxidative impairment and DNA damage induced by 60Co gamma-rays in mice.

Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation

USDA-ARS?s Scientific Manuscript database

A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma ch...

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile

NASA Technical Reports Server (NTRS)

1993-01-01

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile Laboratory N-242. A spin-off of Ames research on both bone density in microgravity and on thermal protection foams is the bone-growth implant shown in 1993.

Vitamin D Supplementation in Elderly Black Women Does Not Prevent Bone Loss, a Randomized Controlled Trial.

PubMed

Aloia, John F; Fazzari, Melissa; Islam, Shahidul; Mikhail, Mageda; Katumuluwa, Subhashini; Dhaliwal, Ruban; Stolberg, Alexandra; Usera, Gianina; Ragolia, Louis

2018-06-15

Black Americans have lower levels of serum 25(OH)D but superior bone health compared to white Americans. There is controversy over whether they should be screened for vitamin D deficiency and have higher vitamin D requirements than recommended by the Institute of Medicine (IOM). The purpose of this trial was to determine whether Vitamin D supplementation in elderly black women prevents bone loss. 260 healthy black American women, 60 years of age and older were recruited to take part in a two arm, double-dummy 3 year RCT of vitamin D 3 vs. placebo. The study was conducted in an ambulatory clinical research center. Vitamin D 3 dose was adjusted to maintain serum 25(OH)D above 75 nmol/L. Bone mineral density (BMD) and serum were measured for [parathyroid hormone (PTH), C-terminal crosslink telopeptide (CTX) and bone specific alkaline phosphatase (BSAP) every 6 months. Baseline serum 25(OH)D 3 was 54.8 ± 16.8 nmol/L. There was no group xtime interaction effect for any BMD measurement. For all BMD measurements, except for total body and spine, there was a statistically significant negative effect of time (P < 0.001). An equivalency analysis showed that the treatment group was equivalent to the control group. Serum PTH and BSAP declined, with a greater decline of PTH in the treatment group. The rate of bone loss with serum 25(OH)D above 75 nmol/L is comparable to the rate of loss with serum 25(OH)D at the RDA of 50 nmol/L. Black Americans should have the same exposure to vitamin D as white Americans. The trial was registered at clinical trials.gov: NCT01153568. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cordyceps sinensis health supplement enhances recovery from taxol-induced leukopenia.

PubMed

Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H; Chiang, Chi-Shiun

2008-04-01

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase-positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-kappaB]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation.

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

NASA Astrophysics Data System (ADS)

Zhang, Xiangming; Wang, Ping; Wang, Ya

2015-11-01

Bone density loss in astronauts on long-term space missions is a chief medical concern. Microgravity in space is the major cause of bone density loss (osteopenia), and it is believed that high linear energy transfer (LET) radiation in space exacerbates microgravity-induced bone density loss; however, the mechanism remains unclear. It is known that acidic serine- and aspartate-rich motif (ASARM) as a small peptide released by matrix extracellular phosphoglycoprotein (MEPE) promotes osteopenia. We previously discovered that MEPE interacted with checkpoint kinase 1 (CHK1) to protect CHK1 from ionizing radiation promoted degradation. In this study, we addressed whether the CHK1-MEPE pathway activated by radiation contributes to the effects of microgravity on bone density loss. We examined the CHK1, MEPE and secreted MEPE/ASARM levels in irradiated (1 Gy of X-ray) and rotated cultured human osteoblast cells. The results showed that radiation activated CHK1, decreased the levels of CHK1 and MEPE in human osteoblast cells and increased the release of MEPE/ASARM. These results suggest that the radiation-activated CHK1/MEPE pathway exacerbates the effects of microgravity on bone density loss, which may provide a novel targeting factor/pathway for a future countermeasure design that could contribute to reducing osteopenia in astronauts.

Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue.

PubMed

Toussaint, Nigel D; Elder, Grahame J; Kerr, Peter G

2009-01-01

Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid-induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis.

B-Vitamins and Bone Health–A Review of the Current Evidence

PubMed Central

Dai, Zhaoli; Koh, Woon-Puay

2015-01-01

Because of ongoing global ageing, there is a rapid worldwide increase in incidence of osteoporotic fractures and the resultant morbidity and mortality associated with these fractures are expected to create a substantial economic burden. Dietary modification is one effective approach for prevention of osteoporosis in the general population. Recently, B vitamins have been investigated for their possible roles in bone health in human studies. In this review, we provide different lines of evidence and potential mechanisms of individual B vitamin in influencing bone structure, bone quality, bone mass and fracture risk from published peer-reviewed articles. These data support a possible protective role of B vitamins, particularly, B2, B6, folate and B12, in bone health. However, results from the clinical trials have not been promising in supporting the efficacy of B vitamin supplementation in fracture reduction. Future research should continue to investigate the underlying mechanistic pathways and consider interventional studies using dietary regimens with vitamin B enriched foods to avoid potential adverse effects of high-dose vitamin B supplementation. In addition, observational and interventional studies conducted in Asia are limited and thus require more attention due to a steep rise of osteoporosis and hip fracture incidence projected in this part of the world. PMID:25961321

Development of countermeasures for medical problems encountered in space flight.

PubMed

Nicogossian, A E; Rummel, J D; Leveton, L; Teeter, R

1992-01-01

By the turn of this century, long-duration space missions, either in low Earth orbit or for got early planetary missions, will become commonplace. From the physiological standpoint, exposure to the weightless environment results in changes in body function, some of which are adaptive in nature and some of which can be life threatening. Important issues such as environmental health, radiation protection, physical deconditioning, and bone and muscle loss are of concern to life scientists and mission designers. Physical conditioning techniques such as exercise are not sufficient to protect future space travellers. A review of past experience with piloted missions has shown that gradual breakdown in bone and muscle tissue, together with fluid losses, despite a vigorous exercise regimen can ultimately lead to increased evidence of renal stones, musculoskeletal injuries, and bone fractures. Biological effects of radiation can, over long periods of time increase the risk of cancer development. Today, a vigorous program of study on the means to provide a complex exercise regimen to the antigravity muscles and skeleton is under study. Additional evaluation of artificial gravity as a mechanism to counteract bone and muscle deconditioning and cardiovascular asthenia is under study. New radiation methods are being developed. This paper will deal with the results of these studies.

FANCD2 protects against bone marrow injury from ferroptosis

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

Song, Xinxin; Xie, Yangchun; Kang, Rui

Bone marrow injury remains a serious concern in traditional cancer treatment. Ferroptosis is an iron- and oxidative-dependent form of regulated cell death that has become part of an emerging strategy for chemotherapy. However, the key regulator of ferroptosis in bone marrow injury remains unknown. Here, we show that Fanconi anemia complementation group D2 (FANCD2), a nuclear protein involved in DNA damage repair, protects against ferroptosis-mediated injury in bone marrow stromal cells (BMSCs). The classical ferroptosis inducer erastin remarkably increased the levels of monoubiquitinated FANCD2, which in turn limited DNA damage in BMSCs. FANCD2-deficient BMSCs were more sensitive to erastin-induced ferroptosismore » (but not autophagy) than FANCD2 wild-type cells. Knockout of FANCD2 increased ferroptosis-associated biochemical events (e.g., ferrous iron accumulation, glutathione depletion, and malondialdehyde production). Mechanically, FANCD2 regulated genes and/or expression of proteins involved in iron metabolism (e.g., FTH1, TF, TFRC, HAMP, HSPB1, SLC40A1, and STEAP3) and lipid peroxidation (e.g., GPX4). Collectively, these findings indicate that FANCD2 plays a novel role in the negative regulation of ferroptosis. FANCD2 could represent an amenable target for the development of novel anticancer therapies aiming to reduce the side effects of ferroptosis inducers.« less

Development of countermeasures for medical problems encountered in space flight

NASA Astrophysics Data System (ADS)

Nicogossian, Arnauld E.; Rummel, John D.; Leveton, Lauren; Teeter, Ron

1992-08-01

By the turn of this century, long-duration space missions, either in low Earth orbit or for got early planetary missions, will become commonplace. From the physiological standpoint, exposure to the weightless environment results in changes in body function, some of which are adaptive in nature and some of which can be life threatening. Important issues such as environmental health, radiation protection, physical deconditioning, and bone and muscle loss are of concern to life scientists and mission designers. Physical conditioning techniques such as exercise are not sufficient to protect future space travellers. A review of past experience with piloted missions has shown that gradual breakdown in bone and muscle tissue, together with fluid losses, despite a vigorous exercise regimen can ultimately lead to increased evidence of renal stones, musculoskeletal injuries, and bone fractures. Biological effects of radiation can, over long periods of time increase the risk of cancer development. Today, a vigorous program of study on the means to provide a complex exercise regimen to the antigravity muscles and skeleton is under study. Additional evaluation of artificial gravity as a mechanism to counteract bone and muscle deconditioning and cardiovascular asthenia is under study. New radiation methods are being developed. This paper will deal with the results of these studies.

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

PubMed

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

2007-02-01

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

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

PubMed Central

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

2007-01-01

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

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

Protection of radiation induced DNA and membrane damages by total triterpenes isolated from Ganoderma lucidum (Fr.) P. Karst.

PubMed

Smina, T P; Maurya, D K; Devasagayam, T P A; Janardhanan, K K

2015-05-25

The total triterpenes isolated from the fruiting bodies of Ganoderma lucidum was examined for its potential to prevent γ-radiation induced membrane damage in rat liver mitochondria and microsomes. The effects of total triterpenes on γ-radiation-induced DNA strand breaks in pBR 322 plasmid DNA in vitro and human peripheral blood lymphocytes ex vivo were evaluated. The protective effect of total triterpenes against γ-radiation-induced micronuclei formations in mice bone marrow cells in vivo were also evaluated. The results indicated the significant effectiveness of Ganoderma triterpenes in protecting the DNA and membrane damages consequent to the hazardous effects of radiation. The findings suggest the potential use of Ganoderma triterpenes in radio therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Improved Dental Implant Drill Durability and Performance Using Heat and Wear Resistant Protective Coatings.

PubMed

Er, Nilay; Alkan, Alper; Ilday, Serim; Bengu, Erman

2018-06-01

The dental implant drilling procedure is an essential step for implant surgery, and frictional heat in bone during drilling is a key factor affecting the success of an implant. The aim of this study was to increase the dental implant drill lifetime and performance by using heat- and wear-resistant protective coatings to decrease the alveolar bone temperature caused by the dental implant drilling procedure. Commercially obtained stainless steel drills were coated with titanium aluminum nitride, diamond-like carbon, titanium boron nitride, and boron nitride coatings via magnetron-sputter deposition. Drilling was performed on bovine femoral cortical bone under the conditions mimicking clinical practice. Tests were performed under water-assisted cooling and under the conditions when no cooling was applied. Coated drill performances and durabilities were compared with those of three commonly used commercial drills with surfaces made from zirconia, black diamond. and stainless steel. Protective coatings with boron nitride, titanium boron nitride, and diamond-like carbon have significantly improved drill performance and durability. In particular, boron nitride-coated drills have performed within safe bone temperature limits for 50 drillings even when no cooling is applied. Titanium aluminium nitride coated drills did not show any improvement over commercially obtained stainless steel drills. Surface modification using heat- and wear-resistant coatings is an easy and highly effective way to improve implant drill performance and durability, which can improve the surgical procedure and the postsurgical healing period. The noteworthy success of different types of coatings is novel and likely to be applicable to various other medical systems.

The parathyroid hormone, its fragments and analogues--potent bone-builders for treating osteoporosis.

PubMed

Whitfield, J; Morley, P; Willick, G

2000-06-01

As populations age a rising number of men and women, but especially women during the first decade after menopause, become victims of a severe, accelerated loss of bone with crippling fractures known as osteoporosis. This often results in costly, prolonged hospitalisation and perhaps indirectly, death. Osteoporosis in women is caused by the menopausal oestrogen decline, which removes several key restraints on the generation, longevity and activity of bone-resorbing osteoclasts. Although there are many antiresorptive drugs on or coming onto the market (calcitonin, bisphosphonates, oestrogen and SERMS) that can slow or stop further bone loss, there are none that can restore lost bone mechanical strength by directly stimulating osteoblast activity and bone growth. However, there is a family of potent bone-building peptides, namely the 84 amino acid parathyroid hormone (PTH). Its 31 to 38 amino acid N-terminal fragments are currently in or about to enter clinical trials. We can predict that these peptides will be effective therapeutics for osteoporosis especially when supplemented with bisphosphonates or SERMs to protect the new bone from osteoclasts. These peptides should also accelerate the healing of fractures in persons of all ages and restore lost bone mass and mechanical strength to astronauts following their return to earth after long voyages in space.

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

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

Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang

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

Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial

USDA-ARS?s Scientific Manuscript database

Knee osteoarthritis (OA), a disorder of cartilage and periarticular bone, is a public health problem without effective medical treatments. Some studies have suggested that vitamin D may protect against structural progression. A 2-year randomized, placebo-controlled, double-blind, clinical trial invo...

Study on the corrosion resistance and anti-infection of modified magnesium alloy.

PubMed

Bai, Ningning; Tan, Cui; Li, Qing; Xi, Zhongxian

2017-01-01

In this paper, a low-cost and multifunctional hydroxyapatite (HA)/pefloxacin (PFLX) drug eluting layer is coated on magnesium (Mg) alloy through a simple hydrothermal and dip process. The drug PFLX could provide effective prevention for bone infection and inflammation due to its broad-spectrum antibacterial property. And HA would promote the growth of new bone and further improve the biocompatibility of implants. Besides, both PFLX and HA exhibits excellent corrosion protection for Mg alloy substrate. This coating is of great value for improving the application of Mg alloy as biomaterials.

PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment

PubMed Central

Kojima, Kensuke; Shikami, Masato; Benito, Julina; Ruvolo, Vivian; Wang, Rui-Yu; McQueen, Teresa; Ciurea, Stefan O.; Miida, Takashi; Andreeff, Michael; Konopleva, Marina

2013-01-01

Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions. Hypoxia caused degradation of Mcl-1 and rendered Mcl-1-overexpressing OCI-AML3 cells sensitive to ABT-737. Our findings suggest that pharmacologic PI3K inhibition by GDC-0941 enhances ABT-737–induced leukemia cell death even under the protective conditions afforded by the bone marrow microenvironment. PMID:23955073

[Stress distribution in abutment teeth and related tissues under different design of connector: three-dimensional finite element analysis].

PubMed

Bai, Li-Ming; Li, Guo-Qiang; Zhang, Qiang; Dong, Xian

2016-08-01

To compare the stress distribution in abutment teeth and related tissues under the same material and different loading between improved major connector design and traditional major connector design. One 55-year-old male patient with unilateral maxillary first molar and second molar missing was chosen. The stress distribution in abutment teeth and related tissues were evaluated with spiral CT scanning, Mimics, Geomagic Studio software, a study model was built and finite element analysis was performed using ANSYS software. With the improved major connector design, the stress of abutment decreased significantly, the stress of periodontal decreased, the stress of edentulous mucosa increased significantly and became more balanced, the trend of stimulated absorption of alveolar bone decreased. For patients with distal free defect of dentition, the design of improved major connector has the effect of stress interruption, can protect the abutment better, detract the stress of the denture and has an good protective effect on the edentulous mucosa and alveolar bone.

Experiments on the mechanism of underwater hearing.

PubMed

Pau, Hans Wilhelm; Warkentin, Mareike; Specht, Olaf; Krentz, Helga; Herrmann, Anne; Ehrt, Karsten

2011-12-01

The findings suggest that underwater sound perception is realized by the middle ear rather than by bone conduction, at least in shallow water conditions. To prove whether underwater sound perception is effected by bone conduction or by conduction via the middle ear. Five divers, breathing through snorkels, were tested in a swimming pool, to determine whether a sound was louder when the acoustic source placed was in front of the head in comparison with a lateral application facing the ear region. The second experiment investigated whether sound perception is influenced by ear protection plugs in underwater conditions. Also, the effect of a 5 mm thick neoprene hood was determined, with and without an additional perforation in the ear region. Sounds were louder when applied from a position laterally facing the ear, louder without than with a protection plug, louder without than with a neoprene hood on, and louder when the neoprene hood had a perforation in the region of the ear than with an intact hood.

Association Between Dietary Fiber Intake and Bone Loss in the Framingham Offspring Study.

PubMed

Dai, Zhaoli; Zhang, Yuqing; Lu, Na; Felson, David T; Kiel, Douglas P; Sahni, Shivani

2018-02-01

Dietary fiber may increase calcium absorption, but its role in bone mineralization is unclear. Furthermore, the health effect of dietary fiber may be different between sexes. We examined the association between dietary fiber (total fiber and fiber from cereal, fruits, vegetables, nuts, and legumes) and bone loss at the femoral neck, trochanter, and lumbar spine (L 2 to L 4 ) in older men and women. In the Framingham Offspring Study, at baseline (1996-2001), diet was assessed using the Willett food-frequency questionnaire, and bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Follow-up BMD was measured in 2001-2005 and 2005-2008 among 792 men (mean age 58.1 years; BMI 28.6 kg/m 2 ) and 1065 women (mean age 57.3 years; BMI 27.2 kg/m 2 ). We used sex-specific generalized estimating equations in multivariable regressions to estimate the difference (β) of annualized BMD change in percent (%ΔBMD) at each skeletal site per 5 g/d increase in dietary fiber. We further estimated the adjusted mean for bone loss (annualized %ΔBMD) among participants in each higher quartile (Q2, Q3, or Q4) compared with those in the lowest quartile (Q1) of fiber intake. Higher dietary total fiber (β = 0.06, p = 0.003) and fruit fiber (β = 0.10, p = 0.008) was protective against bone loss at the femoral neck in men but not in women. When examined in quartiles, men in Q2-Q4 of total fiber had significantly less bone loss at the femoral neck versus those in Q1 (all p < 0.04). For women, we did not observe associations with hip bone loss, although fiber from vegetables appeared to be protective against spine bone loss in women but not men. There were no associations with cereal fiber or nut and legume fiber and bone loss in men or women. Our findings suggest that higher dietary fiber may modestly reduce bone loss in men at the hip. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Cytogenetic studies on Nigella sativa seeds extract and thymoquinone on mouse cells infected with schistosomiasis using karyotyping.

PubMed

Aboul-Ela, Ezzat I

2002-04-26

The protective effect of Nigella sativa seed extract and its main constituents thymoquinone (TQ) was studied on mouse cells infected with schistosomiasis. Bone marrow cells in the in vivo experiments and spleen cells in the in vitro one were used to evaluate the potentially protective effect of these natural compounds on the induction of chromosomal aberrations. Karyotyping of the mice cells illustrated that the main abnormalities were gaps, fragments and deletions especially in chromosomes 2, 6 and some in chromosomes 13 and 14. Both N. sativa extract and TQ were considered as protective agents against the chromosomal aberrations induced as a result of schistosomiasis.

Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats

PubMed Central

Roth, Steven; Dreixler, John C.; Mathew, Biji; Balyasnikova, Irina; Mann, Jacob R.; Boddapati, Venkat; Xue, Lai; Lesniak, Maciej S.

2016-01-01

Purpose We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. Methods Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. Results Eyes injected with hypoxic BMSC–conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. Conclusions The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect. PMID:27367588

The effect of clomiphene on disuse bone loss

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

LeBlanc, A.; Marsh, C.; Spira, M.

1984-01-01

Clomiphene is a synthetic estrogen agonist/antagonist used for many years to induce ovulation in anovulatory women. A recent study demonstrated that clomiphene had a protective effect against bone loss in ovariectomized aged rats. The purpose was to determine if this drug retards resorption of bone associated with disuse in rats with intact ovaries. Eleven adult (300-350g) female rats received a pedicle bone graft (disuse) in one femur with the opposite limb serving as control. Of these, 6 received weekly 10 mg injections of clomiphone (Rx). Three Rx and three untreated (unRx) were sacrificed at 6 weeks while the remainder (3more » Rx, 2 unRx) were sacrificed at 10 weeks after surgery. All received quantitative injections of MDP 24 hrs. before sacrifice and labeled microspheres (5) just prior to sacrifice. The % uptakes of MDP and S, total bone mineral (BMC) and regional BMC (RBMC) were determined. Results are expressed as a ratio of the pedicle bone to the bone from the opposite limb. At 6 weeks, MDP and S are elevated in both groups indicating that metabolic activity is elevated. The Rx group shows no change in BMC while the unRx lost 13%. At 10 weeks, MDP and S are close to one in both groups. The Rx group lost 13% BMC while the unRx lost 29%. The RBMC indicates that the early loss of mineral is located primarily in the metaphysis, a region rich in trabecular bone. These results indicate that clomiphene retards resorption of bone resulting from disuse.« less

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

PubMed

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

2013-08-15

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

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

PubMed

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

2014-09-01

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

Cartilage Protective and Chondrogenic Capacity of WIN-34B, a New Herbal Agent, in the Collagenase-Induced Osteoarthritis Rabbit Model and in Progenitor Cells from Subchondral Bone

PubMed Central

Huh, Jeong-Eun; Park, Yeon-Cheol; Seo, Byung-Kwan; Lee, Jae-Dong; Baek, Yong-Hyeon; Choi, Do-Young; Park, Dong-Suk

2013-01-01

We sought to determine the cartilage repair capacity of WIN-34B in the collagenase-induced osteoarthritis rabbit model and in progenitor cells from subchondral bone. The cartilage protective effect of WIN-34B was measured by clinical and histological scores, cartilage area, and proteoglycan and collagen contents in the collagenase-induced osteoarthritis rabbit model. The efficacy of chondrogenic differentiation of WIN-34B was assessed by expression of CD105, CD73, type II collagen, and aggrecan in vivo and was analyzed by the surface markers of progenitor cells, the mRNA levels of chondrogenic marker genes, and the level of proteoglycan, GAG, and type II collagen in vitro. Oral administration of WIN-34B significantly increased cartilage area, and this was associated with the recovery of proteoglycan and collagen content. Moreover, WIN-34B at 200 mg/kg significantly increased the expression of CD105, CD73, type II collagen, and aggrecan compared to the vehicle group. WIN-34B markedly enhanced the chondrogenic differentiation of CD105 and type II collagen in the progenitor cells from subchondral bone. Also, we confirmed that treatment with WIN-34B strongly increased the number of SH-2(CD105) cells and expression type II collagen in subchondral progenitor cells. Moreover, WIN-34B significantly increased proteoglycan, as measured by alcian blue staining; the mRNA level of type II α1 collagen, cartilage link protein, and aggrecan; and the inhibition of cartilage matrix molecules, such as GAG and type II collagen, in IL-1β-treated progenitor cells. These findings suggest that WIN-34B could be a potential candidate for effective anti-osteoarthritic therapy with cartilage repair as well as cartilage protection via enhancement of chondrogenic differentiation in the collagenase-induced osteoarthritis rabbit model and progenitor cells from subchondral bone. PMID:23983790

Effects of a moderately high-protein diet and interval aerobic training combined with strength-endurance exercise on markers of bone metabolism, microarchitecture and turnover in obese Zucker rats.

PubMed

Nebot, Elena; Aparicio, Virginia A; Coll-Risco, Irene; Camiletti-Moirón, Daniel; Schneider, Johannes; Kapravelou, Garyfallia; Heimel, Patrick; Martínez, Rosario; Andrade, Ana; Slezak, Paul; Redl, Heinz; Porres, Jesús M; López-Jurado, María; Pietschmann, Peter; Aranda, Pilar

2016-11-01

Weight loss is a public health concern in obesity-related diseases such as metabolic syndrome, and the protein level of the diets seem to be crucial for the development and maintenance of bone. The nature of exercise and whether exercise in combination with moderately high-protein dietary interventions could protect against potential bone mass deficits remains unclear. To investigate the effects of a moderately high-protein diet and interval aerobic training combined with strength-endurance exercise (IASE) protocol on bone status, and to assess potential interaction effects (i.e. diet*IASE). Male Zucker fatty rats were randomized distributed into 4 groups (n=8): normoprotein+sedentary; normoprotein+exercise; moderately high-protein+sedentary, and moderately high-protein+exercise. Training groups conducted an IASE program, 5days/week for 2months. Markers of bone metabolism were measured in plasma. Parameters of bone mass and 3D outcomes for trabecular and cortical bone microarchitecture were assessed by micro-computed tomography. Femur length, plasma osteocalcin, sclerostin, osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, insulin, leptin, PTH, uric acid and urinary phosphorus levels were lower in the moderately high-protein compared to the normoprotein groups (all, p<0.05), whereas plasma alkaline phosphatase, aspartate aminotransferase, alanine transaminase, and urinary uric acid concentrations, and cortical total volume (TV) and bone volume (BV) were higher in the moderately high-protein (all, p<0.01). Final body weight and alkaline phosphatase levels were lower in the exercise compared to the sedentary (both, p<0.05), whereas femur length and weight, aminoterminal propeptides of type I procollagen and C-terminal telopeptides of type I collagen concentrations, and cortical TV and BV were higher in the exercise compared to the sedentary groups (all, p<0.05). The combination of interventions may be effective to enhance trabecular bone microarchitecture and BMD, and has a partial impact on cortical bone in obese rats. Nevertheless, they do not induce any alteration on the bone turnover markers. Copyright © 2016 Elsevier Inc. All rights reserved.

ARC-1993-A93-0511-7

NASA Image and Video Library

1993-10-07

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile Laboratory N-242. A spin-off of Ames research on both bone density in microgravity and on thermal protection foams is the bone-growth implant shown in 1993.

Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey A.; Shapiro, Jay; Lang, Thomas F.; Smith, Scott M.; Shackelford, Linda C.; Sibonga, Jean; Evans, Harlan; Spector, Elisabeth;

Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by targeting a NaCl cotransporter in bone

PubMed Central

Dvorak, Melita M; De Joussineau, Cyrille; Carter, D Howard; Pisitkun, Trairak; Knepper, Mark A; Gamba, Gerardo; Kemp, Paul J; Riccardi, Daniela

2008-01-01

Thiazide diuretics are used, worldwide, as the first-choice drug for patients with uncomplicated hypertension. In addition to their anti-hypertensive actions, they increase bone mineral density and reduce the prevalence of fractures, indicating that thiazides may have a role in the management of postmenopausal osteoporosis. Traditionally, the bone-protective effects of thiazides have been attributed to an increase in renal calcium reabsorption, secondary to the inhibition of the sodium chloride cotransporter, NCC, expressed in the kidney distal tubule. Whether thiazides exert a direct osteoanabolic effect independently of their renal action is controversial. Here we demonstrate that freshly frozen sections of human and rat bone express NCC, principally in bone-forming cells, the osteoblasts. In primary and established culture models of osteoblasts, fetal rat calvarial (FRC) and human MG63 cells, NCC protein is virtually absent in proliferating cells while its expression is dramatically increased during differentiation. Thiazides directly stimulate the production of osteoblast markers, runt-related transcription factor 2 (runx2) and osteopontin, in the absence of a proliferative effect. Using overexpression/knockdown studies in FRC cells, we show that thiazides, but not loop diuretics, increase mineralized nodule formation acting on NCC. Overall, our study demonstrates that thiazides stimulate osteoblast differentiation and bone mineral formation independently of their renal actions. In addition to their use as part of a therapeutic treatment plan for elderly, hypertensive individuals, our discovery opens up the possibility that bone-specific drug targeting by thiazides may be developed for the prevention and treatment of osteoporosis in the patient population as a whole. PMID:17656470

Efficacy and safety of bisphosphonates in management of low bone density in inflammatory bowel disease

PubMed Central

Yao, Liwei; Wang, Haiqing; Dong, Wenwei; Liu, Zhenxin; Mao, Haijiao

2017-01-01

Abstract This study aims to determine whether bisphosphonates are safe, as well as effective against bone mineral loss in inflammatory bowel disease (IBD). A computerized search of electronic databases from 1966 to 2016 was performed. Randomized controlled trials (RCTs) were included in this review to evaluate the role of bisphosphonates in the management of osteoporosis in IBD patients. A revised 7-point Jadad scale was used to evaluate the quality of each study. Overall, 13 RCTs and 923 patients met the inclusion criteria of this meta-analysis. The result showed that bisphosphonates decreased bone mass density (BMD) loss at the lumbar spine (P = 0.0002), reduced the risk of new fractures (P = 0.01), and retained the similar adverse events (P = 0.86). Bisphosphonates may provide protection and safety against bone mineral loss in IBD patients. PMID:28099343

Efficacy and safety of bisphosphonates in management of low bone density in inflammatory bowel disease: A meta-analysis.

PubMed

Yao, Liwei; Wang, Haiqing; Dong, Wenwei; Liu, Zhenxin; Mao, Haijiao

2017-01-01

This study aims to determine whether bisphosphonates are safe, as well as effective against bone mineral loss in inflammatory bowel disease (IBD). A computerized search of electronic databases from 1966 to 2016 was performed. Randomized controlled trials (RCTs) were included in this review to evaluate the role of bisphosphonates in the management of osteoporosis in IBD patients. A revised 7-point Jadad scale was used to evaluate the quality of each study. Overall, 13 RCTs and 923 patients met the inclusion criteria of this meta-analysis. The result showed that bisphosphonates decreased bone mass density (BMD) loss at the lumbar spine (P = 0.0002), reduced the risk of new fractures (P = 0.01), and retained the similar adverse events (P = 0.86). Bisphosphonates may provide protection and safety against bone mineral loss in IBD patients.

Effect of surface roughness of hydroxyapatite-coated titanium on the bone-implant interface shear strength.

PubMed

Hayashi, K; Inadome, T; Tsumura, H; Nakashima, Y; Sugioka, Y

1994-11-01

We have investigated the bone-implant interface shear strength of hydroxyapatite (HA)-coated Ti-6Al-4V (HA-coating A) (roughness average, Ra = 3.4 +/- 0.5 microns) and HA-coated Ti-6Al-4V with a rougher surface (HA-coating B) (Ra = 8.4 +/- 1.8 microns). There was no significant difference between HA-coating A and HA-coating B implants with respect to the bone-implant interface shear strength as determined in push-out tests using the transcortical model in adult dogs. The bone-implant interface shear strength of bead-coated porous Ti-6Al-4V was significantly greater than that of both HA-coating A and HA-coating B implants. The failure site, as determined by scanning electron microscopy, was the coating-substrate interface, not the coating-bone interface. This indicates a need to protect the HA coating from the direct shear forces. HA coating enhances early bone growth into the porous surface of the implant. Long-term fixation should depend on bone anchoring to this porous surface. Hydroxyapatite coatings must be developed which do not obstruct the pores of the surface of the implant.

Genistein treatment increases bone mass in obese, hyperglycemic mice

PubMed Central

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Background Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. Methods In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Results Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Conclusion Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight. PMID:27042131

Erythropoietin as a novel brain and kidney protective agent.

PubMed

Moore, E M; Bellomo, R; Nichol, A D

2011-05-01

Erythropoietin is a 30.4 kDa glycoprotein produced by the kidney, which is mostly known for its physiological function in regulating red blood cell production in the bone marrow Accumulating evidence, however suggests that erythropoietin has additional organ protective effects, which may specifically be useful in protecting the brain and kidneys from injury. Experimental evidence suggests that these protective mechanisms are multi-factorial in nature and may include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways and promotion of recovery. In this article we review the physiology of erythropoietin, assess previous work that supports the role of erythropoietin as a general tissue protective agent and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on specific laboratory and clinical data that suggest that erythropoietin has a strong brain protective and kidney protective effect. In addition, we comment on the implications of these studies for clinicians at the bedside and for researchers designing controlled trials to further elucidate the true clinical utility of erythropoietin as a neuroprotective and nephroprotective agent. Finally, we describe EPO-TBI, a double-blinded multi-centre randomised controlled trial involving the authors that is being conducted to investigate the organ protective effects of erythropoietin on the brain, and also assesses its effect on the kidneys.

Biomedical research publications: 1980 - 1982

NASA Technical Reports Server (NTRS)

Pleasant, L. G.; Limbach, L.

1982-01-01

Publications concerning the major physiological and psychological problems encountered by man when he undertakes space flight are listed. Nine research areas are included: cardiovascular deconditioning, motion sickness, bone alterations, muscle atrophy, blood cell alterations, fluid and eletrolyte changes, radiation effects and protection, behavior and performance, and general biomedical research.

Automated cortical bone segmentation for multirow-detector CT imaging with validation and application to human studies

PubMed Central

Li, Cheng; Jin, Dakai; Chen, Cheng; Letuchy, Elena M.; Janz, Kathleen F.; Burns, Trudy L.; Torner, James C; Levy, Steven M.; Saha, Punam K

2015-01-01

Purpose: Cortical bone supports and protects human skeletal functions and plays an important role in determining bone strength and fracture risk. Cortical bone segmentation at a peripheral site using multirow-detector CT (MD-CT) imaging is useful for in vivo assessment of bone strength and fracture risk. Major challenges for the task emerge from limited spatial resolution, low signal-to-noise ratio, presence of cortical pores, and structural complexity over the transition between trabecular and cortical bones. An automated algorithm for cortical bone segmentation at the distal tibia from in vivo MD-CT imaging is presented and its performance and application are examined. Methods: The algorithm is completed in two major steps—(1) bone filling, alignment, and region-of-interest computation and (2) segmentation of cortical bone. After the first step, the following sequence of tasks is performed to accomplish cortical bone segmentation—(1) detection of marrow space and possible pores, (2) computation of cortical bone thickness, detection of recession points, and confirmation and filling of true pores, and (3) detection of endosteal boundary and delineation of cortical bone. Effective generalizations of several digital topologic and geometric techniques are introduced and a fully automated algorithm is presented for cortical bone segmentation. Results: An accuracy of 95.1% in terms of volume of agreement with manual outlining of cortical bone was observed in human MD-CT scans, while an accuracy of 88.5% was achieved when compared with manual outlining on postregistered high resolution micro-CT imaging. An intraclass correlation coefficient of 0.98 was obtained in cadaveric repeat scans. A pilot study was conducted to describe gender differences in cortical bone properties. This study involved 51 female and 46 male participants (age: 19–20 yr) from the Iowa Bone Development Study. Results from this pilot study suggest that, on average after adjustment for height and weight differences, males have thicker cortex (mean difference 0.33 mm and effect size 0.92 at the anterior region) with lower bone mineral density (mean difference −28.73 mg/cm3 and effect size 1.35 at the posterior region) as compared to females. Conclusions: The algorithm presented is suitable for fully automated segmentation of cortical bone in MD-CT imaging of the distal tibia with high accuracy and reproducibility. Analysis of data from a pilot study demonstrated that the cortical bone indices allow quantification of gender differences in cortical bone from MD-CT imaging. Application to larger population groups, including those with compromised bone, is needed. PMID:26233184

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

PubMed

Madan, Babita; McDonald, Mitchell J; Foxa, Gabrielle E; Diegel, Cassandra R; Williams, Bart O; Virshup, David M

2018-01-01

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

[Phytoestrogens role in bone functional structure protection in the ovariectomized rat].

PubMed

Mihalache, Gr; Mihalache, Gr D; Indrei, L L; Indrei, Anca; Hegsted, Maren

2002-01-01

Effects of soy protein diet on bone formation and density were evaluated in ovariectomized rats as a model for postmenopausal women. Twenty-seven 9-month-old rats were assigned to 3 treatment groups for the 9-week study: sham-surgery (Sh, n = 9); ovariectomy (Ovx, n = 9); ovariectomy + soy diet (OvxS, n = 9). Rats had free access to an AIN-93 M diet or AIN-93 M diet with 7% soy protein concentration and water. At sacrifice, rear legs were removed, and the right femur and tibia were cleaned manually. Serum alkaline phosphatase, a marker of bone formation, was measured colorimetrically. Bone density was measured using Archimedes' Principle. Alkaline phosphatase activity was greater in OvxS (114 +/- 19 U/L) and Ovx (128 +/- 26 U/L) compared to Sh (110 +/- 22 U/L). Femur bone density was greater for OvxS (1.520 +/- 0.02 g/cc) compared to Ovx (1.510 +/- 0.017 g/cc), but not to Sh (1532 +/- 0.025 g/cc). Tibia bone density was greater for OvxS (1.560 +/- 0.019 g/cc) compared to Ovx (1.553 +/- 0.015 g/cc), but not to Sh (1566 +/- 0.03 g/cc). In conclusion soy protein diet increased the rate of bone formation and bone density in some bones, suggesting that may help prevent bone loss in postmenopausal women.

Do Environmental Fluoride Exposure and ESRα Genetic Variation Modulate Methylation Modification on Bone Changes in Chinese Farmers?

PubMed

Zhang, Yanli; Huang, Hui; Gong, Biao; Duan, Leizhen; Sun, Long; He, Tongkun; Cheng, Xuemin; Li, Zhiyuan; Cui, Liuxin; Ba, Yue

2017-06-19

Although increasing evidence suggests that estrogen receptor α (ESRα) genetic variation could modify bone damage caused by environmental fluoride exposure, little is known about epigenetic mechanisms in relation to bone changes. A case-control study was conducted among farmers aged 18-55 years in Henan Province, China. X-ray was used to detect bone changes. Methylation status was determined by methylation-specific PCR. Genotypes were identified by Taqman probe and real-time PCR. In this study, we found that methylation status in the promoter region of the ESRα gene was lower in bone change cases than that in controls, which was only observed in male farmers after stratification by gender. Furthermore, methylation level was negatively associated with the urinary fluoride concentration in male farmers. No significant association was found between the distribution of ESRα rs2941740 genotypes and the risk of bone changes. Multivariate logistic regression analysis showed that after adjusting for age and gender, increased serum calcium and methylation status were protective factors for bone changes. No interaction effect was observed between fluoride exposure and ESRα rs2941740 polymorphism on bone changes. In conclusion, the current work suggests that bone changes are associated with methylation status, which might be modulated by fluoride exposure in male farmers. Methylation status and bone changes were not modified by ESRα gene rs2941740 polymorphism in the promoter region.

Potential for thermal damage to articular cartilage by PMMA reconstruction of a bone cavity following tumor excision: A finite element study.

PubMed

Radev, Boyko R; Kase, Jonathan A; Askew, Michael J; Weiner, Scott D

2009-05-29

Benign, giant cell tumors are often treated by intralesional excision and reconstruction with polymethylmethacrylate (PMMA) bone cement. The exothermic reaction of the in-situ polymerizing PMMA is believed to beneficially kill remaining tumor cells. However, at issue is the extent of this necrotic effect into the surrounding normal bone and the adjacent articular cartilage. Finite element analysis (ABAQUS 6.4-1) was used to determine the extent of possible thermal necrosis around prismatically shaped, PMMA implants (8-24cc in volume), placed into a peripheral, sagittally symmetric, metaphyseal defect in the proximal tibia. Temperature/exposure time conditions indicating necrotic potential during the exotherm of the polymerizing bone cement were found in regions of the cancellous bone within 3mm of the superior surface of the PMMA implant. If less than 3mm of cancellous bone existed between the PMMA implant and the subchondral bone layer, regions of the subchondral bone were also exposed to thermally necrotic conditions. However, as long as there were at least 2mm of uniform subchondral bone above the PMMA implant, the necrotic regions did not extend into the overlying articular cartilage. This was the case even when the PMMA was in direct contact with the subchondral bone. If the subchondral bone is not of sufficient thickness, or is not continuous, then care should be taken to protect the articular cartilage from thermal damage as a result of the reconstruction of the tumor cavity with PMMA bone cement.

Isolation, characterization, and radiation protection of Sipunculus nudus L. polysaccharide.

PubMed

Li, Na; Shen, Xianrong; Liu, Yuming; Zhang, Junling; He, Ying; Liu, Qiong; Jiang, Dingwen; Zong, Jie; Li, Jiamei; Hou, Dengyong; Chen, Wei; Wang, Qingrong; Luo, Qun; Li, Kexian

2016-02-01

Sipunculus nudus Linnaeus polysaccharide (SNP) was purified from S. nudus L. via NaOH extraction, trichloroacetic acid deproteination, DEAE-cellulose 52 and Sephacryl S-300 chromatography. The monosaccharide analysis and molecular weight was detected with HPLC. FT-IR, 1H spectrum and 13C NMR spectrum were performed to detect the chemical characteristics. The antioxidant activity was assayed in vitro. The radiation protection effects were detected on mice. The results showed that SNP was composed of mannose, rhamnose, galacturonic acid, glucose, arabinose and fucose, and the average molecular weight was 680 kDa. Above the concentration of 10 mg/mL, SNP showed powerful scavenging activity on hydroxyl radical. In the animals irradiated with a 7.5 Gy γ-rays, the 90 mg/kg and the 270 mg/kg SNP groups survived significantly longer than the radiation control group. In the animals irradiated with a 4.0 Gy γ-rays, SNP showed significant protection effect. The contents of DNA in bone marrow cells were significantly increased by SNP treatment, and the micronucleus rates of 30 mg/kg and 270 mg/kg SNP groups were decrease significantly compared to the radiation control group. These findings suggest that SNP possesses marked antioxidant and bone marrow damage protection capacity which play important roles in the prevention of radiation damage. Copyright © 2015 Elsevier B.V. All rights reserved.

[Secondary osteoporosis or secondary contributors to bone loss in fracture. Endocrinological aspects of bone metabolism].

PubMed

Fukumoto, Seiji

2013-09-01

Bone works to play essential roles in mineral metabolism and hematopoiesis as well as to support our body and protect internal organs as a hard tissue. In order to accomplish these multiple functions, bone needs to communicate with other organs. Endocrine system functions as one of the communication pathways between bone and other organs. It has been known that bone is a target organ of many hormones. In addition, it has been established that bone itself produces hormones and works as an endocrine organ.

Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice

PubMed Central

Craig, Zelieann R.; Marion, Samuel L.; Funk, Janet L.; Bouxsein, Mary L.; Hoyer, Patricia B.

2010-01-01

Previous work showed that retaining residual ovarian tissue protects young mice from accelerated bone loss following ovarian failure. The present study was designed to determine whether this protection is also present in aged animals. Aged (9–12 months) C57BL/6Hsd female mice were divided into: CON (vehicle), VCD (160 mg/kg; 15d), or OVX (ovariectomized). Lumbar BMD was monitored by DXA and μCT used to assess vertebral microarchitecture. BMD was not different between VCD and CON at any time point but was lower (P < .05) than baseline, starting 1 month after ovarian failure in VCD and OVX mice. Following μCT analysis there were no differences between CON and VCD, but OVX mice had lower bone volume fraction, trabecular thickness, and a trend for decreased connectivity density. These findings provide evidence that retention of residual ovarian tissue may protect aged follicle-depleted mice from accelerated bone loss to a lesser extent than that observed in young mice. PMID:20948577

Protective effect of amlodipine on rat bone tissue after orchidectomy.

PubMed

Gradosova, Iveta; Zivna, Helena; Palicka, Vladimir; Hubena, Sona; Svejkovska, Klara; Zivny, Pavel

2012-01-01

Our study aimed to investigate the effect of amlodipine on bone metabolism in orchidectomized rats. Eight-week-old rats were divided into three groups. The sham-operated control group (SHAM) and the control group after orchidectomy (ORX) received the standard laboratory diet (SLD). The experimental group after orchidectomy (ORX+AML) received SLD enriched with amlodipine for 12 weeks. Bone marker concentrations in serum of PINP, OPG and IGF-1, and the levels of CTX-I, BAP and BMP-2 in a bone homogenate were measured using enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. The femurs were used for biomechanical testing. Bone markers (CTX-I, BAP, BMP-2) in ORX were higher versus SHAM. In ORX+AML there was a decrease in PINP, CTX-I, BAP, BMP-2 and OPG versus ORX. IGF-1 was decreased in ORX versus SHAM. In ORX+AML it was increased versus ORX. In ORX, a decrease was demonstrated versus SHAM in BMD of the whole body, in the lumbar vertebrae and in both femurs. In ORX+AML there was an increase in BMD of the whole body versus ORX. Three-point bending test revealed a decrease in maximal load values in ORX versus SHAM. After amlodipine administration there was an increase in the left femur versus ORX. Amlodipine is capable of mitigating the negative effects of orchidectomy and could be a good prevention of osteoporosis. Copyright © 2012 S. Karger AG, Basel.

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

PubMed Central

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

2016-01-01

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

Du-Zhong (Eucommia ulmoides Oliv.) Cortex Extract Alleviates Lead Acetate-Induced Bone Loss in Rats.

PubMed

Qi, Shanshan; Zheng, Hongxing; Chen, Chen; Jiang, Hai

2018-05-09

The purpose of this study was to evaluate the protective effect of Du-Zhong cortex extract (DZCE) on lead acetate-induced bone loss in rats. Forty female Sprague-Dawley rats were randomly divided into four groups: group I (control) was provided with distilled water. Group II (PbAc) received 500 ppm lead acetate in drinking water for 60 days. Group III (PbAc+DZCE) received 500 ppm lead acetate in drinking water, and given intragastric DZCE (100 mg/kg body weight) for 60 days. Group IV (DZCE) was given intragastric DZCE (100 mg/kg body weight) for 60 days. The bone mineral density, serum biochemical markers, bone histomorphology, and bone marrow adipocyte parameters were analyzed using dual-energy X-ray absorptiometry, biochemistry, histomorphometry, and histopathology, respectively. The results showed that the lumbar spine and femur bone mineral density was significantly decreased in PbAc group compared with the control (P < 0.05); however, this decrease was inhibited by the intake of Du-Zhong cortex extract (P < 0.05, vs. PbAc group; P > 0.05, vs. control and DZCE group). Serum calcium and serum phosphorus in the PbAc+DZCE group were greater than that in the PbAc group (P < 0.05). The PbAc group had higher ALP, osteocalcin, and RANKL than the control group (P < 0.01), and they were significantly lower in the PbAc+DZCE group compared with the PbAc group. There were no significant differences of ALP, osteocalcin, and RANKL among the PbAc+DZCE, control, and DZCE groups (P > 0.05). Serum OPG and OPG/RANKL ration were significantly higher in the PbAc+DZCE group than that in the PbAc group (P < 0.05). The bone histomorphometric analyses showed that bone volume and trabecular thickness in the femoral trabecular bone were significantly lower in the PbAc group than that in the control group, but those were restored in the PbAc+DZCE groups. The bone marrow adipocyte number, percent adipocyte volume per tissue volume (AV/TV), and mean adipocyte diameter were significantly increased in the PbAc group compared to the control (P < 0.01), and those were restored in the PbAc+DZCE group. The differences of those parameters between PbAc+DZCE, DZCE, and the control group were not significant. The results above indicate that the Du-Zhong cortex extract has protective effects on both stimulation of bone formation and suppression of bone resorption in lead-exposed rats, therefore, Du-Zhong cortex extract has the potential to prevent or treat osteoporosis resulting from lead expose.

Beneficial effects of paeoniflorin on osteoporosis induced by high-carbohydrate, high-fat diet-associated hyperlipidemia in vivo.

PubMed

Wang, Yanmao; Zhu, Yu; Lu, Shengdi; Hu, Chengfang; Zhong, Wanrun; Chai, Yimin

2018-04-15

Osteoporosis is linked to reduced bone mineral density (BMD) as a major risk factor for fragility fractures. Recent studies indicated an association between BMD and abnormally elevated lipid levels in blood as common indicators for hyperlipidemia. In this study, we assessed the protective effect of paeoniflorin, a phytochemical compound with multiple pharmacological activities, against hyperlipidemia-induced osteoporosis in rats fed a high-carbohydrate, high-fat diet (HCHF). The special diet-fed rats were subjected to an 8-week treatment with either paeoniflorin (20 mg/kg, daily) or vehicle. The control group received a normal diet during the entire study. At study conclusion, serum markers of lipid metabolism and bone turnover were measured. Bone strength was assessed by biomechanical testing, and femurs were scanned using micro-computed tomography to analyze trabecular and cortical bone structure. Interestingly, paeoniflorin controlled the serum lipid profile by significantly decreasing HCHF-induced high levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol. Paeoniflorin significantly improved trabecular and cortical parameters as well as femur length and width that were negatively affected by HCHF diet. Biomechanical strength testing showed that femurs of HCHF diet-fed rats endured significantly lower force but higher displacement and strain than those of control rats, whereas paeoniflorin reversed the negative effects. Moreover, paeoniflorin rescued osteoblast differentiation and cell spreading activities along with bone turnover markers. In conclusion, HCHF-induced hyperlipidemia caused adverse effects on the bone that were rescued by paeoniflorin treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia.

PubMed

Iwaniec, Urszula T; Turner, Russell T

2013-03-01

A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kit(W/W-v)) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to the development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kit(W/W-v) mice. Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kit(W/W-v) mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kit(W/W-v) mice. However, ovx in WT and kit(W/W-v) mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Numerical Investigation of Shock Wave Propagation in Bone-Like Tissue

NASA Astrophysics Data System (ADS)

Nelms, Matt; Rajendran, Arunachalam

In this investigation, the effects of shock wave propagation in bone-like biomineralized tissue was investigated. The Alligator gar (Atractosteus spatula) exoskeleton is comprised of many disparate scales that provide a biological analog for potential design of flexible protective material systems. The penetration resistant fish scale was modeled by simulating a plate impact test configuration using ABAQUS®finite element (FE) software. The gar scale is identified as a two-phase, (1) hydroxyapatite mineral and (2) collagen protein, biological composite with two distinct layers where a stiff, ceramic-like ganoine overlays a soft, highly ductile bone. The geometry and variation of elastic modulus were determined from high-resolution scanning electron microscopy and dynamic nanoindentation experimentation to develop an idealized computational model for RVE-based FE simulations. The numerical analysis shows the effects of different functional material property variations on the stress histories and energy dissipation generated by wave propagation. Given the constitutive behaviors of the two layers are distinctly different, a brittle tensile damage model was employed to describe the ganoine and Drucker-Prager plasticity was used for the nonlinear response of the bone.

Evaluating The Risk Of Osteoporosis Through Bone Mass Density.

PubMed

Sayed, Sayeeda Amber; Khaliq, Asif; Mahmood, Ashar

2016-01-01

Osteoporosis is a bone disorder, characterized by loss of bone mass density. Osteoporosis affects more than 30% of post-menopausal women. Osteoporosis is often associated with restricted body movement, pain and joint deformities. Early identification and early intervention can help in reducing these complications. The primary objective of this study was to estimate the burden of Osteoporosis in Urban setting of Sindh among women of different age groups and to access the effect of different protective measures that can reduce the risk of Osteoporosis. In this study, 500 women's of 3 major cities of Sindh were approached by non-probability convenience sampling technique. Women bearing age 20 years or more were included. Women who fall under inclusion criteria were screened for BMD (Bone mineral density) test and were classified as Healthy, Osteopenic and Osteoporotic based on their T-score. The association of different protective measures and risk of osteoporosis was assessed by prevalence relative risk (PRR). The result of this study indicate that the burden of Osteoporosis is very high among the women of Sindh, only 17.4% (84) women were found to have normal BMD score. The life style of majority of women was sedentary. The PRR calculated for Exposure to sunlight, regular exercise, and use of nutritional supplement was 12.5, 5.19 and 2.72 folds respectively. The results of study reveal that exposure to sunlight, regular physical exercise and use of nutritional supplements found to be effective in reducing the risk of osteoporosis among women of all age group. Health education and promotion toward osteoporosis prevention can significantly contribute in reducing the morbidity of osteoporosis.

Substitution effects of a carbonated hydroxyapatite biomaterial against intoxication chloride nickel-exposed rats.

PubMed

Boulila, Salha; Elfeki, Abdelfattah; Oudadesse, Hassane; Elfeki, Hafed

2015-03-01

This study aimed to investigate the potential effects of a synthetic apatite (carbonated hydroxyapatite) on the detoxification of a group of male "Wistar" rats exposed to nickel chloride. Toxicity was evaluated by rats' bioassay of nickel chloride. Wistar rats received this metal daily by gavage for seven days (4 mg/ml nickel chloride/200 g body weight, BW). To detoxify this organism, a subcutaneous implantation of the apatite is made. The results revealed that exposure to nickel induced oxidative stress, disorders in the balances of ferric phosphocalcic, renal failures, liver toxicity and significant increase in nickel rates in the bones of intoxicated rats. The application of the carbonated hydroxyapatite presented in this study restored those disorders back to normal. The synthetic apatite protected the rats against the toxic effects of nickel by lowering the levels of lipid peroxidation markers and improving the activities of defense enzymes. It also amended ferric and phosphocalcic equilibriums, protected liver and kidney functions and reduced the nickel rate in the bones of the rats. Overall, the results provided strong support for the protective role of carbonated hydroxyapatite in the detoxification of rats exposed to nickel. Those beneficial effects were further confirmed by physico-chemical characterization (X-ray diffraction and infrared spectroscopy), which revealed its property of anionic and cationic substitution, thus supporting its promising candidacy for future biomedical application. The hydroxyapatite is an effective biomaterial to solve health problems, particularly detoxification against metals (nickel).

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

PubMed

Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.

Benzene Metabolite Hydroquinone Up-Regulates Chondromodulin-I and Inhibits Tube Formation in Human Bone Marrow Endothelial Cells

PubMed Central

Zhou, Hongfei; Kepa, Jadwiga K.; Siegel, David; Miura, Shigenori; Hiraki, Yuji; Ross, David

2009-01-01

Bone marrow is a major target of benzene toxicity, and NAD- (P)H:quinone oxidoreductase (NQO1), an enzyme protective against benzene toxicity, is present in human bone marrow endothelial cells, which form the hematopoietic stem cell vascular niche. In this study, we have employed a transformed human bone marrow endothelial cell (TrHBMEC) line to study the adverse effects induced by the benzene metabolite hydroquinone. Hydroquinone inhibited TrHBMEC tube formation at concentrations that were not overtly toxic, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or sulforhodamine B analysis. Hydroquinone was found to up-regulate chondromodulin-I (ChM-I), a protein that promotes chondrocyte growth and inhibits endothelial cell growth and tube formation. Recombinant human ChM-I protein inhibited tube formation in TrHBMECs, suggesting that up-regulation of ChM-I may explain the ability of hydroquinone to inhibit TrHB-MEC tube formation. To explore this possibility further, anti-ChM-I small interfering RNA (siRNA) was used to deplete ChM-I mRNA and protein. Pretreatment with anti-ChM-I siRNA markedly abrogated hydroquinone-induced inhibition of tube formation in TrHBMECs. Overexpression of the protective enzyme NQO1 in TrHBMECs inhibited the up-regulation of ChM-I and abrogated the inhibition of tube formation induced by hydroquinone. In summary, hydroquinone treatment up-regulated ChM-I and inhibited tube formation in TrHBMECs; NQO1 inhibited hydroquinone-induced up-regulation of ChM-I in TrHB-MECs and protected cells from hydroquinone-induced inhibition of tube formation. This study demonstrates that ChM-I up-regulation is one of the underlying mechanisms of inhibition of tube formation and provides a mechanism that may contribute to benzene-induced toxicity at the level of bone marrow endothelium. PMID:19525446

New approaches to pharmacological treatment of osteoporosis.

PubMed Central

Akesson, Kristina

2003-01-01

Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

ESWT and alendronate sodium demonstrate equal protective effects in osteoarthritis of the knee

NASA Astrophysics Data System (ADS)

Wang, Ching-Jen; Chou, Wen-Yi; Hsu, Shan-Ling; Huang, Chien-Yiu; Cheng, Jai-Hong

2016-01-01

This study compared the effects of extracorporeal shock wave therapy (ESWT) and alendronate sodium (alendronate) in osteoarthritis (OA) of rat knees. The control group was subjected to a sham surgery and did not receive either ESWT or alendronate treatment. The OA group underwent anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM) surgery and did not receive either ESWT or alendronate. The ESWT group underwent ACLT and MM surgery and received ESWT after the surgery. The alendronate group received alendronate after ACLT and MM surgery. The evaluations included radiograph, bone mineral density (BMD), serum C-telopeptide collagen II (CTX-II), cartilage oligomeric protein (COMP), alkaline phosphatase and osteocalcin, histopathological examination and immunohistochemical analysis. Radiographs at 12 weeks showed pronounced OA changes in the OA group. The BMD values, CTX-II, COMP, alkaline phosphatase and osteocalcin showed no significant difference between ESWT and alendronate groups. In histopathology, the Mankin and Safranin O scores significantly increased in the OA, ESWT and alendronate groups, but without any significant difference between the ESWT and alendronate groups. In immunohistochemical analysis, the von Willebrand factor (vWF), vascular endothelial factor (VEGF), soluble vascular cell adhesion molecule (sVCAM), proliferating cell nuclear antigen (PCNA), bone morphogenetic protein 2 (BMP-2), and osteocalcin expressions in articular cartilage and subchondral bone showed a significant decrease in the OA group, but no difference was noted between the ESWT and alendronate groups. In conclusion, ESWT and alendronate sodium demonstrate equal protective effects from developing osteoarthritis of the knee in rats.

Gradual downhill running improves age-related skeletal muscle and bone weakness: implication of autophagy and bone morphogenetic proteins.

PubMed

Kim, Jeong-Seok; Lee, Young-Hee; Yi, Ho-Keun

2016-12-01

What is the central question of this study? Exercise training by running has an effect on age-related muscle and bone wasting that improves physical activity and quality of life in the elderly. However, the effect of downhill running on age-related muscle and bone wasting, and its mechanisms, are unclear. What is the main finding and its importance? Gradual downhill running can improve skeletal muscle growth and bone formation by enhancing autophagy and bone morphogenetic protein signalling in aged rats. Therefore, downhill running exercise might be a practical intervention to improve skeletal muscle and bone protection in the elderly. Recent evidence suggests that autophagy and the bone morphogenetic protein (BMP) signalling pathway regulate skeletal muscle growth and bone formation in aged rats. However, the effect of downhill running on muscle growth and bone formation is not well understood. Thus, we investigated the effect of downhill and uphill running on age-related muscle and bone weakness. Young and late middle-aged rats were randomly assigned to control groups (young, YC; and late middle-aged, LMC) and two types of running training groups (late middle-aged downhill, LMD; and late middle-aged uphill, LMU). Training was progressively carried out on a treadmill at a speed of 21 m min -1 with a slope of +10 deg for uphill training versus 16 m min -1 with a slope of -16 deg for downhill training, both for 60 min day -1 , 5 days week -1 for 8 weeks. Downhill and uphill training increased autophagy-related protein 5, microtubule-associated protein light chain, Beclin-1 and p62 proteins in aged rats. In addition, superoxide dismutase, haem oxygenase-1 and the BMP signalling pathway were elevated. Phosphorylation of mammalian target of rapamycin and myogenic differentiation were increased significantly in the LMD and LMU groups. Consequently, in the femur, BMP-2, BMP-7 and autophagy molecules were highly expressed in the LMD and LMU groups. These results suggest that both downhill and uphill training appear to have a positive effect on expression of autophagy molecules and BMPs. In particular, these physiological adaptations from gradual downhill exercise have an effect on bone morphological changes and muscle quality similar to gradual uphill training interventions in ageing. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Polysaccharides of Trametes versicolor Improve Bone Properties in Diabetic Rats.

PubMed

Chen, Chung-Hwan; Kang, Lin; Lo, Hui-Chen; Hsu, Tai-Hao; Lin, Fang-Yi; Lin, Yi-Shan; Wang, Zai-Jie; Chen, Shih-Tse; Shen, Chwan-Li

2015-10-28

This study investigates the effects of Trametes versicolor (L.:Fr.) Pilát (TVP, also known as Yunzhi) on bone properties in diabetic rats. Forty-five male Wistar rats (8 weeks old) were fed either a chow diet (control) or a high-fat diet throughout the study period of 28 days. Animals in the high-fat-diet group were injected with nicotinamide and streptozotocin to induce diabetes mellitus (DM). The DM rats were divided into a group receiving distilled water (vehicle) and another group receiving TVP at 0.1 g/kg weight by gavage. Relative to the vehicle group, TVP gavage lowered postprandial blood sugar (225 ± 18 mg/dL for TVP vs 292 ± 15 mg/dL for vehicle, p < 0.001) on day 26. Compared to the vehicle group, TVP mitigated DM-induced bone deterioration as determined by increasing bone volume of proximal tibia (22.8 ± 1.4% for TVP vs 16.8 ± 1.3% for vehicle, p = 0.003), trabecular number (p = 0.011), and femoral bone strength (11% in maximal load, 22% in stiffness, 14% in modulus, p < 0.001), and by reducing loss of femoral cortical porosity by 25% (p < 0.001). Our study demonstrates the protective effect of TVP on bone properties was mediated through, in part, the improvement of hyperglycemic control in DM animals.

BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.

PubMed

Li, Jinbo; Wang, Qian; Yang, Renlei; Zhang, Jiaqi; Li, Xing; Zhou, Xichao; Miao, Dengshun

2017-05-01

Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and Eμ-BMI-1 transgenic mice with BMI-1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and RANKL production in T cells, thus enhancing osteoclastogenesis and accelerating bone loss. This study clarifies a novel mechanism regulating estrogen deficiency-induced bone loss. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Accelerated bone loss in older men: Effects on bone microarchitecture and strength.

PubMed

Cauley, J A; Burghardt, A J; Harrison, S L; Cawthon, P M; Schwartz, A V; Connor, E Barrett; Ensrud, Kristine E; Langsetmo, Lisa; Majumdar, S; Orwoll, E

2018-05-11

Accelerated bone loss (ABL) shown on routine dual-energy X-ray absorptiometry (DXA) may be accompanied by microarchitectural changes, increased cortical porosity and lower bone strength. To test this hypothesis, we performed a cross-sectional study and used high resolution peripheral quantitative computed tomography (HR-pQCT) scans (SCANCO, Inc., Switzerland) to measure estimated bone strength and microarchitecture in the distal radius and distal and diaphyseal tibia. We studied 1628 men who attended the Year 14 exam of the Osteoporotic Fractures in Men (MrOS) study. We retrospectively characterized areal (a) bone mineral density (BMD) change from the Year 7 to Year 14 exam in 3 categories: "accelerated" >10% loss at either the total hip or femoral neck, (N = 299, 18.4%); "expected" loss, <10%, (N = 1061, 65.2%) and "maintained" BMD, ≥0%, (N = 268, 16.5%). The ABL cutoff was a safety alert established for MrOS. We used regression models to calculate adjusted mean HR-pQCT parameters in men with ABL, expected loss or maintained BMD. Men who experienced ABL were older and had a lower body mass index and aBMD and experienced greater weight loss compared to other men. Total volumetric BMD and trabecular and cortical volumetric BMD were lower in men with ABL compared to the expected or maintained group. Men with ABL had significantly lower trabecular bone volume fraction (BV/TV), fewer trabeculae and greater trabecular separation at both the distal radius and tibia than men with expected loss or who maintained aBMD, all p trend <0.001. Men with ABL had lower cortical thickness and lower estimated bone strength but there was no difference in cortical porosity except at the tibia diaphyseal site In summary, men with ABL have lower estimated bone strength, poorer trabecular microarchitecture and thinner cortices than men without ABL but have similar cortical porosity. These impairments may lead to an increased risk of fracture. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Impact of Weight Loss With Intragastric Balloon on Bone Density and Microstructure in Obese Adults.

PubMed

Madeira, Eduardo; Madeira, Miguel; Guedes, Erika Paniago; Mafort, Thiago Thomaz; Moreira, Rodrigo Oliveira; de Mendonça, Laura Maria Carvalho; Lima, Inayá Correa Barbosa; Neto, Leonardo Vieira; de Pinho, Paulo Roberto Alves; Lopes, Agnaldo José; Farias, Maria Lucia Fleiuss

2018-03-21

The historical concept that obesity protects against bone fractures has been questioned. Weight loss appears to reduce bone mineral density (BMD); however, the results in young adults are inconsistent, and data on the effects of weight loss on bone microstructure are limited. This study aimed to evaluate the impact of weight loss using an intragastric balloon (IGB) on bone density and microstructure. Forty obese patients with metabolic syndrome (mean age 35.1 ± 7.3 yr) used an IGB continuously for 6 mo. Laboratory tests, areal BMD, and body composition measurements via dual-energy X-ray absorptiometry, and volumetric BMD and bone microstructure measurements via high-resolution peripheral quantitative computed tomography were conducted before IGB placement and after IGB removal. The mean weight loss was 11.5%. After 6 mo, there were significant increases in vitamin D and carboxyterminal telopeptide of type 1 collagen levels. After IGB use, areal BMD increased in the spine but decreased in the total femur and the 33% radius. Cortical BMD increased in the distal radius but tended to decrease in the distal tibia. The observed trabecular bone loss in the distal tibia contributed to the decline in the total volumetric BMD at this site. There was a negative correlation between the changes in leptin levels and the measures of trabecular quality in the tibia on high-resolution peripheral quantitative computed tomography. Weight loss may negatively impact bone microstructure in young patients, especially for weight-bearing bones, in which obesity has a more prominent effect. Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2014 CFR

2014-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2011 CFR

2011-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

Vitamin K’s role in age-related bone loss: A critical review

USDA-ARS?s Scientific Manuscript database

The protective role of vitamin K in age-related bone loss continues to be controversial. The results of observational analyses are inconsistent with respect to associations between vitamin K status and bone, which arguably may be related to the limitations of observational study designs and analyt...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2010 CFR

2010-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2012 CFR

2012-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2013 CFR

2013-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

Interstitial ultrasound ablation of tumors within or adjacent to bone: Contributions of preferential heating at the bone surface

NASA Astrophysics Data System (ADS)

Scott, Serena J.; Prakash, Punit; Salgaonkar, Vasant; Jones, Peter D.; Cam, Richard N.; Han, Misung; Rieke, Viola; Burdette, E. Clif; Diederich, Chris J.

2013-02-01

Preferential heating of bone due to high ultrasound attenuation may enhance thermal ablation performed with cathetercooled interstitial ultrasound applicators in or near bone. At the same time, thermally and acoustically insulating cortical bone may protect sensitive structures nearby. 3D acoustic and biothermal transient finite element models were developed to simulate temperature and thermal dose distributions during catheter-cooled interstitial ultrasound ablation near bone. Experiments in ex vivo tissues and tissue-mimicking phantoms were performed to validate the models and to quantify the temperature profiles and ablated volumes for various distances between the interstitial applicator and the bone surface. 3D patient-specific models selected to bracket the range of clinical usage were developed to investigate what types of tumors could be treated, applicator configurations, insertion paths, safety margins, and other parameters. Experiments show that preferential heating at the bone surface decreases treatment times compared to when bone is absent and that all tissue between an applicator and bone can be ablated when they are up to 2 cm apart. Simulations indicate that a 5-7 mm safety margin of normal bone is needed to protect (thermal dose < 6 CEM43°C and T < 45°C) sensitive structures behind ablated bone. In 3D patient-specific simulations, tumors 1.0-3.8 cm (L) and 1.3-3.0 cm (D) near or within bone were ablated (thermal dose > 240 CEM43°C) within 10 min without damaging the nearby spinal cord, lungs, esophagus, trachea, or major vasculature. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in tumors in and near bone compared to other heating modalities.

Radioprotective Effects of Heat-Killed Mycobacterium Tuberculosis in Cultured Cells and Radiosensitive Tissues.

PubMed

Chen, Yuanyuan; Xu, Yang; Du, Jicong; Guo, Jiaming; Lei, Xiao; Cui, Jianguo; Liu, Cong; Cheng, Ying; Li, Bailong; Gao, Fu; Ju, Jintao; Cai, Jianming; Yang, Yanyong

2016-01-01

Exposure to ionizing radiation (IR) often causes severe damage to radiosensitive tissues, which limits the use of radiotherapy in cancer patients. Novel safe and effective radioprotectant is urgently required. It has been reported toll like receptor 2 (TLR2) plays a critical role in radioresistance. In this study, we demonstrated the protective effects of Heat-Killed Mycobacterium tuberculosis (HKMT), a potent TLR2 agonist, against IR. Cell survival and apoptosis were determined by CCK-8 assay and Annexin V assay, respectively. An immunofluorescence staining assay was used to detect the translocation of nuclear faktor-kappa beta (NF-kB) p65. Tissue damage was evaluated by Haematoxilin-Eosin (HE) staining assay. We also used a flow cytometry assay to measure the number of nucleated cells and CD34+ hemopoietic stem cells in bone marrow. A western blot assay was used to detect the changes of proteins involving TLR signaling pathway. We found that HKMT increased cell viability and inhibited cell apoptosis after irradiation. HKMT induced NF-kB translocation and activated Erk1/2, p38 signaling pathway. HKMT also protected bone marrow and testis from destruction. Radiation-induced decreases of nucleated cells and CD34+ hemopoietic stem cells in bone marrow were also inhibited by HKMT treatment. We found that radiation caused increase of inflammatory cytokines was also suppressed by HKMT. Our data showed that HKMT exhibited radioprotective effects in vivo and in vitro through activating NF-kB and MAPK signaling pathway, suggesting a potential of HKMT as novel radioprotector. © 2016 The Author(s) Published by S. Karger AG, Basel.

Recycled palm oil is better than soy oil in maintaining bone properties in a menopausal syndrome model of ovariectomized rat.

PubMed

Shuid, Ahmad Nazrun; Chuan, Loh Hong; Mohamed, Norazlina; Jaarin, Kamsiah; Fong, Yew Su; Soelaiman, Ima Nirwana

2007-01-01

Palm oil is shown to have antioxidant, anticancer and cholesterol lowering effects. It is resistant to oxidation when heated compared to other frying oils such as soy oil. When a frying oil is heated repeatedly, it forms toxic degradation products, such as aldehydes which when consumed, may be absorbed into the systemic circulation. We have studied the effects of taking soy or palm oil that were mixed with rat chow on the bone histomorphometric parameters of ovariectomised rats. Female Sprague-Dawley rats were divided into eight groups: (1) normal control group; (2) ovariectomised-control group; (3) ovariectomised and fresh soy oil; (4) ovariectomised and soy oil heated once; (5) ovariectomised and soy oil heated five times; (6) ovariectomised and fresh palm oil; (7) ovariectomised and palm oil heated once; (8) ovariectomised and palm oil heated five times. These oils were mixed with rat chow at weight ratio of 15:100 and were given to the rats daily for six months. Ovariectomy had caused negative effects on the bone histomorphometric parameters. Ingestion of both fresh and once-heated oils, were able to offer protections against the negative effects of ovariectomy, but these protections were lost when the oils were heated five times. Soy oil that was heated five times actually worsens the histomorphometric parameters of ovariectomised rats. Therefore, it may be better for postmenopausal who are at risk of osteoporosis to use palm oil as frying oil especially if they practice recycling of frying oils.

Specialized connective tissue: bone, the structural framework of the upper extremity

PubMed Central

Weatherholt, Alyssa M.; Fuchs, Robyn K.; Warden, Stuart J.

2011-01-01

Bone is a connective tissue containing cells, fibers and ground substance. There are many functions in the body in which the bone participates, such as storing minerals, providing internal support, protecting vital organs, enabling movement, and providing attachment sites for muscles and tendons. Bone is unique because its collagen framework absorbs energy, while the mineral encased within the matrix allows bone to resist deformation. This article provides an overview of the structure and function of bone tissue from a macroscopic to microscopic level and discusses the physiological processes contributing to upper extremity bone health. It concludes by discussing common conditions influencing upper extremity bone health. PMID:22047807

Osteocytes and Mechano-Transduction (Osteo-4)

NASA Image and Video Library

2015-04-19

ISS043E122574 (04/19/2015) --- ESA (European Space Station) astronaut Samantha Cristoforetti, a flight engineer on the International Space Station, is seen here unpacking the recently arrived Osteo-4 experiment which was carried up on Spacex’s sixth Dragon resupply mission. Osteo-4 is performing research on how microgravity effects changes in the most common cell found in human bones to protect the health of future astronauts. This research could also have implications for patients on Earth in the treatment of bone disorders related to disuse or immobilization, as well as metabolic diseases such as osteoporosis.

Methods for Studying the Role of RAAS in the Modulation of Vascular Repair-Relevant Functions of Stem/Progenitor Cells.

PubMed

Jarajapu, Yagna P R

2017-01-01

In recent years, previously unknown functions have been conferred to the RAAS and have been explored in mechanistic studies and disease models. Implication of bone marrow stem/progenitor cells in the cardiovascular protective or detrimental effects of RAAS is a prominent advancement because of the translational significance. Selected members of RAAS are now known to modulate migration, proliferation, and mobilization of bone marrow cells in response to ischemic insult, which are sensitive indicators of vascular repair-relevant functions. In this Chapter, protocols for most frequently used, in vitro, ex vivo, and in vivo assays to explore the potential of RAAS members to stimulate vascular repair-relevant functions of bone marrow stem/progenitor cells of human and murine origin.

In vivo postirradiation protection by a vitamin E analog, alpha-TMG.

PubMed

Satyamitra, Merriline; Uma Devi, P; Murase, Hironobu; Kagiya, V T

2003-12-01

The water-soluble vitamin E derivative alpha-TMG is an excellent radical scavenger. A dose of 600 mg/kg TMG significantly reduced radiation clastogenicity in mouse bone marrow when administered after irradiation. The present study was aimed at investigating the radioprotective effect of postirradiation treatment with alpha-TMG against a range of whole-body lethal (8.5-12 Gy) and sublethal (1-5 Gy) doses of radiation in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from micronuclei and chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 600 mg/kg TMG within 10 min of lethal irradiation increased survival, giving a dose modification factor (DMF) of 1.09. TMG at doses of 400 mg/kg and 600 mg/kg significantly reduced the percentage of aberrant metaphases, the different types of aberrations, and the number of micronucleated erythrocytes. DMFs of 1.22 and 1.48 for percentage aberrant metaphases and 1.6 and 1.98 for micronuclei were obtained for 400 mg/kg and 600 mg/kg TMG, respectively. No drug toxicity was observed at these doses. The effectiveness of TMG when administered postirradiation suggests its possible utility for protection against unplanned radiation exposures.

Dok-3 and Dok-1/-2 adaptors play distinctive roles in cell fusion and proliferation during osteoclastogenesis and cooperatively protect mice from osteopenia.

PubMed

Kajikawa, Shuhei; Taguchi, Yuu; Hayata, Tadayoshi; Ezura, Yoichi; Ueta, Ryo; Arimura, Sumimasa; Inoue, Jun-Ichiro; Noda, Masaki; Yamanashi, Yuji

2018-04-15

Bone mass is determined by coordinated acts of osteoblasts and osteoclasts, which control bone formation and resorption, respectively. Osteoclasts are multinucleated, macrophage/monocyte lineage cells from bone marrow. The Dok-family adaptors Dok-1, Dok-2 and Dok-3 are expressed in the macrophage/monocyte lineage and negatively regulate many signaling pathways, implying roles in osteoclastogenesis. Indeed, mice lacking Dok-1 and Dok-2, the closest homologues with redundant functions, develop osteopenia with increased osteoclast counts compared to the wild-type controls. Here, we demonstrate that Dok-3 knockout (KO) mice also develop osteopenia. However, Dok-3 KO, but not Dok-1/-2 double-KO (DKO), mice develop larger osteoclasts within the normal cell-count range, suggesting a distinctive role for Dok-3. Indeed, Dok-3 KO, but not Dok-1/-2 DKO, bone marrow-derived cells (BMDCs) generated larger osteoclasts with more nuclei due to augmented cell-to-cell fusion in vitro. In addition, while Dok-1/-2 DKO BMDCs generated more osteoclasts, Dok-1/-2/-3 triple-KO (TKO) BMDCs generated osteoclasts increased in both number and size. Furthermore, Dok-1/-2/-3 TKO mice showed the combined effects of Dok-3 and Dok-1/-2 deficiency: severe osteopenia with more and larger osteoclasts. Together, our findings demonstrate that Dok-3 and Dok-1/-2 play distinctive but cooperative roles in osteoclastogenesis and protect mice from osteopenia, providing physiological and pathophysiological insight into bone homeostasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: A portrait of molecular crosstalk.

PubMed

Adil, Mohammad; Mansoori, Mohd Nizam; Singh, Divya; Kandhare, Amit Dattatraya; Sharma, Manju

2017-10-01

Diabetes mellitus and osteoporosis both are high prevalence disorders, especially in the elderly population. Pioglitazone, a PPAR-γ agonist associated with bone loss and risk of fracture in type 2 diabetes mellitus patients. In this study, ameliorative effect of berberine against pioglitazone-induced bone loss in diabetic rats and possible mechanisms has been explored. Diabetes was induced in male Wistar albino rats by streptozotocin (65 mg/kg, i.v.) after 15min of nicotinamide (230mg/kg, i.p.) administration. Diabetic rats were treated orally with pioglitazone (10mg/kg) and berberine (100mg/kg) alone and in combination of both for 12 weeks. Femur of each rat was isolated and evaluated for the bone micro-architecture, BMD, histology and mRNA expression of PPAR-γ, AMPK, and bone turnover markers (RANKL, OPG, Runx2, and osteocalcin). Urinary calcium and serum TRAP was also measured. Treatment of pioglitazone and berberine alone and in combination significantly ameliorate abnormal blood glucose, serum insulin, and HbA1c levels in streptozotocin-induced diabetic rats. Pioglitazone treatment significantly increased urinary calcium, serum TRAP, mRNA expression of RANKL, PPAR-γ as well as significantly decreased Runx2, OPG, osteocalcin and AMPK levels in diabetic rats. Pioglitazone administration also shows detrimental effect on femur epiphysis micro-architecture, BMD and histology. Whereas, berberine treatment alone and in combination with pioglitazone remarkably ameliorates the abnormal urinary calcium, mRNA expression of AMPK, bone turnover markers, femur epiphysis micro-architecture, histology and also increases BMD in diabetic rats. In conclusion, berberine shows protective effect against pioglitazone-induced bone loss in diabetic rats possibly through AMPK activation pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The evaluation of bone metabolism in children with renal transplantation.

PubMed

Büyükkaragöz, Bahar; Bakkaloglu, Sevcan A; Kandur, Yaşar; Isiyel, Emel; Akcaboy, Meltem; Buyan, Necla; Hasanoglu, Enver

2015-06-01

This study aims to evaluate BMD and bone biomarkers and to investigate the effects of immunosuppressives on bone disease after RTx. Thirty-three RTR aged 16.7 ± 3.7 yr and healthy controls (n = 32) were enrolled. There was no difference between pre-RTx BMD and BMD at the time of study (45.9 ± 30.9 months after RTx), while both values were lower than controls (p < 0.01 and p < 0.05, respectively). Worst BMD scores were obtained at sixth month after RTx (-0.2 ± 0.9) and best at fourth year (1.4 ± 1.3). 25-hydroxy-(OH) vitamin D and OPG were higher in RTR (p < 0.001). BMD z scores negatively correlated with OPG and cumulative CS doses at the time of study (r = -0.344, p < 0.05 and r = -0.371, p < 0.05, respectively). Regression analysis revealed OPG as the only predictor of BMD (β -0.78, 95% CI -0.004 to -0.013, p < 0.001). The increase in OPG, a significant predictor of BMD, could either be secondary to graft dysfunction or for protection against bone loss. CS doses should be minimized to avoid their untoward effects on bone metabolism. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Folic acid improve developmental toxicity induced by aluminum sulphates.

PubMed

Yassa, Heba A; George, Safaa M; Mohamed, Heba K

2017-03-01

Aluminum sulphate has a significant toxic effects for humans. Aluminum is one of the most abundant metal on the Earth crust. The purpose of this study is to evaluate the effects of short term exposure to aluminum sulphate on the bone development of the fetuses in rats, and if folic acid has a protective role upon that effects or not. Forty female rats were used, ten per group, GI served as negative control (receive nothing except normal feeding and water), GII served as positive control (receive water by gastric gavage), GIII treated with aluminum sulphate orally by gastric gavage and GIV treated with aluminum sulphate with folic acid. Mating occurred and known by presence of vaginal plug in the female rats. Rats were killed on day 18 of gestation. The female rats weight were significantly reduced in the treated group if compared with the control group (p>0.001), all parameters of the fetuses, fetal weight, malformation and the crown rump length reduced significantly p value were <0.000, <0.001, and <0.000 respectively. In histopathological results the aluminum treated group showed severe limited area of preossfication in fetuses vertebrae. Folic acid gave a protective role for all the hazardous effects of aluminum sulphate and prove the diameters measured and also the histopathological effects. Aluminum sulphate can produce hazardous effects on bone of the fetuses, which may affect the life style of these fetuses later on. Folic acid might give a protective role and so should be given to females who tried to conceive. Copyright © 2017 Elsevier B.V. All rights reserved.

Maternal Dietary Supplementation with Oligofructose-Enriched Inulin in Gestating/Lactating Rats Preserves Maternal Bone and Improves Bone Microarchitecture in Their Offspring

PubMed Central

Diaz-Castro, Javier; López-Aliaga, Inmaculada; Rueda, Ricardo

2016-01-01

Nutrition during pregnancy and lactation could exert a key role not only on maternal bone, but also could influence the skeletal development of the offspring. This study was performed in rats to assess the relationship between maternal dietary intake of prebiotic oligofructose-enriched inulin and its role in bone turnover during gestation and lactation, as well as its effect on offspring peak bone mass/architecture during early adulthood. Rat dams were fed either with standard rodent diet (CC group), calcium-fortified diet (Ca group), or prebiotic oligofructose-enriched inulin supplemented diet (Pre group), during the second half of gestation and lactation. Bone mineral density (BMD) and content (BMC), as well as micro-structure of dams and offspring at different stages were analysed. Dams in the Pre group had significantly higher trabecular thickness (Tb.Th), trabecular bone volume fraction (BV/TV) and smaller specific bone surface (BS/BV) of the tibia in comparison with CC dams. The Pre group offspring during early adulthood had an increase of the lumbar vertebra BMD when compared with offspring of CC and Ca groups. The Pre group offspring also showed significant increase versus CC in cancellous and cortical structural parameters of the lumbar vertebra 4 such as Tb.Th, cortical BMD and decreased BS/BV. The results indicate that oligofructose-enriched inulin supplementation can be considered as a plausible nutritional option for protecting against maternal bone loss during gestation and lactation preventing bone fragility and for optimizing peak bone mass and architecture of the offspring in order to increase bone strength. PMID:27115490

Protection of intestinal damage by pretreatment with cytarabine (cytosine arabinoside)

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

Phelps, T.A.; Blackett, N.M.

The circumstances in which cytarabine (cytosine arabinoside) ''protects'' intestinal epithelial stem cells against radiation have been investigated. Special attention has been given to this protective effect with radiation doses in the clinically used range in order to determine whether the protective effect might be of use in radiotherapy. It has been shown that 12 hours after cytarabine the D/sub 0/ and extrapolation number are increased when large single doses of radiation are used. To determine the effect of cytarabine at lower doses, it is necessary to use a second irradiation as an ''assay'' dose. By this means it is shownmore » that there is more protection than can be accounted for by the change in D/sub 0/ and extrapolation number at the time of the first dose. Evidence is presented indicating that the rate of stem cell regeneration is not increased by cytarabine pretreatment. Finally, the relation between intestinal protection, bone marrow stem cell enhanced recovery and improved animal survival as a result of cytarabine pretreatment is discussed.« less

Biomechanical and biological aspects of defect treatment in fractures using helical plates.

PubMed

Perren, S M; Regazzoni, P; Fernandez, A A D

2014-01-01

The clinical case of figure 1 through figure 11 shows a series of impressive failures of plate fixation. The plates were repeatedly applied bridging a comminuted bone segment in a heavy patient. The biomechanical analysis elaborates why this happened and proposes an unconventional procedure to prevent this failure with a minimally invasive procedure. A plate bridging an open gap or a defect in a long bone diaphysis is exposed to full functional load. According to clinical observations such plate application often fails even without external load such as weight bearing. The plate risks to break through fatigue when exposed during a long time to cyclic loading. This type of failure has been observed even with broad plates as well in femoral as in tibiae. The first option to avoid such failure consists in protecting the plate by installing load sharing between plate and either bone or an additional implant. This reduces the load carried by the plate to a safe level. Load sharing with bone may be installed at surgery by establishing solid mechanical bridge between the two main fragments of the fractured bone. The optimal load sharing relies on a solid compressed contact between the main fragments. It can be established because the bone is able to take a large load which results in optimal protection of the plate. In the case of an extended comminuted bone segment it may be very difficult, traumatizing and inefficient to reconstruct the bone. In the present case it was impossible to establish load sharing through the bone. The second option protecting the plate is provided by callus bridging of the gap or defect. The formation of a solid callus bridge takes time but the fatigue failure of the plate also takes time. Therefore, the callus bridge may prevent a late fatigue failure. The surgeon may select one of several options: - Replacing the lack of bone support using a second plate which immediately alleviates plate loading. The drawback of application of a second conventional plate is the extent of surgical trauma at the critical site of healing. - Shingling and/or applying an autologous cancellous bone graft: This procedure provides initially no relevant load sharing but will do so after a couple of weeks. The mechanical coupling of the comparably soft graft and the main fracture fragments presents little problems. Applying a cortical bone graft: Such a graft does provide initial only small load sharing and does a less good job inducing callus than a cancellous graft. Furthermore, the coupling by callus between a somewhat rigid bone graft and the mobile main fracture fragments requires a solid maintained contact. If the cortical graft is fixed using implants with small contact area to the graft such as screws or cerclage loops, the local stress may be critical and the graft may break. When the cortical graft is fixed with cerclage wires the procedure must take into account the limited strength of the individual cerclage. Therefore multiple and well-spaced cerclages are required and may lead to success especially if an intramedullary component of the implant contributes to protection (6). The degree of unloading depends apparently on the stiffness of the material of the protecting splint. Though, more important is the effect of the dimensions of the splint. While titanium as a material is about 50% less stiff than steel, the thickness of the implant changes the stiffness with the third power. That is doubling the thickness results in eightfold increased stiffness. When considering the unloading by application of a second plate the leverage of the second plate plays an important role. The larger the distance between the axis of bending and the second implant the larger the protecting effect. The helical plate (2, 3, 7) as introduced by A.A.D. Fernandez offers biological and mechanical advantages. It can be applied without touching the fracture site maintaining the critical biology intact and provides mechanically efficient unloading. Its application is fairly simple: The helical plate is modified conventional long and small plate that is twisted between its ends about 90 degrees. The twist is applied using "bending irons" (4, 5, 8) whereby the force required is small and the exact degree of twist is not critical. Therefore the twist is applicable operating bending irons by hand. Assuming a situation where a plate bridging a defect or non-union has failed the broken plate is replaced by a similar implant: At the distal end of the bone fracture and opposite to the surgical approach a small incision allows to slide in the helical plate in such a way that proximally the plate ends on the same side of the limb as the replaced plate. Ideally the two plate ends meet and the application of the helical plate does not ask for an additional surgical exposure at this location. Otherwise a small minimally invasive exposure is required. The helical plate is then fixed to the main bone fragments using a couple of locked screws. The following case demonstrates the use and efficiency of the helical plate saving a situation where multiple attempts using conventional plates had failed. The successful final treatment of this case was performed by A. A. D. Fernandez.

The role of calcium intake in preventing bone fragility, hypertension, and certain cancers.

PubMed

Barger-Lux, M J; Heaney, R P

1994-08-01

This paper examines the evidence that connects calcium intake and vitamin D status to bone fragility, hypertension, colon cancer, and breast cancer. Human calcium physiology, with an intestinal absorptive barrier and inefficient conservation, reflects the abundance of calcium in the primordial human food supply. The calcium intake of stone-age adults is estimated at 50 to 75 mmol/d, three to five times the median calcium intake of present-day U.S. adults. Long-term calcium restriction and/or insufficient vitamin D may promote the development of bone fragility, high blood pressure, colon cancer, and breast cancer in susceptible individuals. Conversely, improvement in calcium intake and/or in vitamin D status may help to prevent these serious health problems. At least 12 intervention studies have established the skeletal benefit of increased calcium intake among women in the late postmenopause. Other reports suggest that adequate calcium may protect against salt-sensitive and pregnancy-associated hypertension. High intakes of both dietary calcium and vitamin D are associated with reduced development of precancerous changes in colonic mucosa. Preliminary findings also suggest that vitamin D has a protective effect against breast cancer.

Anti-osteoporotic activity of harpagide by regulation of bone formation in osteoblast cell culture and ovariectomy-induced bone loss mouse models.

PubMed

Chung, Hwa-Jin; Kyung Kim, Won; Joo Park, Hyen; Cho, Lan; Kim, Me-Riong; Kim, Min Jeong; Shin, Joon-Shik; Ho Lee, Jin; Ha, In-Hyuk; Kook Lee, Sang

2016-02-17

Harpagide, an iridoid glucoside, is a constituent of the root of Harpagophytum procumbens var. sublobatum (Engl.) Stapf, Devil's claw which has been used in patients with osteoarthritis (OA). In the present study, we investigated the anti-osteoporotic potential of harpagide and its underlying mechanism of action in in vitro cell culture and in vivo bone loss animal models. Harpagide was obtained from the alkalic hydrolysis of harpagoside, a major constituent of H. procumbens var. sublobatum Analysis of biomarkers for bone formation in osteoblastic MC3T3-E1 cells and bone resorption in osteoclast cells derived from mouse bone marrow cells was performed to evaluate the mechanism of action. The protective activity of harpagide against bone loss was also evaluated in ovariectomized (OVX) mouse model. Harpagide improved bone properties by stimulating the process of differentiation and maturation of osteoblast cells and suppressing the process of RANKL-induced differentiation of osteoclast cells. In OVX-induced bone loss mouse model, oral administration of harpagide significantly improved recovery of bone mineral density, trabecular bone volume, and trabecular number in the femur. Harpagide also prevented increase of trabecular separation and structure model index induced by OVX. Harpagide effectively inhibited the serum levels of biochemical markers of bone loss, including alkaline phosphatase, osteocalcin, C-terminal telopeptide, and tartrate-resistant acid phosphatase. Taken together, the present study demonstrates that harpagide has a potential for prevention of bone loss in OVX mice by regulating the stimulation of osteoblast differentiation and the suppression of osteoclast formation. Therefore, these findings suggest that harpagide might serve as a bioactive compound derived from H. procumbens var. sublobatum for improvement of age-dependent bone destruction disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Identification of Proteoglycans and Glycosaminoglycans in Archaeological Human Bones and Teeth

PubMed Central

Coulson-Thomas, Yvette M.; Coulson-Thomas, Vivien J.; Norton, Andrew L.; Gesteira, Tarsis F.; Cavalheiro, Renan P.; Meneghetti, Maria Cecília Z.; Martins, João R.; Dixon, Ronald A.; Nader, Helena B.

2015-01-01

Bone tissue is mineralized dense connective tissue consisting mainly of a mineral component (hydroxyapatite) and an organic matrix comprised of collagens, non-collagenous proteins and proteoglycans (PGs). Extracellular matrix proteins and PGs bind tightly to hydroxyapatite which would protect these molecules from the destructive effects of temperature and chemical agents after death. DNA and proteins have been successfully extracted from archaeological skeletons from which valuable information has been obtained; however, to date neither PGs nor glycosaminoglycan (GAG) chains have been studied in archaeological skeletons. PGs and GAGs play a major role in bone morphogenesis, homeostasis and degenerative bone disease. The ability to isolate and characterize PG and GAG content from archaeological skeletons would unveil valuable paleontological information. We therefore optimized methods for the extraction of both PGs and GAGs from archaeological human skeletons. PGs and GAGs were successfully extracted from both archaeological human bones and teeth, and characterized by their electrophoretic mobility in agarose gel, degradation by specific enzymes and HPLC. The GAG populations isolated were chondroitin sulfate (CS) and hyaluronic acid (HA). In addition, a CSPG was detected. The localization of CS, HA, three small leucine rich PGs (biglycan, decorin and fibromodulin) and glypican was analyzed in archaeological human bone slices. Staining patterns were different for juvenile and adult bones, whilst adolescent bones had a similar staining pattern to adult bones. The finding that significant quantities of PGs and GAGs persist in archaeological bones and teeth opens novel venues for the field of Paleontology. PMID:26107959

Male Astronauts Have Greater Bone Loss and Risk of Hip Fracture Following Long Duration Spaceflights than Females

NASA Technical Reports Server (NTRS)

Ellman, Rachel; Sibonga, Jean; Bouxsein, Mary

2010-01-01

This slide presentation reviews bone loss in males and compares it to female bone loss during long duration spaceflight. The study indicates that males suffer greater bone loss than females and have a greater risk of hip fracture. Two possible reason for the greater male bone loss are that the pre-menopausal females have the estrogen protection and the greater strength of men max out the exercise equipment that provide a limited resistance to 135 kg.

Aging and Bone

PubMed Central

Boskey, A.L.; Coleman, R.

2010-01-01

Bones provide mechanical and protective function, while also serving as housing for marrow and a site for regulation of calcium ion homeostasis. The properties of bones do not remain constant with age; rather, they change throughout life, in some cases improving in function, but in others, function deteriorates. Here we review the modifications in the mechanical function and shape of bones, the bone cells, the matrix they produce, and the mineral that is deposited on this matrix, while presenting recent theories about the factors leading to these changes. PMID:20924069

Effect of delta-tocotrienols and green tea polyphenols on high-fat-diet-induced bone deterioration in male C57BL/6J mice

USDA-ARS?s Scientific Manuscript database

Our previous studies demonstrated an osteo-protective roles for tocotrienols (TT, extracted from annatto consisting of 90% delta-TT and 10% gamma TT) and green tea polyphenols (GTP, extracted from green tea) in obese animals. This study further examined the combined effects of TT with GTP on high-fa...

Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone.

PubMed

Panwar, Preety; Law, Simon; Jamroz, Andrew; Azizi, Pouya; Zhang, Dongwei; Ciufolini, Marco; Brömme, Dieter

2018-03-01

Attempts to generate active site-directed cathepsin K (CatK) inhibitors for the treatment of osteoporosis have failed because of side effects. We have previously shown that an ectosteric tanshinone CatK inhibitor isolated from Salvia miltiorrhiza blocked, selectively, the collagenase activity of CatK, without affecting the active site and demonstrated its bone-preserving activity in vivo. Here, we have characterize the antiresorptive potential of other tanshinones, which may provide a scaffold for side effect-free CatK inhibitors. Thirty-one tanshinones were tested for their activity against CatK in enzymic and cell-based assays. The inhibitory potency against triple helical and fibrillar collagen degradation was determined in enzymic assays, by scanning electron microscopy and mechanical strength measurements. Human osteoclast assays were used to determine the effects of the inhibitors on bone resorption, its reversibility and osteoclastogenesis. Binding sites were characterized by molecular docking. Twelve compounds showed highly effective anti-collagenase activity and protected collagen against destruction and mechanical instability without inhibiting the hydrolysis of non-collagenous substrates. Six compounds were highly effective in osteoclast bone resorption assays with IC 50 values of <500 nM. None of these tanshinones had effects on cell viability, reversibility of bone resorption inhibition and osteoclastogenesis. The core pharmacophore of the tanshinones appears to be the three-ring system with either a para- or ortho-quinone entity. Our study identified several potent ectosteric antiresorptive CatK inhibitors from the medicinal plant, S. miltiorrhiza, which may avoid side effects seen with active site-directed inhibitors in clinical trials. © 2017 The British Pharmacological Society.

[Diet, nutrition and bone health].

PubMed

Miggiano, G A D; Gagliardi, L

2005-01-01

Nutrition is an important "modifiable" factor in the development and maintenance of bone mass and in the prevention of osteoporosis. The improvement of calcium intake in prepuberal age translates to gain in bone mass and, with genetic factor, to achievement of Peak Bone Mass (PBM), the higher level of bone mass reached at the completion of physiological growth. Individuals with higher PBM achieved in early adulthood will be at lower risk for developing osteoporosis later in life. Achieved the PBM, it is important maintain the bone mass gained and reduce the loss. This is possible adopting a correct behaviour eating associated to regular physical activity and correct life style. The diet is nutritionally balanced with caloric intake adequate to requirement of individual. This is moderate in protein (1 g/kg/die), normal in fat and the carbohydrates provide 55-60% of the caloric intake. A moderate intake of proteins is associated with normal calcium metabolism and presumably does'nt alter bone turnover. An adequate intake of alkali-rich foods may help promote a favorable effect of dietary protein on the skeleton. Lactose intolerance may determinate calcium malabsorption or may decrease calcium intake by elimination of milk and dairy products. Omega3 fatty acids may "down-regulate" pro-inflammatory cytokines and protect against bone loss by decreasing osteoclast activation and bone reabsorption. The diet is characterized by food containing high amount of calcium, potassium, magnesium and low amount of sodium. If it is impossible to reach the requirement with only diet, it is need the supplement of calcium and vitamin D. Other vitamins (Vit. A, C, E, K) and mineral (phosphorus, fluoride, iron, zinc, copper and boron) are required for normal bone metabolism, thus it is need adequate intake of these dietary components. It is advisable reduce ethanol, caffeine, fibers, phytic and ossalic acid intake. The efficacy of phytoestrogens is actually under investigation. Some drugs may interfere with calcium and other nutrients and produce an unfavourable effect on bone health.

Protection against radiation (biological, pharmacological, chemical, physical)

NASA Technical Reports Server (NTRS)

Saksonov, P. P.

1975-01-01

Physical, chemical, and biological protection for astronauts from penetrating radiation on long-term space flights is discussed. The status of pharmacochemical protection, development of protective substances, medical use of protective substances, protection for spacecraft ecologic systems, adaptogens and physical conditioning, bone marrow transplants and local protection are discussed. Combined use of local protection and pharmacochemical substances is also briefly considered.

Role of mastoid pneumatization in temporal bone fractures.

PubMed

Ilea, A; Butnaru, A; Sfrângeu, S A; Hedeşiu, M; Dudescu, C M; Berce, P; Chezan, H; Hurubeanu, L; Trombiţaş, V E; Câmpian, R S; Albu, S

2014-07-01

The mastoid portion of the temporal bone has multiple functional roles in the organism, including regulation of pressure in the middle ear and protection of the inner ear. We investigated whether mastoid pneumatization plays a role in the protection of vital structures in the temporal bone during direct lateral trauma. The study was performed on 20 human temporal bones isolated from cadavers. In the study group formed by 10 temporal bone samples, mastoid cells were removed and the resulting neocavities were filled. The mastoids were maintained intact in the control group. All samples were impacted at the same speed and kinetic energy. The resultant temporal bone fractures were evaluated by CT. Temporal squama fractures were 2.88 times more frequent, and mastoid fractures were 2.76 times more frequent in the study group. Facial nerve canal fractures were 6 times more frequent in the study group and involved all the segments of the facial nerve. Carotid canal fractures and jugular foramen fractures were 2.33 and 2.5 times, respectively, more frequent in the study group. The mastoid portion of the temporal bone plays a role in the absorption and dispersion of kinetic energy during direct lateral trauma to the temporal bone, reducing the incidence of fracture in the setting of direct trauma. © 2014 by American Journal of Neuroradiology.

Rhizoma Dioscoreae Extract Protects against Alveolar Bone Loss in Ovariectomized Rats via microRNAs Regulation

PubMed Central

Zhang, Zhiguo; Song, Changheng; Zhang, Fangzhen; Xiang, Lihua; Chen, Yanjing; Li, Yan; Pan, Jinghua; Liu, Hong; Xiao, Gary Guishan; Ju, Dahong

2015-01-01

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-β/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-β/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation. PMID:25690421

Rhizoma Dioscoreae extract protects against alveolar bone loss in ovariectomized rats via microRNAs regulation.

PubMed

Zhang, Zhiguo; Song, Changheng; Zhang, Fangzhen; Xiang, Lihua; Chen, Yanjing; Li, Yan; Pan, Jinghua; Liu, Hong; Xiao, Gary Guishan; Ju, Dahong

2015-02-16

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-β/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-β/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation.

Biomedical Research Division significant accomplishments for FY 1983

NASA Technical Reports Server (NTRS)

Martello, N. V.

1984-01-01

Various research and technology activities of Ames Research Center's Biomedical Research Division are described. Contributions to the Space Administration's goals in the life sciences include research in operational medicine, cardiovascular deconditioning, motion sickness, bone alterations, muscle atrophy, fluid and electrolyte changes, radiation effects and protection, human behavior and performance, general biomedical research, and gravitational biology.

Genotoxicity and Cytotoxicity Evaluation of the Neolignan Analogue 2-(4-Nitrophenoxy)-1Phenylethanone and its Protective Effect Against DNA Damage

PubMed Central

Hanusch, Alex Lucas; de Oliveira, Guilherme Roberto; de Sabóia-Morais, Simone Maria Teixeira; Machado, Rafael Cosme; dos Anjos, Murilo Machado; Chen Chen, Lee

2015-01-01

Neolignans are secondary metabolites found in various groups of Angiosperms. They belong to a class of natural compounds with great diversity of chemical structures and pharmacological activities. These compounds are formed by linking two phenylpropanoid units. Several compounds that have ability to prevent genetic damage have been isolated from plants, and can be used to prevent or delay the development of tumor cells. Genetic toxicology evaluation is widely used in risk assessment of new drugs in preclinical screening tests. In this study, we evaluated the genotoxicity and cytotoxicity of the neolignan analogue 2-(4-nitrophenoxy)-1-phenylethanone (4NF) and its protective effect against DNA damage using the mouse bone marrow micronucleus test and the comet assay in mouse peripheral blood. Our results showed that this neolignan analogue had no genotoxic activity and was able to reduce induced damage both in mouse bone marrow and peripheral blood. Although the neolignan analogue 4NF was cytotoxic, it reduced cyclophosphamide-induced cytotoxicity. In conclusion, it showed no genotoxic action, but exhibited cytotoxic, antigenotoxic, and anticytotoxic activities. PMID:26554835

Prevention and treatment of bone fragility in cancer patient

PubMed Central

Ottanelli, Silva

2015-01-01

Summary It is well known that fractures increase the risk of morbidity and mortality. The various mechanisms responsible for bone loss in cancer patients may have a different impact depending on the characteristics of the clinical case and correlates with the therapies used, or caused by the therapies used against cancer. Some hormonal treatments cause hypogonadism, event which contributes to the progressive loss of bone mass. This is detectable in patients with breast cancer receiving determines that estrogen-deprivation and in men with prostate cancer with therapies that determine androgen deprivation. Chemotherapy treatments used in cancer patients have reduced bone mass. In addition, low bone mass is detectable in patients with lymphoma treated with corticosteroids or radiation or alkylating agents. In premenopausal patients suffering from breast cancer, treatment with cytotoxic therapy or ablation of ovarian function, can lead to an 8% reduction in bone mineral density at the spine and 4% in the femur. With a chemotherapy regimen in CMF, the reduction of BMD is 6.5%; this bone loss is not recovered after discontinuation of therapy. Tamoxifen given for five years reduces bone remodeling and cause a 32% increase in the risk of osteoporotic fractures when used in premenopausal. After menopause, tamoxifen has a protective effect on bone mass, with a reduced risk of new fractures. Aromatase inhibitors in post-menopausal women, depending on the formulation can cause different effects on the reduction of BMD and fracture risk. We have in fact steroids, exemestane and nonsteroidal, letrozole and anastrozole. Patients at increased risk of fragility fractures should undergo preventive therapies as soon as possible after tests performed for the study of bone health. They can be used DEXA and the FRAX algorithm, which can define a secondary osteoporosis. Prevention and treatment of the increased risk of osteoporotic fracture is to maintain adequate levels of calcium and vitamin D. Bisphosphonates and denosumab are used for the management of bone remodeling and bone loss induced by cancer treatments. Bisphosphonates also have anti-tumor effects per se, which are expressed in potentially prevent the development of bone metastases. In men with metastatic prostate cancer and which is induced androgen deprivation, it is usefully used denosumab 120 mg monthly or zoledronic acid 4 mg monthly. PMID:26604936

Effects of Knockout of the Receptor for Advanced Glycation End-products on Bone Mineral Density and Synovitis in Mice with Intra-Articular Fractures.

PubMed

Seol, Dongrim; Tochigi, Yuki; Bogner, Ashley M; Song, Ino; Fredericks, Douglas C; Kurriger, Gail L; Smith, Sonja M; Goetz, Jessica E; Buckwalter, Joseph A; Martin, James A

2018-04-17

Our group employed the mouse closed intra-articular fracture (IAF) model to test the hypothesis that the innate immune system plays a role in initiating synovitis and post-traumatic osteoarthritis (PTOA) in fractured joints. A transgenic strategy featuring knockout of the receptor for advanced glycation end-products (RAGE -/- ) was pursued. The 42 and 84 mJ impacts used to create fractures were in the range previously reported to cause PTOA at 60 days post-fracture. MicroCT (µCT) was used to assess fracture patterns and epiphyseal and metaphyseal bone loss at 30 and 60 days post-fracture. Cartilage degeneration, synovitis, and matrix metalloproteinase (MMP-3, -13) expression were evaluated by histologic analyses. In wild-type mice, µCT imaging showed that 84 mJ impacts led to significant bone loss at 30 days (p < 0.05), but recovered to normal at 60 days. Bone losses did not occur in RAGE -/- mice. Synovitis was significantly elevated in 84 mJ impact wild-type mice at both endpoints (30 day, p = 0.001; 60 day, p = 0.05), whereas in RAGE -/- mice synovitis was elevated only at 30 days (p = 0.02). Mankin scores were slightly elevated in both mouse strains at 30 days, but not at 60 days. Immunohistochemistry revealed significant fracture-related increases in MMP-3 and -13 expression at 30 days (p < 0.05), with no significant difference between genotypes. These findings indicated that while RAGE -/- accelerated recovery from fracture and diminished synovitis, arthritic changes were temporary and too modest to detect an effect on the pathogenesis of PTOA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

PubMed Central

Tomaszewska, Ewa; Muszyński, Siemowit; Blicharski, Tomasz; Pierzynowski, Stefan G

2017-01-01

Synthetic glucocorticoids (GCs) are widely used in the variety of dosages for treatment of premature infants with chronic lung disease, respiratory distress syndrome, allergies, asthma, and other inflammatory and autoimmune conditions. Yet, adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Conversely, 2-oxoglutarate (2-Ox), a precursor of glutamine, glutamate, and collagen amino acids, exerts protective effects on bone development. Our aim was to elucidate the effect of dietary administered 2-Ox on bone loss caused by neonatal treatment with clinically relevant maximal therapeutic dexamethasone (Dex) dose. Long bones of neonatal female piglets receiving Dex, Dex+2-Ox, or untreated were examined through measurements of mechanical properties, density, mineralization, geometry, histomorphometry, and histology. Selected hormones, bone turnover, and growth markers were also analyzed. Neonatal administration of clinically relevant maximal dose of Dex alone led to over 30% decrease in bone mass and the ultimate strength (P < 0.001 for all). The length (13 and 7% for femur and humerus, respectively) and other geometrical parameters (13–45%) decreased compared to the control (P < 0.001 for all). Dex impaired bone growth and caused hormonal imbalance. Dietary 2-Ox prevented Dex influence and vast majority of assessed bone parameters were restored almost to the control level. Piglets receiving 2-Ox had heavier, denser, and stronger bones; higher levels of growth hormone and osteocalcin concentration; and preserved microarchitecture of trabecular bone compared to the Dex group. 2-Ox administered postnatally had a potential to maintain bone structure of animals simultaneously treated with maximal therapeutic doses of Dex, which, in our opinion, may open up a new opportunity in developing combined treatment for children treated with GCs. Impact statement The present study has showed, for the first time, that dietary 2-oxoglutarate (2-Ox) administered postnatally has a potential to improve/maintain bone structure of animals simultaneously treated with maximal therapeutic doses of dexamethasone (Dex). It may open the new direction in searching and developing combined treatment for children treated with glucocorticoids (GCs) since growing group of children is exposed to synthetic GCs and adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Currently proposed combined therapies have numerous side effects. Thus, this study proposed a new direction in combined therapies utilizing dietary supplementation with glutamine derivative. Impairment caused by Dex in presented long bones animal model was prevented by dietary supplementation with 2-Ox and vast majority of assessed bone parameters were restored almost to the control level. These results support previous thesis on the regulatory mechanism of nutrient utilization regulated by glutamine derivatives and enrich the nutritional science. PMID:28178857

Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health

NASA Technical Reports Server (NTRS)

Alwood, J. S.; Limoli, C. L.; Delp, M. D.; Castillo, A. B.; Globus, R. K.

2012-01-01

Weightlessness causes a cephalad fluid shift and reduction in mechanical stimulation, adversely affecting both cortical and trabecular bone tissue in astronauts. In rodent models of weightlessness, the onset of bone loss correlates with reduced skeletal perfusion, reduced and rarified vasculature and lessened vasodilation, which resembles blood-bone symbiotic events that can occur with fracture repair and aging. These are especially serious risks for long term, exploration class missions when astronauts will face the challenge of increased exposure to space radiation and abrupt transitions between different gravity environments upon arrival and return. Previously, we found using the mouse hindlimb unloading model and exposure to heavy ion radiation, both disuse and irradiation cause an acute bone loss that was associated with a reduced capacity to produce bone-forming osteoblasts from the bone marrow. Together, these findings led us to hypothesize that exposure to space radiation exacerbates weightlessness-induced bone loss and impairs recovery upon return, and that treatment with anti-oxidants may mitigate these effects. The specific aims of this recently awarded grant are to: AIM 1 Determine the functional and structural consequences of prolonged weightlessness and space radiation (simulated spaceflight) for bone and skeletal vasculature in the context of bone cell function and oxidative stress. AIM 2 Determine the extent to which an anti-oxidant protects against weightlessness and space radiation-induced bone loss and vascular dysfunction. AIM 3 Determine how space radiation influences later skeletal and vasculature recovery from prolonged weightlessness and the potential of anti-oxidants to preserve adaptive remodeling.

Classical and emerging roles of vitamin D in hepatitis C virus (HCV) infection

PubMed Central

Gutierrez, Julio A.; Parikh, Neil; Branch, Andrea D.

2014-01-01

The risk of clinically-significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL, according to the Institute of Medicine. By this standard, most cirrhotic hepatitis C virus (HCV)-positive patients and many non-cirrhotic patients are vitamin D deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin D's beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. The article concludes with information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients. PMID:22189978

Classical and emerging roles of vitamin D in hepatitis C virus infection.

PubMed

Gutierrez, Julio A; Parikh, Neil; Branch, Andrea D

2011-11-01

According to the Institute of Medicine, the risk of clinically significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL. By this standard, most cirrhotic hepatitis C virus- (HCV-) positive patients and many noncirrhotic patients are vitamin D-deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin D's beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. Information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients is provided. © Thieme Medical Publishers.

Finite element study of human pelvis model in side impact for Chinese adult occupants.

PubMed

Ma, Zhengwei; Lan, Fengchong; Chen, Jiqing; Liu, Weiguo

2015-01-01

The occupant's pelvis is very vulnerable to side collision in road accidents. Finite element (FE) studies on pelvic injury help to design occupant protection devices to improve vehicle safety. This study was aimed to develop a highly biofidelic pelvis model of Chinese adults and assess its sensitivity to variations in pelvis cortical bone thickness, bone material properties, and loading conditions. In this study, 4 different FE models of the pelvis were developed from the computed tomography (CT) data of a volunteer representing the 50th percentile Chinese male. Two of them were meshed using entirely hexahedral elements with variable and constant cortical thickness distribution (the V-Hex and C-Hex models), and the others were modeled with hexahedral elements for cancellous bone and variable or constant thickness shell elements for cortical bone (the V-HS and C-HS models). In model developments, the semi-automatic multiblock meshing approach was employed to maintain the pelvis geometric curvature and generate a high-quality hexahedral mesh. Then, several simulations with postmortem human subjects (PMHS) tests were performed to obtain the most accurate model in predicting pelvic injury. Based on the most accurate model, sensitivity studies were conducted to analyze the effects of the cortex thickness, Young's modulus of the cortical and cancellous bone, impactor velocity, and impactor with or without padding on the biomechanical responses and injuries of pelvis. The results indicate that the models with variable cortical bone thickness can give more accurate predictions than those with constant cortical thickness. Both the V-Hex and V-HS models are favorable for simulating pelvic response and injury, but the simulation results of the V-Hex model agree with the tests better. The sensitivity study shows that pelvic response is more sensitive to alterations in the Young's modulus of cortical bone than cancellous bone. Compared to failure displacement, peak force is more sensitive to the cortical bone thickness. However, displacement is more sensitive to the Young's modulus of cancellous bone than peak force. The padding attached on the impactor plays a significant role in absorbing the impact energy and alleviating pelvic injury. The all-hex meshing method with variable cortical bone thickness has the highest accuracy but is time-consuming. The cortical bone plays a determining role in resisting pelvic fracture. Peak impact force appears to be a reasonable injury predictor for pelvic injury assessment. Some appropriate energy absorbers installed in the car door can significantly reduce pelvic injury and will be beneficial for occupant protection.

Disorders of Bone Remodeling

PubMed Central

Feng, Xu; McDonald, Jay M.

2013-01-01

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

Exercise, Hormones, and Skeletal Adaptations During Childhood and Adolescence

PubMed Central

Farr, Joshua N.; Laddu, Deepika R.; Going, Scott B.

2015-01-01

Although primarily considered a disorder of the elderly, emerging evidence suggests the antecedents of osteoporosis are established during childhood and adolescence. A complex interplay of genetic, environmental, hormonal and behavioral factors determines skeletal development, and a greater effort is needed to identify the most critical factors that establish peak bone strength. Indeed, knowledge of modifiable factors that determine skeletal development may permit optimization of skeletal health during growth and could potentially offset reductions in bone strength with aging. The peripubertal years represent a unique period when the skeleton is particularly responsive to loading exercises, and there is now overwhelming evidence that exercise can optimize skeletal development. While this is not controversial, the most effective exercise prescription and how much investment in this prescription is needed to significantly impact bone health continues to be debated. Despite considerable progress, these issues are not easy to address, and important questions remain unresolved. This review focuses on the key determinants of skeletal development, whether exercise during childhood and adolescence should be advocated as a safe and effective strategy for optimizing peak bone strength, and whether investment in exercise early in life protects against the development of osteoporosis and fractures later in life. PMID:25372373

Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading.

PubMed

Heep, Hansjoerg; Wedemeyer, Christian; Wegner, Alexander; Hofmeister, Sebastian; von Knoch, Marius

2008-06-15

It is known that bone mineral density (BMD) and the strength of bone is predicted by body mass. Fat mass is a significant predictor of bone mineral density which correlates with body weight. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure by micro-CT the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin. Animals with an ad-libitum-diet (Group A) were found to increase body weight significantly at the age of six weeks in comparison with lean mice (Group B). From this point on, the difference increased constantly. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone (BV/TV, trabecular number (Tb.N.), trabecular thickness (Tb.Th.)) revealed that the only statistically significant difference between the two groups was the Tb.N. for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Compared with the control-diet Group B, the BV/TV and Tb.N. were slightly higher in the controlled-diet Group A, but not the Tb.Th.. However, correlation was found between Tb.N. and BMD on the one hand and body weight on the other hand. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in cortical and trabecular bone will be examined in later studies. It is not possible to conclude that these results also apply to human beings.

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35 mg once weekly or placebo, concomitant with calcium and vitamin D supplementation.

PubMed

van Bodegraven, Ad A; Bravenboer, Nathalie; Witte, Birgit I; Dijkstra, Gerard; van der Woude, C Janneke; Stokkers, Pieter C M; Russel, Maurice G; Oldenburg, Bas; Pierik, Marieke; Roos, Jan C; van Hogezand, Ruud A; Dik, Vincent K; Oostlander, Angela E; Netelenbos, J Coen; van de Langerijt, Lex; Hommes, Daniel W; Lips, Paul

2014-09-01

Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Influence of electromagnetic fields and protective effect of CAPE on bone mineral density in rats.

PubMed

Yildiz, Mustafa; Cicek, Ekrem; Cerci, Sevim Sureyya; Cerci, Celal; Oral, Baha; Koyu, Ahmet

2006-10-01

Most mobile phones emit electromagnetic radiation at 900 MHz or 1800 MHz. An electromagnetic field has some biological effects on the behavior of the cell population of bone. The aim of this work is to evaluate the effects of the radiation emitted by mobile phones on bone mineral density (BMD). The effects of caffeic acid phenethyl ester (CAPE) on the radiation-induced changes were also investigated. In the study, 48 Sprague Dawley rats were used. Rats were divided into five groups as follows: control, irradiated with 900 MHz, irradiated with 900 MHz and treatment, irradiated with 1800 MHz, irradiated with 1800 MHz and treatment groups. The rats in the control group (first group) were left within the experimental setup during 30 min/day for 28 days without radiation exposure. Nine hundred-MHz radiation group was exposed to irradiate both second and third groups for 28 days (30 min/day); 1800-MHz radiation group was exposed to irradiate both fourth and fifth groups for 28 days (30 min/day). Third and fifth groups were also treated by CAPE for 28 days. Treatment groups received 10 microml/kg/day CAPE i.p. before the irradiation. Bone mineral densities were determined in all groups. BMD was found to be decreased in the irradiated groups and to be increased in the treatment groups. The changes were not significant (p >0.05).

Pathogenesis and management of primary osteoporosis.

PubMed

Bauwens, S F; Drinka, P J; Boh, L E

1986-08-01

The pathophysiology of primary osteoporosis and the various therapeutic regimens that have been used are reviewed. Osteoporosis is a major public health problem because the incidence of hip, wrist, and vertebral fractures associated with bone loss is high. Postmenopausal women are at increased risk for developing osteoporosis because bone mineral content is lower in women than in men, dietary calcium intake is frequently insufficient, intestinal absorption of calcium decreases with age, and the rate of bone loss accelerates at menopause. The efficacy of many single and combination therapies in preventing or treating osteoporosis has been studied. Differences in study design and diagnostic techniques and the heterogeneous nature of osteoporosis make evaluation of clinical trials difficult. Exercise helps to maintain skeletal mass, but amenorrhea caused by vigorous activity may be harmful. The efficacy of estrogen replacement therapy is documented best; many studies have shown that estrogens slow the rate of bone loss and reduce the incidence of fractures, but the association of estrogen use with endometrial cancer and breast cancer is of concern. Progesterones may protect against endometrial cancer, but undesirable effects of oral contraceptives have resulted in a hesitancy to use combination hormonal therapy. All adults should meet daily nutritional requirements for calcium, but this intake may be insufficient for elderly persons and is below recommended doses for treating osteoporosis. A daily intake of at least 1000-1500 mg of elemental calcium has been shown to slow the rate of bone loss. Nutritional requirements for vitamin D should be met, but benefits from pharmacologic doses have not been demonstrated. The role of fluoride, calcitonin, anabolic steroids, and vitamin D metabolites is unclear. Fluoride has the potential to increase bone mass, but effects on bone histology and fracture rates require further study. The major goals for the management of osteoporosis are maintenance of bone mass and prevention of fractures. An adequate intake of calcium and regular weight-bearing exercise are important preventive measures. Despite the documented effectiveness of estrogens, risks associated with long-term use are of concern.

Physalis angulata induces in vitro differentiation of murine bone marrow cells into macrophages.

PubMed

da Silva, Bruno José Martins; Rodrigues, Ana Paula D; Farias, Luis Henrique S; Hage, Amanda Anastácia P; Do Nascimento, Jose Luiz M; Silva, Edilene O

2014-10-03

The bone marrow is a hematopoietic tissue that, in the presence of cytokines and growth factors, generates all of the circulating blood cells. These cells are important for protecting the organism against pathogens and for establishing an effective immune response. Previous studies have shown immunomodulatory effects of different products isolated from plant extracts. This study aimed to evaluate the immunomodulatory properties of aqueous Physalis angulata (AEPa) extract on the differentiation of bone marrow cells. Increased cellular area, higher spreading ability and several cytoplasmatic projections were observed in the treated cells, using optical microscopy, suggesting cell differentiation. Furthermore, AEPa did not promote the proliferation of lymphocytes and polymorphonuclear leukocytes, however promotes increased the number of macrophages in the culture. The ultrastructural analysis by Transmission Electron Microscopy of treated cells showed spreading ability, high number of cytoplasmatic projections and increase of autophagic vacuoles. Moreover, a high level of LC3b expression by treated cells was detected by flow cytometry, suggesting an autophagic process. Cell surface expression of F4/80 and CD11b also indicated that AEPa may stimulate differentiation of bone marrow cells mainly into macrophages. In addition, AEPa did not differentiate cells into dendritic cells, as assessed by CD11c analysis. Furthermore, no cytotoxic effects were observed in the cells treated with AEPa. Results demonstrate that AEPa promotes the differentiation of bone marrow cells, particularly into macrophages and may hold promise as an immunomodulating agent.

Physalis angulata induces in vitro differentiation of murine bone marrow cells into macrophages

PubMed Central

2014-01-01

Background The bone marrow is a hematopoietic tissue that, in the presence of cytokines and growth factors, generates all of the circulating blood cells. These cells are important for protecting the organism against pathogens and for establishing an effective immune response. Previous studies have shown immunomodulatory effects of different products isolated from plant extracts. This study aimed to evaluate the immunomodulatory properties of aqueous Physalis angulata (AEPa) extract on the differentiation of bone marrow cells. Results Increased cellular area, higher spreading ability and several cytoplasmatic projections were observed in the treated cells, using optical microscopy, suggesting cell differentiation. Furthermore, AEPa did not promote the proliferation of lymphocytes and polymorphonuclear leukocytes, however promotes increased the number of macrophages in the culture. The ultrastructural analysis by Transmission Electron Microscopy of treated cells showed spreading ability, high number of cytoplasmatic projections and increase of autophagic vacuoles. Moreover, a high level of LC3b expression by treated cells was detected by flow cytometry, suggesting an autophagic process. Cell surface expression of F4/80 and CD11b also indicated that AEPa may stimulate differentiation of bone marrow cells mainly into macrophages. In addition, AEPa did not differentiate cells into dendritic cells, as assessed by CD11c analysis. Furthermore, no cytotoxic effects were observed in the cells treated with AEPa. Conclusion Results demonstrate that AEPa promotes the differentiation of bone marrow cells, particularly into macrophages and may hold promise as an immunomodulating agent. PMID:25281406

Immobilization and Application of Electrospun Nanofiber Scaffold-based Growth Factor in Bone Tissue Engineering.

PubMed

Chen, Guobao; Lv, Yonggang

2015-01-01

Electrospun nanofibers have been extensively used in growth factor delivery and regenerative medicine due to many advantages including large surface area to volume ratio, high porosity, excellent loading capacity, ease of access and cost effectiveness. Their relatively large surface area is helpful for cell adhesion and growth factor loading, while storage and release of growth factor are essential to guide cellular behaviors and tissue formation and organization. In bone tissue engineering, growth factors are expected to transmit signals that stimulate cellular proliferation, migration, differentiation, metabolism, apoptosis and extracellular matrix (ECM) deposition. Bolus administration is not always an effective method for the delivery of growth factors because of their rapid diffusion from the target site and quick deactivation. Therefore, the integration of controlled release strategy within electrospun nanofibers can provide protection for growth factors against in vivo degradation, and can manipulate desired signal at an effective level with extended duration in local microenvironment to support tissue regeneration and repair which normally takes a much longer time. In this review, we provide an overview of growth factor delivery using biomimetic electrospun nanofiber scaffolds in bone tissue engineering. It begins with a brief introduction of different kinds of polymers that were used in electrospinning and their applications in bone tissue engineering. The review further focuses on the nanofiber-based growth factor delivery and summarizes the strategies of growth factors loading on the nanofiber scaffolds for bone tissue engineering applications. The perspectives on future challenges in this area are also pointed out.

Obesity-related changes in bone structural and material properties in hyperphagic OLETF rats and protection by voluntary wheel running

USDA-ARS?s Scientific Manuscript database

We conducted a study to examine how the development of obesity and the associated insulin resistance affect bone structural and material properties, and bone formation and resorption markers in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model. This was a 36-week study of sedentary, hyperphag...

Guiding bone formation in a critical-sized defect and assessments.

PubMed

Jannetty, Joseph; Kolb, Eric; Boxberger, John; Deslauriers, Richard; Ganey, Timothy

2010-11-01

Development of alternatives to autologous bone has been served by many hypotheses and developments. Favorable properties of synthetic materials used currently in bone grafting support tissue differentiation without shielding capacity for integrated modeling. Ideally, new materials provide tissue compatibility and minimize patient morbidity and are attractive because of potential for in situ delivery, isothermal polymerization, porous structure, and nontoxic chemistry. For application in cranial bone, ability for materials to be laid adjacent to brain and offer postsurgical protection without neural risk is a critical asset. Kryptonite Bone Cement (KBC) meets the property criteria for cranial bone repair with regard to adhesive, conductive, and biologic transparency and US Food and Drug Administration approval for cranial bone void repair. To better delineate the morphology effective in cranial bone repair, a comparison was made between KBC and BoneSource, another material approved for the same indication. After Institutional Animal Care and Use Committee approval, the study assessed 24 rabbits, each with 2 separate cranial implants, to evaluate integration and absorption of the biomaterial at defined time points of 12, 18, 24, and 36 weeks. The 36-week assessment demonstrated near-complete resorption/integration of the BoneSource graft material. Bone was present within the biomaterial as well as independent of contact. The KBC was similarly integrated throughout the mass of the material, and new bone was in contact with the grafting material and also seen as separate islands of new bone. The bone demonstrated lamellar bone architecture with clear trabecular morphology. At higher magnification, the bone architecture can be clearly delineated, and comparison between the graft fillers is not obvious relative to the bone that has formed. Despite microscopic similarities, the most striking difference was maintenance of scaffold anatomy during bone regeneration. Kryptonite Bone Cement meets the criteria described in the introduction; properties of biologic transparency, osteoconductivity, and ergonomic utility offer other potential uses in bone repair. Key tenets of bone tissue regeneration observed in this analysis included adequate cell differentiation and tissue support. Bone that formed demonstrated lamellar rather than woven bone to suggest response to loading strain rather than merely biochemical precipitation. Over the 36-week study, the graft showed progressive bioabsorbable potential with calibrated replacement.

Calcium and Vitamin D

MedlinePlus

... A calcium-rich diet (including dairy, nuts, leafy greens and fish) helps to build and protect your bones. Calcium is a mineral that is necessary for life. In addition to building bones and keeping them healthy, calcium enables our ...

An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment.

PubMed

Thiolloy, Sophie; Edwards, James R; Fingleton, Barbara; Rifkin, Daniel B; Matrisian, Lynn M; Lynch, Conor C

2012-01-01

Breast to bone metastases frequently induce a "vicious cycle" in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (μCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). Collectively, these studies identify a novel "mini-vicious cycle" between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFβ would be beneficial for the treatment of bone metastases.

Abutment Disconnection/Reconnection Affects Peri-implant Marginal Bone Levels: A Meta-Analysis.

PubMed

Koutouzis, Theofilos; Gholami, Fatemeh; Reynolds, John; Lundgren, Tord; Kotsakis, Georgios A

Preclinical and clinical studies have shown that marginal bone loss can be secondary to repeated disconnection and reconnection of abutments that affect the peri-implant mucosal seal. The aim of this systematic review and meta-analysis was to evaluate the impact of abutment disconnections/reconnections on peri-implant marginal bone level changes. To address this question, two reviewers independently performed an electronic search of three major databases up to October 2015 complemented by manual searches. Eligible articles were selected on the basis of prespecified inclusion and exclusion criteria after a two-phase search strategy and assessed for risk of bias. A random-effects meta-analysis was performed for marginal bone loss. The authors initially identified 392 titles and abstracts. After evaluation, seven controlled clinical studies were included. Qualitative assessment of the articles revealed a trend toward protective marginal bone level preservation for implants with final abutment placement (FAP) at the time of implant placement compared with implants for which there were multiple abutment placements (MAP). The FAP group exhibited a marginal bone level change ranging from 0.08 to 0.34 mm, whereas the MAP group exhibited a marginal bone level change ranging from 0.09 to 0.55 mm. Meta-analysis of the seven studies reporting on 396 implants showed significantly greater bone loss in cases of multiple abutment disconnections/reconnections. The weighted mean difference in marginal bone loss was 0.19 mm (95% confidence interval, 0.06-0.32 mm), favoring bone preservation in the FAP group. Within the limitations of this meta-analysis, abutment disconnection and reconnection significantly affected peri-implant marginal bone levels. These findings pave the way for revisiting current restorative protocols at the restorative treatment planning stage to prevent incipient marginal bone loss.

Placenta hominis protects osteoporosis in ovariectomized rats.

PubMed

Chae, H J; Choi, K H; Chae, S W; Kim, H M; Shin, T K; Lee, G Y; Jeong, G S; Park, H R; Choi, H I; Kim, S B; Yoo, S K; Kim, H R

2006-01-01

In China, Japan, and Korea, placenta hominis extracts (PHEs) are used clinically for the treatment of osteoporosis. The anti-osteoporotic effect of PHEs was studied. The trabecular bone area and thickness in OVX rats decreased by 50% from those in sham-operated rats; these decreases were completely inhibited by administration of PHEs for 7 weeks. Osteoclast numbers and the osteoblast surface were enhanced in OVX rats, but PHEs had no effect on these phenomena. Serum phosphorus and alkaline phosphatase in OVX rats increased compared to those in sham-operated rats, but the increases were not affected by the administration of PHEs. Thyroxine (T4) level was stimulated in OVX rats. The extracts inhibited the T4 level in the OVX rats. These results strongly suggest that PHEs be effective in preventing the development of bone loss induced by OVX in rats.

Chemopreventive activity of compounds extracted from Casearia sylvestris (Salicaceae) Sw against DNA damage induced by particulate matter emitted by sugarcane burning near Araraquara, Brazil

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

Prieto, A.M.; Santos, A.G.; Csipak, A.R.

Ethanolic extract of Casearia sylvestris is thought to be antimutagenic. In this study, we attempted to determine whether this extract and casearin X (a clerodane diterpene from C. sylvestris) are protective against the harmful effects of airborne pollutants from sugarcane burning. To that end, we used the Tradescantia micronucleus test in meiotic pollen cells of Tradescantia pallida, the micronucleus test in mouse bone marrow cells, and the comet assay in mouse blood cells. The mutagenic compound was total suspended particulate (TSP) from air. For the Tradescantia micronucleus test, T. pallida cuttings were treated with the extract at 0.13, 0.25, ormore » 0.50 mg/ml. Subsequently, TSP was added at 0.3 mg/ml, and tetrads from the inflorescences were examined for micronuclei. For the micronucleus test in mouse bone marrow cells and the comet assay in mouse blood cells, Balb/c mice were treated for 15 days with the extract—3.9, 7.5, or 15.0 mg/kg body weight (BW)—or with casearin X—0.3, 0.25, or 1.2 mg/kg BW—after which they received TSP (3.75 mg/kg BW). In T. pallida and mouse bone marrow cells, the extract was antimutagenic at all concentrations tested. In mouse blood cells, the extract was antigenotoxic at all concentrations, whereas casearin X was not antimutagenic but was antigenotoxic at all concentrations. We conclude that C. sylvestris ethanolic extract and casearin X protect DNA from damage induced by airborne pollutants from sugarcane burning. -- Highlights: ► We assessed DNA protection of C. sylvestris ethanolic extract. ► We assessed DNA protection of casearin X. ► We used Tradescantia pallida micronucleus test as screening. ► We used comet assay and micronucleus test in mice. ► The compounds protected DNA against sugar cane burning pollutants.« less

25-Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density Secondary Analysis of a Randomized Controlled Trial.

PubMed

Macdonald, Helen M; Reid, Ian R; Gamble, Gregory D; Fraser, William D; Tang, Jonathan C; Wood, Adrian D

2018-04-17

Most trials of vitamin D supplementation have shown no benefits on bone density (BMD), though severe vitamin D deficiency causes osteomalacia which is associated with profound BMD deficits. Recently, the ViDA-BMD study from New Zealand demonstrated a threshold of baseline 25-hydroxyvitamin D (30 nmol/L) below which vitamin D supplementation did benefit BMD. We have now re-examined data from a similar trial in Aberdeen to determine whether a baseline 25-hydroxyvitamin D threshold of 30 nmol/L is also observed in that database. The Aberdeen study recruited 305 postmenopausal women in late winter and randomized them to receive placebo, vitamin D 400 IU/day or vitamin D 1000 IU/day over one year. As previously reported, BMD loss at the hip was reduced by vitamin D 1000 IU/day only, and there was no significant treatment effect of either dose at the lumbar spine. In the present analysis, when the trial participants were grouped according to whether their baseline 25-hydroxyvitamin D was ≤30 nmol/L or above this threshold, significant treatment effects were apparent at both the spine and hip in those with baseline 25-hydroxyvitamin D ≤30 nmol/L, but no significant effects were apparent in those with baseline 25-hydroxyvitamin D above this level. There was evidence of a similar threshold for effects on parathyroid hormone, but no groups showed changes in bone turnover markers during the study. It is concluded that vitamin D supplements only increase bone density in adults with nadir 25-hydroxyvitamin D ≤30 nmol/L. This moves us further towards a trial-based definition of vitamin D deficiency in adults with adequate calcium intakes, and suggests that supplement use should be targeted accordingly. Future trials of vitamin D supplementation should focus on individuals with 25-hydroxyvitamin D concentrations in this range. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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.

Interactions of dietary calcium with toxic levels of lead and zinc in pigs

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

Hsu, F.A.; Krook, L.; Pond, W.G.

1975-01-01

Twenty-four weanling Yorkshire pigs were used in a 2 x 2 x 2 factorial arrangement of treatments to determine their response to high levels of dietary lead (Pb) (1000 ppm) and zinc (Zn) (4000 ppm) (as lead acetate and zinc oxide), to investigate the influence of high dietary calcium (Ca) (1.1%) on the biochemical and morphological manifestations of Pb and Zn toxicity, and to determine the effect of excess Zn on Pb toxicity. Clinical signs of Pb toxicity included behavioral changes, lameness, and anorexia. Pb content of blood, soft tissues, and bone was increased markedly by 1000 ppm Pb inmore » the diet during the 13-week experiment. Zn and Pb fed together, as compared with Pb alone, tended to increase Pb levels in blood, soft tissues, and bone and to enhance the toxic effects of Pb as shown by reduced weight gains, severe clinical signs, and pathological changes. High Ca reduced blood and bone Zn and Pb concentrations. The results indicate that high dietary Ca has a protective effect against the adverse effects of diet Pb and Zn, and that Zn aggravates Pb toxicity in growing pigs.« less

Bone Metabolism on ISS Missions

NASA Technical Reports Server (NTRS)

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

2014-01-01

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

Protection from radiation-induced apoptosis by the radioprotector amifostine (WR-2721) is radiation dose dependent.

PubMed

Ormsby, Rebecca J; Lawrence, Mark D; Blyth, Benjamin J; Bexis, Katrina; Bezak, Eva; Murley, Jeffrey S; Grdina, David J; Sykes, Pamela J

2014-02-01

The radioprotective agent amifostine is a free radical scavenger that can protect cells from the damaging effects of ionising radiation when administered prior to radiation exposure. However, amifostine has also been shown to protect cells from chromosomal mutations when administered after radiation exposure. As apoptosis is a common mechanism by which cells with mutations are removed from the cell population, we investigated whether amifostine stimulates apoptosis when administered after radiation exposure. We chose to study a relatively low dose which is the maximum radiation dose for radiation emergency workers (0.25 Gy) and a high dose relevant to radiotherapy exposures (6 Gy). Mice were administered 400 mg/kg amifostine 30 min before, or 3 h after, whole-body irradiation with 0.25 or 6 Gy X-rays and apoptosis was analysed 3 or 7 h later in spleen and bone marrow. We observed a significant increase in radiation-induced apoptosis in the spleen of mice when amifostine was administered before or after 0.25 Gy X-rays. In contrast, when a high dose of radiation was used (6 Gy), amifostine caused a reduction in radiation-induced apoptosis 3 h post-irradiation in spleen and bone marrow similar to previously published studies. This is the first study to investigate the effect of amifostine on radiation-induced apoptosis at a relatively low radiation dose and the first to demonstrate that while amifostine can reduce apoptosis from high doses of radiation, it does not mediate the same effect in response to low-dose exposures. These results suggest that there may be a dose threshold at which amifostine protects from radiation-induced apoptosis and highlight the importance of examining a range of radiation doses and timepoints.

PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment.

PubMed

Jin, Linhua; Tabe, Yoko; Kojima, Kensuke; Shikami, Masato; Benito, Julina; Ruvolo, Vivian; Wang, Rui-Yu; McQueen, Teresa; Ciurea, Stefan O; Miida, Takashi; Andreeff, Michael; Konopleva, Marina

2013-12-01

Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here, we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions. Hypoxia caused degradation of Mcl-1 and rendered Mcl-1-overexpressing OCI-AML3 cells sensitive to ABT-737. Our findings suggest that pharmacologic PI3K inhibition by GDC-0941 enhances ABT-737-induced leukemia cell death even under the protective conditions afforded by the bone marrow microenvironment. Combined blockade of PI3K and Bcl-2 pathways down-regulates anti-apoptotic Mcl-1 expression PI3K and Bcl-2 induced Mcl-1 down-regulation activates BAX PI3K and Bcl-2 blockage induces apoptosis in AML under hypoxic BM microenvironment.

Effects of Astragalus membranaceus with supplemental calcium on bone mineral density and bone metabolism in calcium-deficient ovariectomized rats.

PubMed

Kang, Se-Chan; Kim, Hee Jung; Kim, Mi-Hyun

2013-01-01

It has been reported that Astragalus membranaceus, an Asian traditional herb, has an estrogenic effect in vitro. To examine the possible role of A. membranaceus extract with supplemental calcium (Ca) on bone status in calcium-deficient (LCa) ovariectomized (OVX) rats, a total of 48 female rats were divided into six groups: (1) normal control, (2) sham operation with LCa (sham-LCa), (3) OVX with LCa (OVX-LCa), (4) A. membranaceus supplementation with OVX-LCa (OVX-MLCa), (5) Ca supplementation with OVX (OVX-Ca), and (6) A. membranaceus and Ca supplementation with OVX (OVX-MCa). A. membranaceus ethanol extract (500 mg/kg BW) and/or Ca (800 mg/kg BW) were administered orally for 8 weeks along with a Ca-deficient diet. Results revealed that Ca supplementation with or without A. membranaceus extract significantly improved bone mineral density, biomechanical strength, and ash weight of the femur and tibia in OVX rats. High Ca with A. membranaceus combination supplementation significantly increased the ash weight of the femur and tibia and decreased urinary Ca excretion compared with supplementation of Ca alone. Uterine weight was not changed by A. membranaceus administration in OVX rats. These results suggest that A. membranaceus extract combined with supplemental Ca may be more protective against the Ca loss of bone than A. membranaceus or supplementation of Ca alone in calcium-insufficient postmenopausal women.

The protective effects of silibinin in the treatment of streptozotocin-induced diabetic osteoporosis in rats.

PubMed

Wang, Te; Cai, Leyi; Wang, Yangyang; Wang, Qingqing; Lu, Di; Chen, Hua; Ying, Xiaozhou

2017-05-01

Diabetic osteoporosis (DO) is a complication of diabetes mellitus. Our previous study showed that silibinin can attenuate high glucose mediated human bone marrow stem cells dysfunction through antioxidant effect. However, no study has yet investigated the effect of silibinin in diabetic rats. Therefore, we assessed the effects of silibinin on bone characteristics in streptozotocin-induced diabetic rats. The aim of our study was to determine whether providing silibinin in the different supplementation could prevent bone loss in diabetic rats or not. Rats were randomly divided into four groups: (1) control group (CG) (n=10); (2) diabetic group (DG) (n=10); (3) diabetic group with 50mgkg -1 day -1 of silibinin orally (DG-50) (n=10); and (4) diabetic group with 100mgkg -1 day -1 of silibinin orally (DG-100) (n=10). 12 weeks after streptozotocin (STZ) injection, the femora from all rats were assessed and oxidative stress was evaluated. Bone mineral density was significantly decreased in diabetic rats; these effects were prevented by treatment with silibinin (100mgkg -1 day -1 orally). Similarly, in the DG and DG-50 groups, changes in microarchitecture of femoral metaphysis assessed by microcomputed tomography demonstrated simultaneous existence of diabetic osteoporosis; these impairments were prevented by silibinin (100mgkg -1 day -1 orally). In conclusion, silibinin supplementation may have potential use as a possible therapy for maintaining skeletal health and these results can enhance the understanding of diabetic osteoporosis induced by diabetes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Physical activity and dark skin tone: protective factors against low bone mass in Mexican men.

PubMed

Vivanco-Muñoz, Nalleli; Jo, Talavera; Gerardo, Huitron-Bravo; Juan, Tamayo; Clark, Patricia

2012-01-01

A cross-sectional study was conducted on 268 Mexican men between the ages of 13 and 80 yr to evaluate the association of clinical factors related with bone mass. Men from high schools, universities, and retirement homes were invited to participate. Body mass index (BMI) was measured, and bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry for L1-L4 and total hip. Factors related to bone mass were assessed by questionnaire and analyzed using a logistic regression model. Demographic factors (age, education, and occupation), clinical data (BMI, skin tone, previous fracture, history of osteoporosis [OP], and history of fractures), and lifestyle variables (diet, physical activity, sun exposure, and smoking) were evaluated. Physical activity (≥ 60 min/5 times a week) reduced the risk for low BMD for age, osteopenia, and OP at the spine and total hip (odds ratio [OR]: 0.276; 95% confidence interval [CI]: 0.099-0.769; p=0.014; and OR: 0.184; 95% CI: 0.04-0.849; p=0.03, respectively). Dark skin tone was a protective factor, decreasing the risk by up to 70%. In this population of healthy Mexican men (aged 13-80 yr), dark skin and physical activity were protective factors against low bone mass. Copyright © 2012 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

Dietary aspartyl-phenylalanine-1-methyl ester delays osteoarthritis and prevents associated bone loss in STR/ORT mice

PubMed Central

Manion, Carl V.; Hochgeschwender, Ute; Edmundson, Allen B.; Hugli, Tony E.

2011-01-01

Objective. STR/ORT mice provide a well-known model for murine idiopathic OA, with histological joint lesions resembling those of human OA. This model was used to investigate protective effects of the dipeptide aspartyl-phenylalanine-1-methyl ester (Asp-Phe-OMe or aspartame) via the oral route vs a regular diet. Methods. STR/ORT mice were housed individually and fed diets with or without Asp-Phe-OMe (4 mg/kg), after weaning at the age of 3 weeks, until 15 months of age (average of 20 animals per group). The study groups were kept blinded to the investigators, who measured food consumption and body weight and performed gait mobility tests. Radiographic scans were also performed at regular time intervals to evaluate differential radiographic anomalies associated with progress of OA in response to oral Asp-Phe-OMe therapy. Results. The Asp-Phe-OMe-fed animals presented a pattern of significantly delayed disease onset. In addition, their muscle and bone mass were highly preserved, even at later time points after OA was established. Moreover, control animals presented a higher variability in gait motility in comparison with the Asp-Phe-OMe-fed animals, suggesting a protective effect from movement limitations associated with advanced OA. Conclusion. Asp-Phe-OMe, given orally, delays OA in the spontaneous STR/ORT model, improves bone cortical density and muscle mass, and may contribute to a better quality of life for these diseased animals. PMID:21372000

Bone preserving level of osteotomy in short-stem total hip arthroplasty does not influence stress shielding dimensions - a comparing finite elements analysis.

PubMed

Burchard, Rene; Braas, Sabrina; Soost, Christian; Graw, Jan Adriaan; Schmitt, Jan

2017-08-07

The main objective of every new development in total hip arthroplasty (THA) is the longest possible survival of the implant. Periprosthetic stress shielding is a scientifically proven phenomenon which leads to inadvertent bone loss. So far, many studies have analysed whether implanting different hip stem prostheses result in significant preservation of bone stock. The aim of this preclinical study was to investigate design-depended differences of the stress shielding effect after implantation of a selection of short-stem THA-prostheses that are currently available. Based on computerised tomography (CT), a finite elements (FE) model was generated and a virtual THA was performed with different stem designs of the implant. Stems were chosen by osteotomy level at the femoral neck (collum, partial collum, trochanter sparing, trochanter harming). Analyses were performed with previously validated FE models to identify changes in the strain energy density (SED). In the trochanteric region, only the collum-type stem demonstrated a biomechanical behaviour similar to the native femur. In contrast, no difference in biomechanical behaviour was found between partial collum, trochanter harming and trochanter sparing models. All of the short stem-prostheses showed lower stress-shielding than a standard stem. Based on the results of this study, we cannot confirm that the design of current short stem THA-implants leads to a different stress shielding effect with regard to the level of osteotomy. Somehow unexpected, we found a bone stock protection in metadiaphyseal bone by simulating a more distal approach for osteotomy. Further clinical and biomechanical research including long-term results is needed to understand the influence of short-stem THA on bone remodelling and to find the optimal stem-design for a reduction of the stress shielding effect.

Green Tea Polyphenols and Vitamin D3 Protect Bone Microarchitecture in Female Rats with Chronic Inflammation

USDA-ARS?s Scientific Manuscript database

Our recent study showed that green tea polyphenols (GTP) in conjunction with 1-a-OH¬vit-D3 (vitD3) treatment mitigates lipopolysaccharide (LPS)-induced bone mineral density loss in female rats. This study was undertaken to further explore the mechanism and bone microarchitecture of GTP plus vitD3 in...

A study of stress-free living bone and its application to space flight

NASA Technical Reports Server (NTRS)

Leblanc, A.; Spira, M.

1983-01-01

Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

PubMed Central

Gur-Cohen, Shiri; Itkin, Tomer; Chakrabarty, Sagarika; Graf, Claudine; Kollet, Orit; Ludin, Aya; Golan, Karin; Kalinkovich, Alexander; Ledergor, Guy; Wong, Eitan; Niemeyer, Elisabeth; Porat, Ziv; Erez, Ayelet; Sagi, Irit; Esmon, Charles T; Ruf, Wolfram; Lapidot, Tsvee

2016-01-01

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance. PMID:26457757

Icariin Ameliorate Thiram-Induced Tibial Dyschondroplasia via Regulation of WNT4 and VEGF Expression in Broiler Chickens

PubMed Central

Zhang, Hui; Mehmood, Khalid; Li, Kun; Rehman, Mujeeb U.; Jiang, Xiong; Huang, Shucheng; Wang, Lei; Zhang, Lihong; Tong, Xiaole; Nabi, Fazul; Yao, Wangyuan; Iqbal, Muhammad K.; Shahzad, Muhammad; Li, Jiakui

2018-01-01

Tibial dyschondroplasia (TD) is main bone problem in fast growing poultry birds that effect proximal growth plate (GP) of tibia bone. TD is broadly defined as non-vascularized and non-mineralized, and enlarged GP with tibia bone deformation and lameness. Icariin (Epimedium sagittatum) is a traditional Chinese medicine, which is commonly practiced in the treatment of various bone diseases. Recently, many researcher reports about the beneficial effects of icariin in relation to various types of bone conditions but no report is available about promoting effect of icariin against TD. Therefore, current study was conducted to explore the ameliorating effect of icariin in thiram-induced TD chickens. A total of 180 broiler chicks were equally distributed in three groups; control, TD induced by thiram (50 mg/kg), and icariin group (treated with icariin @10 mg/kg). All groups were administered with normal standard diet ad libitum regularly until the end of experiment. The wingless-type member 4 (WNT4) and vascular endothelial growth factor (VEGF) genes and proteins expression were analyzed by quantitative real-time polymerase chain reaction and western blot analysis respectively. Tibial bone parameters, physiological changes in serum, antioxidant enzymes, and chicken growth performance were determined to assess advantage and protective effect of the medicine in broiler chicken. The expression of WNT4 was decreased while VEGF increased significantly (P < 0.05) in TD affected chicks. TD enhanced the GP, lameness, and irregular chondrocytes, while reduced the liver function, antioxidant enzymes in liver, and performance of chickens. Icariin treatment up-regulated WNT4 and down-regulated VEGF gene and protein expressions significantly (P < 0.05), restored the GP width, increased growth performance, corrected liver functions and antioxidant enzymes levels in liver, and mitigated the lameness in broiler chickens. In conclusion, icariin administration recovered GP size, normalized performance and prevented lameness significantly. Therefore, icariin treatments are encouraged to reduce the incidence of TD in broiler chickens. PMID:29527166

Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

PubMed Central

Cui, Zhuang; Crane, Janet; Xie, Hui; Jin, Xin; Zhen, Gehua; Li, Changjun; Xie, Liang; Wang, Long; Bian, Qin; Qiu, Tao; Wan, Mei; Xie, Min; Ding, Sheng; Yu, Bin; Cao, Xu

2016-01-01

Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA. PMID:26470720

High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice.

PubMed

Carvalho, Adriana Lelis; DeMambro, Victoria E; Guntur, Anyonya R; Le, Phuong; Nagano, Kenichi; Baron, Roland; de Paula, Francisco José Albuquerque; Motyl, Katherine J

2018-02-01

There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ)-induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies. © 2017 Wiley Periodicals, Inc.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

Melanin-covered nanoparticles for protection of bone marrow during radiation therapy of cancer.

PubMed

Schweitzer, Andrew D; Revskaya, Ekaterina; Chu, Peter; Pazo, Valeria; Friedman, Matthew; Nosanchuk, Joshua D; Cahill, Sean; Frases, Susana; Casadevall, Arturo; Dadachova, Ekaterina

2010-12-01

Protection of bone marrow against radiotoxicity during radioimmunotherapy and in some cases external beam radiation therapy such as hemi-body irradiation would permit administration of significantly higher doses to tumors, resulting in increased efficacy and safety of treatment. Melanin, a naturally occurring pigment, possesses radioprotective properties. We hypothesized that melanin, which is insoluble, could be delivered to the bone marrow by intravenously administrated melanin-covered nanoparticles (MNs) because of the human body's "self-sieving" ability, protecting it against ionizing radiation. The synthesis of MNs was performed via enzymatic polymerization of 3,4-dihydroxyphenylalanine and/or 5-S-cysteinyl-3,4-dihydroxyphenylalanine on the surface of 20-nm plain silica nanoparticles. The biodistribution of radiolabeled MNs in mice was done at 3 and 24 h. Healthy CD-1 mice (Charles River Laboratories International, Inc., Wilmington, MA) or melanoma tumor-bearing nude mice were given MNs intravenously, 50 mg/kg of body weight, 3 h before either whole-body exposure to 125 cGy or treatment with 1 mCi of (188)Re-labeled 6D2 melanin-binding antibody. Polymerization of melanin precursors on the surface of silica nanoparticles resulted in formation of a 15-nm-thick melanin layer as confirmed by light scattering, transmission electron microscopy, and immunofluorescence. The biodistribution after intravenous administration showed than MN uptake in bone marrow was 0.3% and 0.2% of injected dose per gram at 3 and 24 h, respectively, whereas pre-injection with pluronic acid increased the uptake to 6% and 3% of injected dose per gram, respectively. Systemic MN administration reduced hematologic toxicity in mice treated with external radiation or radioimmunotherapy, whereas no tumor protection by MNs was observed. MNs or similar structures provide a novel approach to protection of bone marrow from ionizing radiation based on prevention of free radical formation by melanin. Copyright © 2010 Elsevier Inc. All rights reserved.

Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals

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

Tolba, Mai F.

Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered as a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases besides its use as adjuvant to several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on themore » modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX)-mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclastogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in the attenuation of GIO. - Highlights: • Caffeic acid phenethyl ester (CAPE) counteracts DEX-induced osteoporosis. • CAPE hinders DEX-induced alterations in oxidation parameters as GSH, SOD and MDA. • CAPE opposes osteoclastogenesis via suppressing RANL/OPG ratio and Akt signals. • CAPE supports the osteoblasts via modulating caspase-3 and RUNX2 signals.« less

Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison's disease on glucocorticoid and mineralocorticoid replacement therapy.

PubMed

Camozzi, Valentina; Betterle, Corrado; Frigo, Anna Chiara; Zaccariotto, Veronica; Zaninotto, Martina; De Caneva, Erica; Lucato, Paola; Gomiero, Walter; Garelli, Silvia; Sabbadin, Chiara; Salvà, Monica; Costa, Miriam Dalla; Boscaro, Marco; Luisetto, Giovanni

2018-02-01

to assess bone damage and metabolic abnormalities in patients with Addison's disease given replacement doses of glucocorticoids and mineralocorticoids. A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison's disease patients and 47 controls and assessed using Genant's classification. Nineteen Addison's disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12-8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison's disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine. Addison's disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients' increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

Three-dimensional plotted alginate fibers embedded with diclofenac and bone cells coated with chitosan for bone regeneration during inflammation.

PubMed

Lin, Hsin-Yi; Chang, Tsang-Wen; Peng, Tie-Kun

2018-06-01

Alginate hydrogel fibers embedded with bone cells and diclofenac were coated with a layer of chitosan hydrogel and made into a porous scaffold by three-dimensional (3D) printing for drug release and bone regeneration. It was hypothesized that the chitosan coating could improve the scaffold's drug retention and release properties and biocompatibility. Macrophage cells were stimulated and cocultured with the scaffold. Tests were conducted to show how the chitosan coating affected the scaffold's drug release efficacy and how the release efficacy affected the cellular activities of stimulated macrophages and bone cells. The bone cells encapsulated in the coated scaffold demonstrated good viability after the acidic/basic coating process. The coating improved the retention and release efficacy of diclofenac and hence significantly inhibited interleukin-6 and tumor necrosis factor-α secretion from macrophages (p < 0.05). The bone cells in the coated sample mineralized more extensively than the control (p < 0.01). They also more actively expressed genes that produce proteins for extracellular matrix remodeling, MMP13, and interacting with the mineral matrix, OPN (both p < 0.01). It is believed that on days 7 and 10, when diclofenac was depleted and the concentrations of inflammatory compounds surged, the coating effectively blocked the harmful compounds and protected the bone cells within the fibers. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1511-1521, 2018. © 2018 Wiley Periodicals, Inc.

The influence of dairy consumption and physical activity on ultrasound bone measurements in Flemish children.

PubMed

De Smet, Stephanie; Michels, Nathalie; Polfliet, Carolien; D'Haese, Sara; Roggen, Inge; De Henauw, Stefaan; Sioen, Isabelle

2015-03-01

The study's aim was to analyse whether children's bone status, assessed by calcaneal ultrasound measurements, is influenced by dairy consumption and objectively measured physical activity (PA). Moreover, the interaction between dairy consumption and PA on bone mass was studied. Participants of this cross-sectional study were 306 Flemish children (6-12 years). Body composition was measured with air displacement plethysmography (BodPod), dairy consumption with a Food Frequency Questionnaire, PA with an accelerometer (only in 234 of the 306 children) and bone mass with quantitative ultrasound, quantifying speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness Index (SI). Regression analyses were used to study the associations between dairy consumption, PA, SOS, BUA and SI. Total dairy consumption and non-cheese dairy consumption were positively associated with SOS and SI, but no significant association could be demonstrated with BUA. In contrast, milk consumption, disregarding other dairy products, had no significant effect on calcaneal bone measurements. PA [vigorous PA, moderate to vigorous physical activity (MVPA) and counts per minute] was positively associated and sedentary time was negatively associated with BUA and SI, but no significant influence on SOS could be detected. Dairy consumption and PA (sedentary time and MVPA) did not show any interaction influencing bone measurements. In conclusion, even at young age, PA and dairy consumption positively influence bone mass. Promoting PA and dairy consumption in young children may, therefore, maximize peak bone mass, an important protective factor against osteoporosis later in life.

Strain gauges used in the mechanical testing of bones. Part II: "In vitro" and "in vivo" technique.

PubMed

Cordey, J; Gautier, E

1999-01-01

How to choose and prepare the strain gauges for bonding on bones "in vitro" and "in vivo"? This communication aims to elucidate technical details and some applications: direct assessment of the axial load, the bending moment, and the torque applied to long bones by the physiological loads. As a typical example of application, we will show the assessment of stress protection due to plates on the bones in the sheep tibia.

Molecular genetic diversity and maternal origin of Chinese black-bone chicken breeds.

PubMed

Zhu, W Q; Li, H F; Wang, J Y; Shu, J T; Zhu, C H; Song, W T; Song, C; Ji, G G; Liu, H X

2014-04-29

Chinese black-bone chickens are valued for the medicinal properties of their meat in traditional Chinese medicine. We investigated the genetic diversity and systematic evolution of Chinese black-bone chicken breeds. We sequenced the DNA of 520 bp of the mitochondrial cyt b gene of nine Chinese black-bone chicken breeds, including Silky chicken, Jinhu black-bone chicken, Jiangshan black-bone chicken, Yugan black-bone chicken, Wumeng black-bone chicken, Muchuan black-bone chicken, Xingwen black-bone chicken, Dehua black-bone chicken, and Yanjin black-bone chicken. We found 13 haplotypes. Haplotype and nucleotide diversity of the nine black-bone chicken breeds ranged from 0 to 0.78571 and 0.00081 to 0.00399, respectively. Genetic diversity was the richest in Jinhu black-bone chickens and the lowest in Yanjin black-bone chickens. Analysis of phylogenetic trees for all birds constructed based on hyplotypes indicated that the maternal origin of black-bone chickens is predominantly from three subspecies of red jungle fowl. These results provide basic data useful for protection of black-bone chickens and help determine the origin of domestic chickens.

Evaluation of genotoxicity and DNA protective effects of mangiferin, a glucosylxanthone isolated from Mangifera indica L. stem bark extract.

PubMed

Rodeiro, I; Hernandez, S; Morffi, J; Herrera, J A; Gómez-Lechón, M J; Delgado, R; Espinosa-Aguirre, J J

2012-09-01

Mangiferin is a glucosylxantone isolated from Mangifera indica L. stem bark. Several studies have shown its pharmacological properties which make it a promising candidate for putative therapeutic use. This study was focused to investigate the in vitro genotoxic effects of mangiferin in the Ames test, SOS Chromotest and Comet assay. The genotoxic effects in bone marrow erythrocytes from NMRI mice orally treated with mangiferin (2000 mg/kg) were also evaluated. Additionally, its potential antimutagenic activity against several mutagens in the Ames test and its effects on CYP1A1 activity were assessed. Mangiferin (50-5000 μg/plate) did not increased the frequency of reverse mutations in the Ames test, nor induced primary DNA damage (5-1000 μg/mL) to Escherichia coli PQ37 cells under the SOS Chromotest. It was observed neither single strand breaks nor alkali-labile sites in blood peripheral lymphocytes or hepatocytes after 1h exposition to 10-500 μg/mL of mangiferin under the Comet assay. Furthermore, micronucleus studies showed mangiferin neither induced cytotoxic activity nor increased the frequency of micronucleated/binucleated cells in mice bone marrow. In short, mangiferin did not induce cytotoxic or genotoxic effects but it protect against DNA damage which would be associated with its antioxidant properties and its capacity to inhibit CYP enzymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

Morinda citrifolia L. Leaf Extract Protects against Cerebral Ischemia and Osteoporosis in an In Vivo Experimental Model of Menopause

PubMed Central

Thipkaew, Cholathip; Thukham-mee, Wipawee; Wannanon, Panakaporn

2018-01-01

We aimed to determine the protective effects against cerebral ischemia and osteoporosis of Morinda citrifolia extract in experimental menopause. The neuroprotective effect was assessed by giving M. citrifolia leaf extract at doses of 2, 10, and 50 mg/kg BW to the bilateral ovariectomized (OVX) rats for 7 days. Then, they were occluded in the right middle cerebral artery (MCAO) for 90 minutes. The neurological score, brain infarction volume, oxidative stress status, and ERK1/2 and eNOS activities were assessed 24 hours later. M. citrifolia improved neurological score, brain infarction, and brain oxidative stress status in the cortex of OVX rats plus the MCAO. No changes in ERK 1/2 signal pathway and NOS expression were observed in this area. Our data suggested that the neuroprotective effect of the extract might occur partly via the improvement of oxidative stress status in the cortex. The antiosteoporotic effect in OVX rats was also assessed after an 84-day intervention of M. citrifolia. The serum levels of calcium, osteocalcin, and alkaline phosphatase and osteoblast density in the tibia were increased, but the density of osteoclast was decreased in OVX rats which received the extract. Therefore, the current data suggested that the extract possessed antiosteoporotic effect by increasing bone formation but decreasing bone resorption. PMID:29765488

Morinda citrifolia L. Leaf Extract Protects against Cerebral Ischemia and Osteoporosis in an In Vivo Experimental Model of Menopause.

PubMed

Wattanathorn, Jintanaporn; Thipkaew, Cholathip; Thukham-Mee, Wipawee; Muchimapura, Supaporn; Wannanon, Panakaporn; Tong-Un, Terdthai

2018-01-01

We aimed to determine the protective effects against cerebral ischemia and osteoporosis of Morinda citrifolia extract in experimental menopause. The neuroprotective effect was assessed by giving M. citrifolia leaf extract at doses of 2, 10, and 50 mg/kg BW to the bilateral ovariectomized (OVX) rats for 7 days. Then, they were occluded in the right middle cerebral artery (MCAO) for 90 minutes. The neurological score, brain infarction volume, oxidative stress status, and ERK1/2 and eNOS activities were assessed 24 hours later. M. citrifolia improved neurological score, brain infarction, and brain oxidative stress status in the cortex of OVX rats plus the MCAO. No changes in ERK 1/2 signal pathway and NOS expression were observed in this area. Our data suggested that the neuroprotective effect of the extract might occur partly via the improvement of oxidative stress status in the cortex. The antiosteoporotic effect in OVX rats was also assessed after an 84-day intervention of M. citrifolia . The serum levels of calcium, osteocalcin, and alkaline phosphatase and osteoblast density in the tibia were increased, but the density of osteoclast was decreased in OVX rats which received the extract. Therefore, the current data suggested that the extract possessed antiosteoporotic effect by increasing bone formation but decreasing bone resorption.

The Triple Functions of D2 Silencing in Treatment of Periapical Disease.

PubMed

Pan, Jie; Wang, Jue; Hao, Liang; Zhu, Guochun; Nguyen, Diep N; Li, Qian; Liu, Yuehua; Zhao, Zhihe; Li, Yi-Ping; Chen, Wei

2017-02-01

Dental caries is the most widespread chronic infectious disease. Inflammation in pulp tissues caused by dental caries will lead to periapical granulomas, bone erosion, loss of the tooth, and severe pain. Despite numerous efforts in recent studies to develop effective treatments for dental caries, the need for a potent therapy is still urgent. In this study, we applied a gene-based therapy approach by administering recombinant adeno-associated virus (AAV)-mediated Atp6v0d2 (d2) RNA interference knockdown of d2 gene expression to prevent periapical bone loss and suppress periapical inflammation simultaneously. The results showed that d2 depletion is simultaneously capable of reducing bone resorption with 75% protection through reducing osteoclasts, enhancing bone formation by increasing osterix expression, and inhibiting inflammation by decreasing T-cell infiltration. Notably, AAV-mediated gene therapy of d2 knockdown significantly reduced proinflammatory cytokine expression, including tumor necrosis factor α, interferon-γ, interleukin-1α, and interleukin 6 levels in periapical diseases caused by bacterial infection. Quantitative real-time polymerase chain reaction revealed that d2 knockdown reduced osteoclast-specific functional genes (ie, Acp5 and Ctsk) and increased osteoblast marker genes (ie, Osx and Opg) in periapical tissues. Collectively, our results showed that AAV-mediated d2 depletion in the periapical lesion area can prevent the progression of endodontic disease and bone erosion while significantly reducing the inflammatory over-response. These findings show that the depletion of d2 simultaneously reduces bone resorption, enhances bone formation, and inhibits inflammation caused by periapical diseases and provide significant insights into the potential effectiveness of AAV-sh-d2-mediated d2 silencing gene therapy as a major endodontic treatment. Copyright © 2016. Published by Elsevier Inc.

Effect of 1-year dietary supplementation with vitaminized olive oil on markers of bone turnover and oxidative stress in healthy post-menopausal women.

PubMed

Mazzanti, Laura; Battino, Maurizio; Nanetti, Laura; Raffaelli, Francesca; Alidori, Alessandro; Sforza, Giulia; Carle, Flavia; Quagliarini, Veronica; Cester, Nelvio; Vignini, Arianna

2015-11-01

Osteoporosis represents a serious health problem worldwide associated with an increased risk of fractures and mortality. Nutrition should form part of bone disease prevention strategies, especially in the light of the population ageing and the diet effect on bone health. Thus the study aimed at verifying whether 1 year of oral supplementation with either extra virgin olive oil (VOO) enriched with vitamins D3, K1 and B6 (VitVOO) or VOO used as placebo (PlaVOO) is able to modify some bone turnover and oxidative stress markers. Bone mineral density (BMD) was assessed in 60 healthy post-menopausal women together with the bone vitamin K status by measuring undercarboxylated osteocalcine (ucOC) plasma levels, the ratio between ucOC and carboxylated osteocalcine (UCR) and the relations with oxidative stress markers. After 1 year (T 1), subjects taking VitVOO showed lower ucOC levels than those taking PlaVOO; the same trend was found for UCR. As far as BMD is concerned, a significant increase in T-score at T 1 in VitVOO subjects compared to PlaVOO was found. All oxidative stress markers as thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes showed a significant reduction after VitVOO supplementation, whilst plasma total antioxidant capacity values was significantly increased in VitVOO group compared to PlaVOO group at T 1. It might be suggested that the use of VitVOO in the diet of post-menopausal women could represent a proper tool for bone protection and a useful strategy against oxidative stress and related diseases, thus confirming the antioxidant role played by the added vitamins.

Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells

PubMed Central

Day, Yuan-Ji; Huang, Liping; McDuffie, Marcia J.; Rosin, Diane L.; Ye, Hong; Chen, Jiang-Fan; Schwarzschild, Michael A.; Fink, J. Stephen; Linden, Joel; Okusa, Mark D.

2003-01-01

Activation of A2A adenosine receptors (A2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow–derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP→WT, A2A-KO→WT, or WT→WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A2A-KO mice or A2A-KO→WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT→WT chimera. ATL146e reduced the induction of IL-6, IL-1β, IL-1ra, and TGF-α mRNA in WT→WT mice but not in A2A-KO→WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells. PMID:12975473

Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment

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

Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim

Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulatedmore » with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. • Betulinic acid inhibited RANKL-induced osteoclastogenesis in bone marrow macrophages. • Betulinic acid decreased bone resorption by suppressing osteoclast activity. • Orally administered betulinic acid inhibited cancer-associated bone diseases in mice.« less

Correlative microscopy of the constituents of a dinosaur rib fossil and hosting mudstone: Implications on diagenesis and fossil preservation.

PubMed

Kim, Jung-Kyun; Kwon, Yong-Eun; Lee, Sang-Gil; Kim, Chang-Yeon; Kim, Jin-Gyu; Huh, Min; Lee, Eunji; Kim, Youn-Joong

2017-01-01

We have applied correlative microscopy to identify the key constituents of a dorsal rib fossil from Koreanosaurus boseongensis and its hosting mudstone discovered at the rich fossil site in Boseong, South Korea, to investigate the factors that likely contributed to diagenesis and the preservation of fossil bone. Calcite and illite were the commonly occurring phases in the rib bone, hosting mudstone, and the boundary region in-between. The boundary region may have contributed to bone preservation once it fully formed by acting as a protective shell. Fluorapatite crystals in the rib bone matrix signified diagenetic alteration of the original bioapatite crystals. While calcite predominantly occupied vascular channels and cracks, platy illite crystals widely occupied miniscule pores throughout the bone matrix. Thorough transmission electron microscopy (TEM) study of illite within the bone matrix indicated the solid-state transformation of 1M to 2M without composition change, which was more evident from the lateral variation of 1M to 2M within the same layer. The high level of lattice disordering of 2M illite suggested an early stage of 1M to 2M transformation. Thus, the diagenetic alteration of both apatite and illite crystals within the bone matrix may have increased its overall density, as the preferred orientation of apatite crystals from moderate to strong degrees was evident despite the poor preservation of osteohistological features. The combined effects of rapid burial, formation of a boundary region, and diagenesis of illite and apatite within the bone matrix may have contributed to the rib bone preservation.

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

NASA Technical Reports Server (NTRS)

Schreurs, A.-S.; Torres, S.; Truong, T.; Kumar, A.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

2014-01-01

Exposure to musculoskeletal disuse and radiation result in bone loss; we hypothesized that these catabolic treatments cause excess reactive oxygen species (ROS), and thereby alter the tight balance between bone resorption by osteoclasts and bone formation by osteoblasts, culminating in bone loss. To test this, we used transgenic mice which over-express the human gene for catalase, targeted to mitochondria (MCAT). Catalase is an anti-oxidant that converts the ROS hydrogen peroxide into water and oxygen. MCAT mice were shown previously to display reduced mitochondrial oxidative stress and radiosensitivity of the CNS compared to wild type controls (WT). As expected, MCAT mice expressed the transgene in skeletal tissue, and in marrow-derived osteoblasts and osteoclast precursors cultured ex vivo, and also showed greater catalase activity compared to wildtype (WT) mice (3-6 fold). Colony expansion in marrow cells cultured under osteoblastogenic conditions was 2-fold greater in the MCAT mice compared to WT mice, while the extent of mineralization was unaffected. MCAT mice had slightly longer tibiae than WT mice (2%, P less than 0.01), although cortical bone area was slightly lower in MCAT mice than WT mice (10%, p=0.09). To challenge the skeletal system, mice were treated by exposure to combined disuse (2 wk Hindlimb Unloading) and total body irradiation Cs(137) (2 Gy, 0.8 Gy/min), then bone parameters were analyzed by 2-factor ANOVA to detect possible interaction effects. Treatment caused a 2-fold increase (p=0.015) in malondialdehyde levels of bone tissue (ELISA) in WT mice, but had no effect in MCAT mice. These findings indicate that the transgene conferred protection from oxidative damage caused by treatment. Unexpected differences between WT and MCAT mice emerged in skeletal responses to treatment.. In WT mice, treatment did not alter osteoblastogenesis, cortical bone area, moment of inertia, or bone perimeter, whereas in MCAT mice, treatment increased these parameters. Taken together, this typically catabolic treatment (disuse and irradiation) appeared to stimulate cortical expansion in MCAT mice but not WT mice. In conclusion, these results reveal the importance of mitochondrial ROS generation in skeletal remodeling and show that MCAT mice provide a useful animal model for bone studies.

Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

DTIC Science & Technology

2017-12-01

using isogenic (mutant/complemented) human cell line pairs from patients with Fanconi anemia (FA), a heritable human bone marrow failure (BMF) syndrome ...small molecules could be therapeutically useful in reducing the risk of BMF in diseases such as Fanconi anemia, and perhaps after radiation exposure...damage-repair, DNA damage response, Fanconi anemia and associated bone marrow failure syndromes and environmental and molecular toxicology will all be

Estimation Of Organ Doses From Solar Particle Events For Future Space Exploration Missions

NASA Technical Reports Server (NTRS)

Kim, Myung-Hee; Cucinotta, Francis A.

2006-01-01

Radiation protection practices define the effective dose as a weighted sum of equivalent dose over major organ sites for radiation cancer risks. Since a crew personnel dosimeter does not make direct measurement of the effective dose, it has been estimated with skin-dose measurements and radiation transport codes for ISS and STS missions. If sufficient protection is not provided near solar maximum, the radiation risk can be significant due to exposure to sporadic solar particle events (SPEs) as well as to the continuous galactic cosmic radiation (GCR) on future exploratory-class and long-duration missions. For accurate estimates of overall fatal cancer risks from SPEs, the specific doses at various blood forming organs (BFOs) were considered, because proton fluences and doses vary considerably across marrow regions. Previous estimates of BFO doses from SPEs have used an average body-shielding distribution for the bone marrow based on the computerized anatomical man model (CAM). With the development of an 82-point body-shielding distribution at BFOs, the mean and variance of SPE doses in the major active marrow regions (head and neck, chest, abdomen, pelvis and thighs) will be presented. Consideration of the detailed distribution of bone marrow sites is one of many requirements to improve the estimation of effective doses for radiation cancer risks.

Resveratrol Increases Osteoblast Differentiation In Vitro Independently of Inflammation.

PubMed

Ornstrup, Marie Juul; Harsløf, Torben; Sørensen, Lotte; Stenkjær, Liselotte; Langdahl, Bente Lomholt; Pedersen, Steen Bønløkke

2016-08-01

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

[Effects of soybean isoflavone on born metabolism and morphology in animal model of osteoporosis rats].

PubMed

Yu, Qing; Su, Yi-xiang; Wang, Wen-wei; Li, An-le; Liu, Cun-li; Wang, Yi-long; Hu, Wan-li

2007-07-01

To study the effects of soybean isoflavone (SI) on born metabolism and morphology in animal model of osteoporosis rats. All 70 female Sprague-Dawley (SD) rats were randomly divided into 7 groups according to the levels of total cholesterol (TC) in serum: hyper-lipoid group, estrogen group, low-dose SI group, middle-dose SI group, high-dose SI group, sham group and normal control groups. Bilateral ovaries were extirpated except sham and normal control groups. Except the rats in normal control group, the other rats were fed with high fat diet. Body weight was weighted ad unam vice per week. The estrogen, different dose of SI or deionized water were fed with intragastric administration for 12 weeks. Vena caudalis serum were collected after being ovariectomized, administered for 4 w, 8 w and killed. Serum alkaline phosphatase (AKP) activity and bone density were measured etc. To interfere of estrogen and SI might recover AKP enzyme activity after its being ovariectomized. There almost sowed no differences between high dose SI intervention and estrogen on bone density and microstructure. Bone loss due to being ovariectomized was relieved after SI intervention. SI might protect cardiocyte myofilament and mitochondrial ultramicrostructure. There was mirror image in estrogen, high dose SI group resembling the normal control group, and there was obvious damage in hyper-lipoids group. There should be effects of high dose SI on bone metabolism and morphology in animal model of osteoporosis rats. Serum AKP enzyme activity and bone density should have significantly recovered, the serum level of calcium and phosphorus were maintained after high dose intervened but no significant effects for low dose of SI.

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

PubMed

Chan, Deva D; Li, Jun; Luo, Wei; Predescu, Dan N; Cole, Brian J; Plaas, Anna

2018-01-01

Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1 -/- ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1 -/- mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1 -/- mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Exercise reverses pain-related weight asymmetry and differentially modulates trabecular bone microarchitecture in a rat model of osteoarthritis.

PubMed

Cormier, Jim; Cone, Katherine; Lanpher, Janell; Kinens, Abigail; Henderson, Terry; Liaw, Lucy; Bilsky, Edward J; King, Tamara; Rosen, Clifford J; Stevenson, Glenn W

2017-07-01

There is great interest in developing and utilizing non-pharmacological/non-invasive forms of therapy for osteoarthritis (OA) pain including exercise and other physical fitness regimens. The present experiments determined the effects of prior wheel running on OA-induced weight asymmetry and trabecular bone microarchitecture. Wheel running included 7 or 21days of prior voluntary access to wheels followed by OA induction, followed by 21days post-OA access to wheels. OA was induced with monosodium iodoacetate (MIA), and weight asymmetry was measured using a hind limb weight bearing apparatus. Bone microarchitecture was characterized using ex vivo μCT. Relative to saline controls, MIA (3.2mg/25μl) produced significant weight asymmetry measured on post-days (PDs) 3, 7, 14, 21 in sedentary rats. Seven days of prior running failed to alter MIA-induced weight asymmetry. In contrast, 21days of prior running resulted in complete reversal of MIA-induced weight asymmetry on all days tested. As a comparator, the opioid agonist morphine (3.2-10mg/kg) dose-dependently reversed weight asymmetry on PDs 3, 7, 14, but was ineffective in later-stage (PD 21) OA. In runners, Cohen's d (effect sizes) for OA vs. controls indicated large increases in bone volume fraction, trabecular number, trabecular thickness, and connective density in lateral compartment, and large decreases in the same parameters in medial compartment. In contrast, effect sizes were small to moderate for sedentary OA vs. Results indicate that voluntary exercise may protect against OA pain, the effect varies as a function of prior exercise duration, and is associated with distinct trabecular bone modifications. Copyright © 2017 Elsevier Inc. All rights reserved.

Research and technology activities at Ames Research Center's Biomedical Research Division

NASA Technical Reports Server (NTRS)

Martello, N.

1985-01-01

Various research and technology activities at Ames Research Center's Biomedical Research Division are described. Contributions to the Space Administration's goals in the life sciences include descriptions of research in operational medicine, cardiovascular deconditioning, motion sickness, bone alterations, muscle atrophy, fluid and electrolyte changes, radiation effects and protection, behavior and performance, gravitational biology, and life sciences flight experiments.

Anticlastogenic activity exhibited by botryosphaeran, a new exopolysaccharide produced by Botryosphaeria rhodina MAMB-05.

PubMed

Miranda, Carolina C B O; Dekker, Robert F H; Serpeloni, Juliana M; Fonseca, Eveline A I; Cólus, Ilce M S; Barbosa, Aneli M

2008-03-01

Biopolymers such as exopolysaccharides (EPS) are produced by microbial species and possess unusual properties known to modify biological responses, among them are antimutagenicity and immunomodulation. Botryosphaeran, a newly described fungal (1-->3; 1-->6)-beta-d-glucan produced by Botryosphaeria rhodina MAMB-05, was administered by gavage to mice at three doses (7.5, 15 and 30mg/kgb.w.per day) over 15 days, and found to be non-genotoxic by the micronucleus test in peripheral blood and bone marrow. Botryosphaeran administered at doses of 15 and 30mg EPS/kgb.w. decreased significantly (p<0.001) the clastogenic effect of cyclophosphamide-induced micronucleus formation resulting in a reduction of the frequency of micronucleated cells of 78 and 82% in polychromatic erythrocytes of bone marrow, and reticulocytes in peripheral blood, respectively. The protective effect was dose-dependent, and strong anticlastogenic activity was exerted at low EPS doses. Variance analysis (ANOVA) showed no significant differences (p<0.05) among the median body weights of the groups of mice treated with botryosphaeran during experiments evaluating genotoxic and protective activities of botryosphaeran. This is the first report on the biological activity attributed to botryosphaeran.

Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer's disease-induced estrogen deficient rats.

PubMed

Shin, Bae Kun; Kang, Suna; Kim, Da Sol; Park, Sunmin

2018-02-01

Intermittent fasting may be an effective intervention to protect against age-related metabolic disturbances, although it is still controversial. Here, we investigated the effect of intermittent fasting on the deterioration of the metabolism and cognitive functions in rats with estrogen deficiency and its mechanism was also explored. Ovariectomized rats were infused with β-amyloid (25-35; Alzheimer's disease) or β-amyloid (35-25, Non-Alzheimer's disease; normal cognitive function) into the hippocampus. Each group was randomly divided into two sub-groups: one with intermittent fasting and the other fed ad libitum: Alzheimer's disease-ad libitum, Alzheimer's disease-intermittent fasting, Non-Alzheimer's disease-ad libitum, and Non-Alzheimer's disease-intermittent fasting. Rats in the intermittent fasting groups had a restriction of food consumption to a 3-h period every day. Each group included 10 rats and all rats fed a high-fat diet for four weeks. Interestingly, Alzheimer's disease increased tail skin temperature more than Non-Alzheimer's disease and intermittent fasting prevented the increase. Alzheimer's disease reduced bone mineral density in the spine and femur compared to the Non-Alzheimer's disease, whereas bone mineral density in the hip and leg was reduced by intermittent fasting. Fat mass only in the abdomen was decreased by intermittent fasting. Intermittent fasting decreased food intake without changing energy expenditure. Alzheimer's disease increased glucose oxidation, whereas intermittent fasting elevated fat oxidation as a fuel source. Alzheimer's disease and intermittent fasting deteriorated insulin resistance in the fasting state but intermittent fasting decreased serum glucose levels after oral glucose challenge by increasing insulin secretion. Alzheimer's disease deteriorated short and spatial memory function compared to the Non-Alzheimer's disease, whereas intermittent fasting prevented memory loss in comparison to ad libitum. Unexpectedly, cortisol levels were increased by Alzheimer's disease but decreased by intermittent fasting. Intermittent fasting improved dyslipidemia and liver damage index compared to ad libitum. Alzheimer's disease lowered low-density lipoprotein cholesterol and serum triglyceride levels compared to Non-Alzheimer's disease. In conclusion, Alzheimer's disease impaired not only cognitive function but also disturbed energy, glucose, lipid, and bone metabolism in ovariectomized rats. Intermittent fasting protected against the deterioration of these metabolic parameters, but it exacerbated bone mineral density loss and insulin resistance at fasting in Alzheimer's disease-induced estrogen-deficient rats. Impact statement Intermittent fasting was evaluated for its effects on cognitive function and metabolic disturbances in a rat model of menopause and Alzheimer's disease. Intermittent fasting decreased skin temperature and fat mass, and improved glucose tolerance with decreasing food intake. Intermittent fasting also prevented memory loss: short-term and special memory loss. Therefore, intermittent fasting may prevent some of the metabolic pathologies associated with menopause and protect against age-related memory decline.

Vitamin E Phosphate Coating Stimulates Bone Deposition in Implant-related Infections in a Rat Model.

PubMed

Lovati, Arianna B; Bottagisio, Marta; Maraldi, Susanna; Violatto, Martina B; Bortolin, Monica; De Vecchi, Elena; Bigini, Paolo; Drago, Lorenzo; Romanò, Carlo L

2018-06-01

Implant-related infections are associated with impaired bone healing and osseointegration. In vitro antiadhesive and antibacterial properties and in vivo antiinflammatory effects protecting against bone loss of various formulations of vitamin E have been demonstrated in animal models. However, to the best of our knowledge, no in vivo studies have demonstrated the synergistic activity of vitamin E in preventing bacterial adhesion to orthopaedic implants, thus supporting the bone-implant integration. The purpose of this study was to test whether a vitamin E phosphate coating on titanium implants may be able to reduce (1) the bacterial colonization of prosthetic implants and (2) bone resorption and osteomyelitis in a rat model of Staphylococcus aureus-induced implant-related infection. Twelve rats were bilaterally injected in the femurs with S aureus UAMS-1-Xen40 and implanted with uncoated or vitamin E phosphate-coated titanium Kirschner wires without local or systemic antibiotic prophylaxis. Eight rats represented the uninfected control group. A few hours after surgery, two control and three infected animals died as a result of unexpected complications. With the remaining rats, we assessed the presence of bacterial contamination with qualitative bioluminescence imaging and Gram-positive staining and with quantitative bacterial count. Bone changes in terms of resorption and osteomyelitis were quantitatively analyzed through micro-CT (bone mineral density) and semiquantitatively through histologic scoring systems. Six weeks after implantation, we found only a mild decrease in bacterial count in coated versus uncoated implants (Ti versus controls: mean difference [MD], -3.705; 95% confidence interval [CI], -4.416 to -2.994; p < 0.001; TiVE versus controls: MD, -3.063; 95% CI, -3.672 to -2.454; p < 0.001), whereas micro-CT analysis showed a higher bone mineral density at the knee and femoral metaphysis in the vitamin E-treated group compared with uncoated implants (knee joint: MD, -11.88; 95% CI, -16.100 to -7.664; p < 0.001 and femoral metaphysis: MD, -19.87; 95% CI, -28.82 to -10.93; p < 0.001). We found decreased osteonecrosis (difference between medians, 1.5; 95% CI, 1-2; p < 0.002) in the infected group receiving the vitamin E-coated nails compared with the uncoated nails. These preliminary findings indicate that vitamin E phosphate implant coatings can exert a protective effect on bone deposition in a highly contaminated animal model of implant-related infection. The use of vitamin E coatings may open new perspectives for developing coatings that can limit septic loosening of infected implants with bacterial contamination. However, a deeper insight into the mechanism of action and the local release of vitamin E as a coating for orthopaedic implants is required to be used in clinics in the near future. Although this study cannot support the antimicrobial properties of vitamin E, promising results were obtained for bone-implant osseointegration. These preliminary results will require further in vivo investigations to optimize the host response in the presence of antibiotic prophylaxis.

Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways.

PubMed

Wang, Tao; Liu, Qian; Zhou, Lin; Yuan, Jin Bo; Lin, Xixi; Zeng, Rong; Liang, Xiaonan; Zhao, Jinmin; Xu, Jiake

2015-11-17

Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.

THE EFFECT OF ANTISERUM, ALONE AND WITH HYDROCORTISONE, ON FOETAL MOUSE BONES IN CULTURE

PubMed Central

Fell, Honor B.; Weiss, L.

1965-01-01

1. The effects of normal rabbit serum and of rabbit antiserum to whole foetal mouse tissues, on the isolated limb bones of late foetal mice were studied in organ culture, and the influence of hydrocortisone on these effects was investigated. 2. Unheated normal serum caused slight loss of metachromatic material from the cartilage matrix, and some resorption of both cartilage and bone. 3. In unheated antiserum to foetal mouse tissues, the terminal cartilage was smaller and less metachromatic than in paired controls in normal serum, while osteoclasis was so intense that in many explants the bone had almost disappeared. The amount of necrosis varied with different batches of antiserum. 4. The changes produced by normal serum and antiserum could be largely prevented by heating the sera to 57°C for 45 minutes. 5. The effects could also be inhibited by the addition of hydrocortisone to the unheated sera; as little as 0.1 µg hydrocortisone per ml of medium had a well marked protective action. 6. It is suggested that (a) unheated antiserum causes a release of lysosomal enzymes with consequent breakdown of intercellular material, (b) this release is due to an indirect action on the lysosome via an increased permeability of the cell membrane, (c) hydrocortisone does not affect the antigen-antibody reaction, but inhibits the autolytic changes that normally follow this reaction, possibly by stabilising both the lysosomal and cell membranes. PMID:14276776

Study of sex differences in the association between hip fracture risk and body parameters by DXA-based biomechanical modeling.

PubMed

Nasiri, Masoud; Luo, Yunhua

2016-09-01

There is controversy about whether or not body parameters affect hip fracture in men and women in the same way. In addition, although bone mineral density (BMD) is currently the most important single discriminator of hip fracture, it is unclear if BMD alone is equally effective for men and women. The objective of this study was to quantify and compare the associations of hip fracture risk with BMD and body parameters in men and women using our recently developed two-level biomechanical model that combines a whole-body dynamics model with a proximal-femur finite element model. Sideways fall induced impact force of 130 Chinese clinical cases, including 50 males and 80 females, were determined by subject-specific dynamics modeling. Then, a DXA-based finite element model was used to simulate the femur bone under the fall-induced loading conditions and calculate the hip fracture risk. Body weight, body height, body mass index, trochanteric soft tissue thickness, and hip bone mineral density were determined for each subject and their associations with impact force and hip fracture risk were quantified. Results showed that the association between impact force and hip fracture risk was not strong enough in both men (r=-0.31,p<0.05) and women (r=0.42,p<0.001) to consider the force as a sole indicator of hip fracture risk. The correlation between hip BMD and hip fracture risk in men (r=-0.83,p<0.001) was notably stronger than that in women (r=-0.68,p<0.001). Increased body mass index was not a protective factor against hip fracture in men (r=-0.13,p>0.05), but it can be considered as a protective factor among women (r=-0.28,p<0.05). In contrast to men, trochanteric soft tissue thickness can be considered as a protective factor against hip fracture in women (r=-0.50,p<0.001). This study suggested that the biomechanical risk/protective factors for hip fracture are sex-specific. Therefore, the effect of body parameters should be considered differently for men and women in hip fracture risk assessment tools. These findings support further exploration of sex-specific preventive and protective measurements to reduce the incidence of hip fractures. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparative limb bone loading in the humerus and femur of the tiger salamander: testing the 'mixed-chain' hypothesis for skeletal safety factors.

PubMed

Kawano, Sandy M; Economy, D Ross; Kennedy, Marian S; Dean, Delphine; Blob, Richard W

2016-02-01

Locomotion imposes some of the highest loads upon the skeleton, and diverse bone designs have evolved to withstand these demands. Excessive loads can fatally injure organisms; however, bones have a margin of extra protection, called a 'safety factor' (SF), to accommodate loads that are higher than normal. The extent to which SFs might vary amongst an animal's limb bones is unclear. If the limbs are likened to a chain composed of bones as 'links', then similar SFs might be expected for all limb bones because failure of the system would be determined by the weakest link, and extra protection in other links could waste energetic resources. However, Alexander proposed that a 'mixed-chain' of SFs might be found amongst bones if: (1) their energetic costs differ, (2) some elements face variable demands, or (3) SFs are generally high. To test whether such conditions contribute to diversity in limb bone SFs, we compared the biomechanical properties and locomotor loading of the humerus and femur in the tiger salamander (Ambystoma tigrinum). Despite high SFs in salamanders and similar sizes of the humerus and femur that would suggest similar energetic costs, the humerus had lower bone stresses, higher mechanical hardness and larger SFs. SFs were greatest in the anatomical regions where yield stresses were highest in the humerus and lowest in the femur. Such intraspecific variation between and within bones may relate to their different biomechanical functions, providing insight into the emergence of novel locomotor capabilities during the invasion of land by tetrapods. © 2016. Published by The Company of Biologists Ltd.

Asymmetric bone adaptations to soleus mechanical loading after spinal cord injury

PubMed Central

Dudley-Javoroski, S.; Shields, R.K.

2009-01-01

The purpose of this report is to examine longitudinal bone mineral density (BMD) changes in individuals with spinal cord injury (SCI) who began unilateral soleus electrical stimulation early after injury. Twelve men with SCI and seven without SCI underwent peripheral quantitative computed tomography assessment of distal tibia BMD. After 4.5 to 6 years of training, average trained limb BMD was 27.5% higher than untrained limb BMD. The training effect was more pronounced in the central core of the tibia cross-section (40.5% between-limb difference). No between-limb difference emerged in the anterior half of the tibia (19.2 mg/cm3 difference, p>0.05). A robust between-limb difference emerged in the posterior half of the tibia (76.1 mg/cm3 difference, p=0.0439). The posterior tibia BMD of one subject remained within the range of non-SCI values for 3.8 years post-SCI. The results support that the constrained orientation of soleus mechanical loads, administered over several years, elicited bone-sparing effects in the posterior tibia. This study provides a demonstration of the bone-protective potential of a carefully controlled dose of mechanical load. The specific orientation of applied mechanical loads may strongly influence the manifestation of BMD adaptations in humans with SCI. PMID:18799855

Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells.

PubMed

Zhao, Yi; Zhan, Yuxia; Burke, Kathleen A; Anderson, W French

2005-04-01

Ionizing radiation-induced myeloablation can be rescued via bone marrow transplantation (BMT) or administration of cytokines if given within 2 hours after radiation exposure. There is no evidence for the existence of soluble factors that can rescue an animal after a lethal dose of radiation when administered several hours postradiation. We established a system that could test the possibility for the existence of soluble factors that could be used more than 2 hours postirradiation to rescue animals. Animals with an implanted TheraCyte immunoisolation device (TID) received lethal-dose radiation and then normal bone marrow Lin- cells were loaded into the device (thereby preventing direct interaction between donor and recipient cells). Animal survival was evaluated and stem cell activity was tested with secondary bone marrow transplantation and flow cytometry analysis. Donor cell gene expression of five antiapoptotic cytokines was examined. Bone marrow Lin- cells rescued lethally irradiated animals via soluble factor(s). Bone marrow cells from the rescued animals can rescue and repopulate secondary lethally irradiated animals. Within the first 6 hours post-lethal-dose radiation, there is no significant change of gene expression of the known radioprotective factors TPO, SCF, IL-3, Flt-3 ligand, and SDF-1. Hematopoietic stem cells can be protected in lethally irradiated animals by soluble factors produced by bone marrow Lin- cells.

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

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

Choi, Yoon Jung; Lee, Jue Yeon; Research Center, Nano Intelligent Biomedical Engineering Corporation

Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinicallymore » used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone metabolism.« less

[Effect of a novel soy fermented product enriched with isoflavones and calcium on bone tissue of rats].

PubMed

Bedani, Raquel; Rossi, Elizeu Antonio; Lepera, José Salvador; Wang, Charles Chenwei; de Valdez, Graciela Font

2006-06-01

The objective was to evaluate the effect of soy fermented product intake on the corporal weight and bone tissue of ovariectomized mature rats. This product was fermented with Enterococcus faecium and Lactobacillus jugurti and enriched with isoflavones and calcium. The animals were divided in 5 groups: sham-ovariectomized; ovariectomized; ovariectomized treated with soy fermented product enriched with isoflavones and calcium; ovariectomized treated with soy fermented product enriched with calcium and ovariectomized treated with non-fermented product enriched only with calcium. In order to evaluate the effect of the tested product on bone tissue (femur and tibia), the following parameters were analyzed: length; mechanical assay of three points; density (Archimedes principle); mineral content; calcium content; measure of the trabecular widths. The corporal weight of group treated with soy fermented product containing isoflavones and calcium showed no statistical difference from sham-ovariectomized group and trabecular widths tended to have larger than ovariectomized group. However, there was no significant difference to the other evaluated parameters in result of the diverse treatments. Thus, soy fermented product enriched with isoflavones and calcium inhibited the increasing of corporal weight caused by ovariectomy and revealed a tendency to trabecular protection after castration.

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

PubMed

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

2000-03-01

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

Vitamin C reverses hypogonadal bone loss

USDA-ARS?s Scientific Manuscript database

Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, ...

Enhancement of healing in osteochondral defects by collagen sponge implants.

PubMed

Speer, D P; Chvapil, M; Volz, R G; Holmes, M D

1979-10-01

Implants of porous, highly cross-linked collagen sponge (CS) were tested for their capacity to enhance the healing of osteochondral defects in rabbits. Comparison was made to the healing of similar defects with polyvinyl alcohol sponge (PVAS) implants and with no implants (CONT). Evaluation was carried out up to 44 weeks following implantation and included observation of host cellular response, biodegradability of implant, gross appearance of restored joint surface, collagenous architecture of repair tissue, and properties of the junctions of implants and host articular cartilage, subchondral bone, and medullary bone. Collagen sponge proved most effective in promoting healing of osteochondral defects with fibrous and fibrocartilaginous tissue over restored subchondral bone. Collagen sponge showed many desirable properties as a potential material for biologic resurfacing of damaged joints. These properties included porosity, biodegradability, biocompatability, ability to mechanically protect cells and matrix while directing cell ingrowth, and an available chemical technology for modifying its biomechanical and biological properties. Comparative analysis of results of healing of CS, PVAS, and CONT osteochondral defects suggest rational design criteria for implant materials to improve their effectiveness in restoration of articular surfaces.

Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials.

PubMed

Kawasaki, Haruhisa; Guan, Jianjun; Tamama, Kenichi

2010-07-02

Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion. Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study. Copyright 2010 Elsevier Inc. All rights reserved.

Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials

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

Kawasaki, Haruhisa; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210; Guan, Jianjun

2010-07-02

Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion.more » Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study.« less

Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: A randomized, double-blind, phase 2, parallel group study.

PubMed

McClung, Michael R; Brown, Jacques P; Diez-Perez, Adolfo; Resch, Heinrich; Caminis, John; Meisner, Paul; Bolognese, Michael A; Goemaere, Stefan; Bone, Henry G; Zanchetta, Jose R; Maddox, Judy; Bray, Sarah; Grauer, Andreas

2018-04-25

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased BMD in postmenopausal women with low BMD (NCT00896532). Herein we report the study extension evaluating 24 months treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women age 55-85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70mg, 140mg, 210mg monthly [QM]; 140mg Q3M; 210mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140mg QM for 12 months. Eligible participants were then re-randomized 1:1 within original treatment groups to placebo or denosumab 60mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210mg QM, bone formation marker P1NP initially increased following treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; and bone resorption marker β-CTX rapidly decreased following treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, while after transition to placebo, P1NP returned to baseline and β-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Antioxidative Peptides Derived from Enzyme Hydrolysis of Bone Collagen after Microwave Assisted Acid Pre-Treatment and Nitrogen Protection

PubMed Central

Lin, Yun-Jian; Le, Guo-Wei; Wang, Jie-Yun; Li, Ya-Xin; Shi, Yong-Hui; Sun, Jin

2010-01-01

This study focused on the preparation method of antioxidant peptides by enzymatic hydrolysis of bone collagen after microwave assisted acid pre-treatment and nitrogen protection. Phosphoric acid showed the highest ability of hydrolysis among the four other acids tested (hydrochloric acid, sulfuric acid and/or citric acid). The highest degree of hydrolysis (DH) was 9.5% using 4 mol/L phosphoric acid with a ratio of 1:6 under a microwave intensity of 510 W for 240 s. Neutral proteinase gave higher DH among the four protease tested (Acid protease, neutral protease, Alcalase and papain), with an optimum condition of: (1) ratio of enzyme and substrate, 4760 U/g; (2) concentration of substrate, 4%; (3) reaction temperature, 55 °C and (4) pH 7.0. At 4 h, DH increased significantly (P < 0.01) under nitrogen protection compared with normal microwave assisted acid pre-treatment hydrolysis conditions. The antioxidant ability of the hydrolysate increased and reached its maximum value at 3 h; however DH decreased dramatically after 3 h. Microwave assisted acid pre-treatment and nitrogen protection could be a quick preparatory method for hydrolyzing bone collagen. PMID:21151439

Accessibility of ³H-secoisolariciresinol diglycoside lignan metabolites in skeletal tissue of ovariectomized rats.

PubMed

Sacco, Sandra M; Thompson, Lilian U; Ganss, Bernhard; Ward, Wendy E

2011-10-01

Flaxseed, rich in the phytoestrogen lignan secoisolariciresinol diglycoside (SDG), provides protection against bone loss at the lumbar vertebrae primarily when combined with low-dose estrogen therapy in the ovariectomized rat model of postmenopausal osteoporosis. Whether SDG metabolites are accessible to skeletal tissue, and thus have the potential to interact with low-dose estrogen therapy to exert direct local action on bone metabolism, is unknown. The objective of this study was to determine whether metabolites of SDG are accessible to the skeleton of ovariectomized rats and to compare the distribution of SDG metabolites in skeletal tissue with that in other tissues. Rats were fed a 10% flaxseed diet and gavaged daily with tritium-labeled SDG (7.4 kBq/g of body weight) in deionized water (500 μL) (n=3) or deionized water alone (n=3) for 7 days, after which tissues were collected for liquid scintillation counting. Radioactivity was detected in similar concentrations in the lumbar vertebrae, femurs, and tibias. Compared with non-skeletal tissues, total radioactivity in the skeleton was significantly lower than in the liver, heart, kidney, thymus, and brain (P < .001). There were no significant differences in levels of radioactivity between skeletal tissue versus the spleen, lung, bladder, uterus, vagina, and mammary gland. In conclusion, SDG metabolites are accessible to skeletal tissue of ovariectomized rats. Thus, it is biologically plausible that SDG metabolites may play a direct role in the protective effects of flaxseed combined with low-dose estrogen therapy against the loss of bone mass and bone strength in the ovariectomized rat model of postmenopausal osteoporosis.

Hardness map of human meta tarsals and phalanges of toes.

PubMed

Manarvi, Irfan

2016-08-01

Predicting location of fracture in human bones has been a keen area of research for the past few decades. A variety of tests for hardness, deformation and strain field measurement have been conducted in the past; but considered insufficient due to various limitations. Researchers therefore have proposed further studies due to inaccuracies in measurement methods, testing machines and experimental errors. Advancement and availability of hardware, measuring instrumentation and testing machines can now provide remedies to these limitations. Human foot is a critical part of body exposed to various forces throughout its life. A number of products are developed for using over it for protection and care. Which many times do not provide sufficient protection and may itself become a source of stress due to non-consideration of the delicacy of bones in the feet. A continuous strain or overloading on feet may occur resulting to discomfort and even fracture. Not knowing how the hardness is spread all over the Meta tarsals and phalanges is one of major contributory factor for unsatisfactory design of foot protection products. This paper provides a complete hardness distribution map developed by experimental testing of all the Meta tarsals and Phalanges of toes for a typical human foot. The bones were taken from two left feet of a 40 and 42 year old male cadaver. These were dehydrated prior to measurements of hardness using Leeb hardness testing method. Hardness was measured around the circumference of a bone as well as along its length. Hardness values can be related to tensile strength of the bones to predict possible values of stress that could be borne by these bones. Results may also be used for design and developing various accessories for human feet health care and comfort.

Investigation of interstitial ultrasound ablation of spinal and paraspinal tumors: A patient-specific and parametric simulation study

NASA Astrophysics Data System (ADS)

Scott, Serena J.; Salgaonkar, Vasant; Prakash, Punit; Burdette, E. Clif; Diederich, Chris J.

2017-03-01

Preferential acoustic absorption and heating of bone can significantly impact interstitial ultrasound ablation of tumors within or bordering the spine. Furthermore, intervening cortical bone may provide acoustic and thermal insulation that can protect sensitive structures nearby, such as the spinal cord. The objectives of this study are firstly, to apply parametric and patient-specific models to theoretically assess the feasibility of interstitial ultrasound ablation of tumors within and near the spine, and secondly, to identify potential energy delivery strategies, safety criteria, advantages, and disadvantages of interstitial ultrasound in this setting. Transient biothermal models using previously validated approximations for power deposition within bone from interstitial sources were employed. Multilayered axisymmetric models were used to perform a parametric assessment of the impact of tumor dimensions, attenuation (dependent on residual bone content), perfusion, and maximum temperature thresholds on necessary treatment parameters and on treatment effectiveness. 3D patient-specific finite element models were generated based on segmented CT scans for nine representative patient cases selected to bracket a range of clinical interest, with tumors in or near the vertebrae, sacrum, and ilium. Tumors were 10-27 mm in diameter, 10-43 mm long, and 0-14 mm from the spinal canal. Paraspinal tumors, osteolytic vertebral tumors, and a mixed osteolytic/osteoblastic iliac bone tumor were considered. 7 MHz (1.5 mm OD) and 3.0 MHz (3.2 mm OD) applicators with an array of 1-4 tubular transducers (0.5 -1.5 cm long, 150-360° sector angles), were applied in various implant configurations. Variable thicknesses of bone insulating critical anatomy from the tumor and insulation of the spinal cord with injected carbon dioxide were also investigated for definition of safety margins and possible protection of critical structures. 6-44 mm diameter osteolytic tumors surrounded by bone and blastic (high bone content) lesions up to 20 mm in diameter could be fully ablated by 7 MHz interstitial ultrasound using 120-5,900 J and treatment durations of 0.4-15 min. 100% of the volumes of five simulated tumors located 4.3-14 mm from the spinal canal and 94.6-99.9% of the volumes of four simulated tumors 0-4.5 mm from the spinal canal were ablated (>240 EM43°C) within 15 min without damaging (<6 EM43°C) critical nerves. Preferential ultrasound absorption and concomitant heating at bone surfaces allowed for faster, more effective ablations with less delivered energy. 3-5 mm of normal cortical bone was found to provide a safety margin and reduce temperature elevations in untargeted tissues. Critical anatomy less than 3-5 mm from a tumor encapsulated by bone could be preserved by reducing the acoustic energy aimed towards these structures and/or through injection of insulating CO2. Parametric and patient-specific studies demonstrated the feasibility of interstitial ultrasound ablation of paraspinal tumors and osteolytic tumors within the spine. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in highly osteolytic and soft tissue tumors in and near bone compared to other heating modalities. This work was supported by the NIH grant R44CA112852.

High Serum 25-hydroxyvitamin D is Associated with Low Incidence of Stress Fractures

DTIC Science & Technology

2011-06-01

hypocalcemia , and is essential for bone formation and resorption (1-4). Adequate serum concentration of 25-hydroxyvitamin D (25(OH)D) is associated with...nutritional status, since it includes the effects of solar ultraviolet (UVB) exposure and oral intake from food and supplements, and it has a markedly...subjects may not have been high enough for a protective effect on fractures to occur. Previous research has shown that amenorrhea and history of

CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage

PubMed Central

Chang, Yan; Jia, Xiaoyi; Wei, Fang; Wang, Chun; Sun, Xiaojing; Xu, Shu; Yang, Xuezhi; Zhao, Yingjie; Chen, Jingyu; Wu, Huaxun; Zhang, Lingling; Wei, Wei

2016-01-01

Paeoniflorin-6′-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin (Pae), was evaluated in rats with adjuvant-induced arthritis (AA) to study its potential anti-arthritic activity. AA rats were treated with CP-25 (25, 50, or 100 mg/kg) from days 17 to 29 after immunization. CP-25 effectively reduced clinical and histopathological scores compared with the AA groups. CP-25-treated rats exhibited decreases in pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) coupled with an increase in the anti-inflammatory cytokine TGF-β1 in the serum. CP-25 treatment inhibited M1 macrophage activation and enhanced M2 macrophage activation by influencing cytokine production. Decreases in Th17-IL-17 and the Th17-associated transcription factor RAR-related orphan receptor gamma (ROR-γt) dramatically demonstrated the immunomodulatory effects of CP-25 on abnormal immune dysfunction. In addition, CP-25 suppressed the production of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase (MMP) 9, which supported its anti-osteoclastic effects. The data presented here demonstrated that CP-25 significantly inhibited the progression of rat AA by reducing inflammation, immunity and bone damage. The protective effects of CP-25 in AA highlight its potential as an ideal new anti-arthritic agent for human RA. PMID:27184722

CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage.

PubMed

Chang, Yan; Jia, Xiaoyi; Wei, Fang; Wang, Chun; Sun, Xiaojing; Xu, Shu; Yang, Xuezhi; Zhao, Yingjie; Chen, Jingyu; Wu, Huaxun; Zhang, Lingling; Wei, Wei

2016-05-17

Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin (Pae), was evaluated in rats with adjuvant-induced arthritis (AA) to study its potential anti-arthritic activity. AA rats were treated with CP-25 (25, 50, or 100 mg/kg) from days 17 to 29 after immunization. CP-25 effectively reduced clinical and histopathological scores compared with the AA groups. CP-25-treated rats exhibited decreases in pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) coupled with an increase in the anti-inflammatory cytokine TGF-β1 in the serum. CP-25 treatment inhibited M1 macrophage activation and enhanced M2 macrophage activation by influencing cytokine production. Decreases in Th17-IL-17 and the Th17-associated transcription factor RAR-related orphan receptor gamma (ROR-γt) dramatically demonstrated the immunomodulatory effects of CP-25 on abnormal immune dysfunction. In addition, CP-25 suppressed the production of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase (MMP) 9, which supported its anti-osteoclastic effects. The data presented here demonstrated that CP-25 significantly inhibited the progression of rat AA by reducing inflammation, immunity and bone damage. The protective effects of CP-25 in AA highlight its potential as an ideal new anti-arthritic agent for human RA.

Vitamin D3 contributes to enhanced osteogenic differentiation of MSCs under oxidative stress condition via activating the endogenous antioxidant system.

PubMed

Zhou, J; Wang, F; Ma, Y; Wei, F

2018-06-02

The anti-oxidative effects of vitamin D3 (Vd3) on mesenchymal stem cells (MSCs) have not been studied before. The present study suggested that Vd3 could not only promote the osteogenic differentiation of MSCs under normal condition but also partly protect it from oxidative stress damage by activating the endogenous antioxidant system. Evolving evidence proved that oxidative stress caused by reactive oxygen species (ROS) overproduction might lead to bone loss. Vd3, a commonly used osteogenic induction drug, was proved to exhibit potent anti-oxidative effects on other cell types. The present study aims to investigate the protective effects of Vd3 on oxidative stress-induced dysfunctions of MSCs, as well as its underlying mechanisms. The H 2 O 2 was used as exogenous reactive oxygen species (ROS). The influence of ROS and anti-oxidative protection of Vd3 on MSCs were analyzed too. Multi-techniques were used to assess the beneficial effects of Vd3 on MSCs under oxidative stress condition. The results demonstrated that Vd3 could significantly attenuate the H 2 O 2 -induced cell injury of MSCs via Sirt1/FoxO1 signaling pathway, and reduced the H 2 O 2 exposure-induced intracellular oxidative stress status of MSCs. What's more, the H 2 O 2 exposure resulted in the decreased osteogenic differentiation of MSCs, as evidenced by decreased alkaline phosphatase activity, calcium deposition level, and osteogenic differentiation gene mRNA levels, but the injury was restored via Vd3 administration. The results suggested that Vd3 could not only promote the osteogenic differentiation of osteoblastic cells under normal condition but also partly protect the cell from oxidative stress damage by activating endogenous antioxidant system. The study shed light on the new roles of Vd3 in bone modeling and remodeling regulation.

Kefir improves bone mass and microarchitecture in an ovariectomized rat model of postmenopausal osteoporosis.

PubMed

Chen, H-L; Tung, Y-T; Chuang, C-H; Tu, M-Y; Tsai, T-C; Chang, S-Y; Chen, C-M

2015-02-01

Kefir treatment in ovariectomized (OVX) rats could significantly decrease the levels of bone turnover markers and prevent OVX-induced bone loss, deterioration of trabecular microarchitecture, and biomechanical dysfunction that may be due to increase intracellular calcium uptake through the TRPV6 calcium channel. Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to an increased fracture risk. The incidence of osteoporosis increases with age and occurs most frequently in postmenopausal women due to estrogen deficiency, as the balance between bone resorption and bone formation shifts towards increased levels of bone resorption. Among various methods of prevention and treatment for osteoporosis, an increase in calcium intake is the most commonly recommended preventive measure. Kefir is a fermented milk product made with kefir grains that degrade milk proteins into various peptides with health-promoting effects, including immunomodulating-, antithrombotic-, antimicrobial-, and calcium-absorption-enhancing bioactivities. The aim of this study is to investigate the effect of kefir on osteoporosis prophylaxis in an ovariectomized rat model. A total of 56 16-week-old female Sprague-Dawley (SD) rats were divided into 7 experimental groups: sham (normal), OVX/Mock, OVX/1X kefir (164 mg/kg BW/day), OVX/2X kefir (328 mg/kg BW/day), OVX/4X kefir (656 mg/kg BW/day), OVX/ALN (2.5 mg/kg BW/day), and OVX/REBONE (800 mg/kg BW/day). After 12-week treatment with kefir, the bone physiology in the OVX rat model was investigated. Accordingly, the aim of this study was to investigate the possible transport mechanism involved in calcium absorption using the Caco-2 human cell line. A 12-week treatment with kefir on the OVX-induced osteoporosis model reduced the levels of C-terminal telopeptides of type I collagen (CTx), bone turnover markers, and trabecular separation (Tb. Sp.). Additionally, treatment with kefir increased trabecular bone mineral density (BMD), bone volume (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. N), and the biomechanical properties (hardness and modulus) of the distal femur with a dose-dependent efficacy. In addition, in in vitro assay, we found that kefir increased intracellular calcium uptake in Caco-2 cell through TRPV6 calcium channels and not through L-type voltage-operated calcium channels. The protective effect of kefir in the OVX rat model may occur through increasing intracellular calcium uptake through the TRPV6 calcium channel.

Effects of melatonin on DNA damage induced by cyclophosphamide in rats

PubMed Central

Ferreira, S.G.; Peliciari-Garcia, R.A.; Takahashi-Hyodo, S.A.; Rodrigues, A.C.; Amaral, F.G.; Berra, C.M.; Bordin, S.; Curi, R.; Cipolla-Neto, J.

2013-01-01

The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP), an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg). Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water). Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg)-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE) of chromosomal aberrations in pinealectomized (PINX) animals treated with melatonin and CP (2.50 ± 0.50/100 cells) was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells), thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy. PMID:23471360

Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System

PubMed Central

Alwood, Joshua S.; Tran, Luan H.; Schreurs, Ann-Sofie; Shirazi-Fard, Yasaman; Kumar, Akhilesh; Hilton, Diane; Tahimic, Candice G. T.; Globus, Ruth K.

2017-01-01

Space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized that ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-weeks old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 MeV/n) or high-LET 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA’s Space Radiation Lab. Five weeks or one year after irradiation, tissues were harvested and analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed by RT-PCR during the proliferative or mineralizing phase of growth, and differentiation was analyzed by imaging mineralized nodules. As expected, a high dose (200 cGy), but not lower doses, of either 56Fe or protons caused a loss of cancellous bone volume/total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; 56Fe (200 cGy) inhibited osteoblastogenesis by more than 90% (5 weeks and 1 year post-IR). After 5 weeks, irradiation (protons or 56Fe) caused few changes in gene expression levels during osteoblastogenesis, although a high dose 56Fe (200 cGy) increased Catalase and Gadd45. The addition of exogenous superoxide dismutase (SOD) protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET (137Cs γ) when irradiated in vitro, but had limited protective effects on high-LET 56Fe-exposed cells. In sum, either protons or 56Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET 56Fe increased redox-related gene expression, albeit to a limited extent, and inhibited osteoblastogenesis. Doses below 50 cGy did not elicit widespread responses in any parameter measured. We conclude that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss. PMID:28994728

Bone accretion in adolescents using the combined estrogen and progestin transdermal contraceptive method Ortho Evra: a pilot study.

PubMed

Harel, Zeev; Riggs, Suzanne; Vaz, Rosalind; Flanagan, Patricia; Harel, Dalia; Machan, Jason T

2010-02-01

To date, there are no data regarding the effect of the transdermal combined estrogen and progestin contraceptive Ortho Evra on bone mineral content (BMC) and bone mineral density (BMD). We examined the effects of transdermally delivered ethinyl estradiol and norelgestromin on whole body (WB) BMC and BMD of the hip and lumbar spine (LS) of adolescent girls. In a matched case-control study, girls (n = 5) who applied Ortho Evra for days 1-21 followed by days 22-28 free of medication for 13 cycles (about 12 months) were compared with 5 age- and ethnicity-matched control girls. Evaluations of calcium intake; bone-protective physical activity; bone densitometry (DXA, QDR 4500A, Hologic); bone formation markers serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP); bone resorption marker urinary N-telopeptide (uNTX); insulin growth factor-1 (IGF-1); and sex hormone binding globulin (SHBG) were carried out at initiation, 6 months, and 12 months. Changes from baseline were compared using mixed models, adjusting for follow-up comparisons using the Holm Test (sequential Bonferroni). There were no significant differences (SD) between groups at baseline in age, gynecologic age, WBBMC, hip BMD, and LSBMD. Girls on Ortho Evra did not change significantly in WBBMC (12-month mean increase 0.2% +/- 0.8%), whereas controls did (3.9% +/- 1.8%, P < or = .001, adjusted P = .002), with SD between the 2 groups (P = .007, adjusted P = .036). Adolescents on Ortho Evra did not change significantly in hip BMD (12-month mean increase 0.5% +/- 0.6%), whereas controls did (2.7% +/- 0.6%, P < or = .001, adjusted P = .004), with SD between the 2 groups (P = .024) prior to adjustment for multiple comparisons, but no SD after adjustment (P = .096). Similarly, although the increase in LSBMD within the control group after 12 months (mean increase 2.8% +/- 1.0%) was statistically significant (P = .009, adjusted P = .044), the change within the treatment group (12-month mean increase 0.8% +/- 0.8%) was not. However, percent LSBMD changes after 12 months did not significantly differ between the 2 groups before or after adjustment for multiple comparisons. Calcium intake and bone-protective physical activity did not significantly predict BMC and BMD changes of study participants. There was a significantly greater increase in SHBG levels in the treatment group after 6 months (P = .003, adjusted P = .013) and 12 months (P < or = .001, adjusted P < or = .001) than in controls. Changes in levels of OC, BAP, uNTX, and IGF-1 were not significantly different between the 2 groups. Ortho Evra use attenuates bone mass acquisition in young women who are still undergoing skeletal maturation. This attenuation may be attributed in part to increased SHBG levels, which reduce the concentrations of free estradiol and free testosterone that are available to interact with receptors on the bone. Clinical implications remain to be determined in studies with a larger number of adolescents. Copyright 2010 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

FK506 protects against articular cartilage collagenous extra-cellular matrix degradation.

PubMed

Siebelt, M; van der Windt, A E; Groen, H C; Sandker, M; Waarsing, J H; Müller, C; de Jong, M; Jahr, H; Weinans, H

2014-04-01

Osteoarthritis (OA) is a non-rheumatologic joint disease characterized by progressive degeneration of the cartilage extra-cellular matrix (ECM), enhanced subchondral bone remodeling, activation of synovial macrophages and osteophyte growth. Inhibition of calcineurin (Cn) activity through tacrolimus (FK506) in in vitro monolayer chondrocytes exerts positive effects on ECM marker expression. This study therefore investigated the effects of FK506 on anabolic and catabolic markers of osteoarthritic chondrocytes in 2D and 3D in vitro cultures, and its therapeutic effects in an in vivo rat model of OA. Effects of high and low doses of FK506 on anabolic (QPCR/histochemistry) and catabolic (QPCR) markers were evaluated in vitro on isolated (2D) and ECM-embedded chondrocytes (explants, 3D pellets). Severe cartilage damage was induced unilaterally in rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with FK506 orally and compared to twenty untreated controls. Subchondral cortical and trabecular bone changes (longitudinal microCT) and macrophage activation (SPECT/CT) were measured. Articular cartilage was analyzed ex vivo using contrast enhanced microCT and histology. FK506 treatment of osteoarthritic chondrocytes in vitro induced anabolic (mainly collagens) and reduced catabolic ECM marker expression. In line with this, FK506 treatment clearly protected ECM integrity in vivo by markedly decreasing subchondral sclerosis, less development of subchondral pores, depletion of synovial macrophage activation and lower osteophyte growth. FK506 protected cartilage matrix integrity in vitro and in vivo. Additionally, FK506 treatment in vivo reduced OA-like responses in different articular joint tissues and thereby makes Cn an interesting target for therapeutic intervention of OA. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Selection of the Optimal Herbal Compositions of Red Clover and Pomegranate According to Their Protective Effect against Climacteric Symptoms in Ovariectomized Mice.

PubMed

Kang, Su Jin; Choi, Beom Rak; Kim, Seung Hee; Yi, Hae Yeon; Park, Hye Rim; Song, Chang Hyun; Ku, Sae Kwang; Lee, Young Joon

2016-07-23

This study aimed to ascertain the optimal range of red clover dry extracts (RC) and dried pomegranate concentrate powder (PCP) to induce anti-climacteric effects. Thus, the dose ranges showing protective effect of mixed formulae consisting of RC and PCP were examined in ovariectomized mice. At 28 days after bilateral ovariectomy (OVX), mixed herbal compositions (RC:PCP = 1:1, 1:2, 1:4, 1:8, 2:1, 4:1, and 8:1) were administered orally, at 120 mg/kg once daily for 84 days. We evaluated that RC and PCP mixture attenuate OVX-caused obesity, hyperlipidemia, hepatic steatosis, and osteoporosis. Compared to OVX-induced control mice, body weight and abdominal fat weight in OVX-induced mice were significantly decreased, concomitantly with increase of uterus weight by RC:PCP mixture. Additionally, significant increases in serum estradiol levels were observed in all RC:PCP-treated mice. RC:PCP mixture also showed protective effect against OVX-induced hyperlipidemia, hepatic steatosis. Total body and femur mean bone mineral density (BMD), osteocalcin, bALP contents were effectively increased by RC:PCP mixture. Taken together, RC:PCP mixture (2:1, 1:1, and 4:1) has remarkable protective effects against the changes induced by OVX. In particular, RC:PCP mixture (2:1) shows the strongest effect and may be considered as a potential protective agent against climacteric symptoms.

Selection of the Optimal Herbal Compositions of Red Clover and Pomegranate According to Their Protective Effect against Climacteric Symptoms in Ovariectomized Mice

PubMed Central

Kang, Su Jin; Choi, Beom Rak; Kim, Seung Hee; Yi, Hae Yeon; Park, Hye Rim; Song, Chang Hyun; Ku, Sae Kwang; Lee, Young Joon

2016-01-01

This study aimed to ascertain the optimal range of red clover dry extracts (RC) and dried pomegranate concentrate powder (PCP) to induce anti-climacteric effects. Thus, the dose ranges showing protective effect of mixed formulae consisting of RC and PCP were examined in ovariectomized mice. At 28 days after bilateral ovariectomy (OVX), mixed herbal compositions (RC:PCP = 1:1, 1:2, 1:4, 1:8, 2:1, 4:1, and 8:1) were administered orally, at 120 mg/kg once daily for 84 days. We evaluated that RC and PCP mixture attenuate OVX-caused obesity, hyperlipidemia, hepatic steatosis, and osteoporosis. Compared to OVX-induced control mice, body weight and abdominal fat weight in OVX-induced mice were significantly decreased, concomitantly with increase of uterus weight by RC:PCP mixture. Additionally, significant increases in serum estradiol levels were observed in all RC:PCP-treated mice. RC:PCP mixture also showed protective effect against OVX-induced hyperlipidemia, hepatic steatosis. Total body and femur mean bone mineral density (BMD), osteocalcin, bALP contents were effectively increased by RC:PCP mixture. Taken together, RC:PCP mixture (2:1, 1:1, and 4:1) has remarkable protective effects against the changes induced by OVX. In particular, RC:PCP mixture (2:1) shows the strongest effect and may be considered as a potential protective agent against climacteric symptoms. PMID:27455321

Toll-like receptor (TLR)-1/2 triggering of multiple myeloma cells modulates their adhesion to bone marrow stromal cells and enhances bortezomib-induced apoptosis.

PubMed

Abdi, Jahangir; Mutis, Tuna; Garssen, Johan; Redegeld, Frank A

2014-01-01

In multiple myeloma (MM), the malignant plasma cells usually localize to the bone marrow where they develop drug resistance due to adhesion to stromal cells and various environmental signals. Hence, modulation of this interaction is expected to influence drug sensitivity of MM cells. Toll-like receptor (TLR) ligands have displayed heterogeneous effects on B-cell malignancies and also on MM cells in a few recent studies, but effects on adhesion and drug sensitivity of myeloma cells in the context of bone marrow stromal cells (BMSCs) have never been investigated. In the present study, we explored the modulatory effects of TLR1/2 ligand (Pam3CSK4) on adhesion of human myeloma cells to BMSCs. It is shown that TLR1/2 triggering has opposite effects in different HMCLs on their adhesion to BMSCs. Fravel, L363, UM-6, UM-9 and U266 showed increased adhesion to BMSC in parallel with an increased surface expression of integrin molecules α4 and αVβ3. OPM-1, OPM-2 and NCI-H929 showed a dose-dependent decrease in adhesion upon TLR activation following a downregulation of β7 integrin expression. Importantly, TLR1/2 triggering increased cytotoxic and apoptotic effects of bortezomib in myeloma cells independent of the effect on stromal cell adhesion. Moreover, the apoptosis-enhancing effect of Pam3CSK4 paralleled induction of cleaved caspase-3 protein in FACS analysis suggesting a caspase-dependent mechanism. Our findings uncover a novel role of TLR activation in MM cells in the context of bone marrow microenvironment. Stimulation of TLR1/2 bypasses the protective shield of BMSCs and may be an interesting strategy to enhance drug sensitivity of multiple myeloma cells.

Gastrodin: an ancient Chinese herbal medicine as a source for anti-osteoporosis agents via reducing reactive oxygen species.

PubMed

Huang, Qiang; Shi, Jun; Gao, Bo; Zhang, Hong-Yang; Fan, Jing; Li, Xiao-Jie; Fan, Jin-Zhu; Han, Yue-Hu; Zhang, Jin-Kang; Yang, Liu; Luo, Zhuo-Jing; Liu, Jian

2015-04-01

Increased levels of reactive oxygen species (ROS) are a crucial pathogenic factor of osteoporosis. Gastrodin, isolated from the traditional Chinese herbal agent Gastrodia elata, is a potent antioxidant. We hypothesized that gastrodin demonstrates protective effects against osteoporosis by partially reducing reactive oxygen species in human bone marrow mesenchymal stem cells (hBMMSCs) and a macrophage cell line (RAW264.7 cells). We investigated gastrodin on osteogenic and adipogenic differentiation under oxidative stress in hBMMSCs. We also tested gastrodin on osteoclastic differentiation in RAW264.7 cells. Hydrogen peroxide (H2O2) was used to establish an oxidative cell injury model. Our results showed that gastrodin significantly promoted the proliferation of hBMMSCs, improved some osteogenic markers, reduced lipid generation and inhibited the mRNA expression of several adipogenic genes in hBMMSCs. Moreover, gastrodin reduced the number of osteoclasts, TRAP activity and the expression of osteoclast-specific genes in RAW264.7 cells. Gastrodin suppressed the production of reactive oxygen species in both hBMMSCs and RAW264.7 cells. In vivo, we established a murine ovariectomized (OVX) osteoporosis model. Our data revealed that gastrodin treatment reduced the activity of serum bone degradation markers, such as CTX-1 and TRAP. Importantly, it ameliorated the micro-architecture of trabecular bones. Gastrodin decreased osteoclast numbers in vivo by TRAP staining. To conclude, these results indicated that gastrodin shows protective effects against osteoporosis linking to a reduction in reactive oxygen species, suggesting that gastrodin may be useful in the prevention and treatment of osteoporosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of alpha-galactosylceramides on bone marrow cells in vitro and hematopoiesis in vivo.

PubMed

Motoki, K; Morita, M; Kobayashi, E; Uchida, T; Fukushima, H; Koezuka, Y

1996-07-01

We found that AGL-517, an alpha-galactosylceramide (alpha-GalCer), possesses potent radioprotective activities against mice irradiated with 9 Gy of X-ray in contrast to its having no effect on mice irradiated with 10 Gy of X-ray. The result suggested the possibility that alpha-GalCers protect mice from bone marrow death. To examine this possibility, we examined the effects of two kinds of alpha- and beta-GalCers on counts of platelets (PLT) and white blood cells (WBC) in the peripheral blood of normal mice and mice irradiated in a whole body with 5 Gy of X-ray. alpha-GalCers significantly increased the PLT and WBC counts of both mice in comparison with the vehicle-treated group, and their potencies were stronger than those of their beta-types. Furthermore, we evaluated the in vitro bone marrow cell-proliferation stimulatory activities of four kinds of GalCers, and found that alpha-GalCers show stronger stimulatory effects than beta-types. These results demonstrate that the alpha-configuration of GalCers plays an important role in the manifestation of the above-mentioned activities of GalCers. The results also suggest that alpha-GalCers may be useful as hematopoietic stimulators as well as radioprotective agents.

The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

PubMed

Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-07-15

The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

An Osteoblast-Derived Proteinase Controls Tumor Cell Survival via TGF-beta Activation in the Bone Microenvironment

PubMed Central

Thiolloy, Sophie; Edwards, James R.; Fingleton, Barbara; Rifkin, Daniel B.; Matrisian, Lynn M.; Lynch, Conor C.

2012-01-01

Background Breast to bone metastases frequently induce a “vicious cycle” in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. Methodology/Principal Findings To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (μCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). Conclusion/Significance Collectively, these studies identify a novel “mini-vicious cycle” between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFβ would be beneficial for the treatment of bone metastases. PMID:22238668

Development of processing techniques for advanced thermal protection materials

NASA Technical Reports Server (NTRS)

Selvaduray, Guna S.

1995-01-01

The main purpose of this work has been in the development and characterization of materials for high temperature applications. Thermal Protection Systems (TPS) are constantly being tested, and evaluated for increased thermal shock resistance, high temperature dimensional stability, and tolerance to environmental effects. Materials development was carried out through the use of many different instruments and methods, ranging from extensive elemental analysis to physical attributes testing. The six main focus areas include: (1) protective coatings for carbon/carbon composites; (2) TPS material characterization; (3) improved waterproofing for TPS; (4) modified ceramic insulation for bone implants; (5) improved durability ceramic insulation blankets; and (6) ultra-high temperature ceramics. This report describes the progress made in these research areas during this contract period.

Effect of fluoride and low versus high levels of dietary calcium on mRNA expression of osteoprotegerin and osteoprotegerin ligand in the bone of rats.

PubMed

Yu, Jun; Gao, Yanhui; Sun, Dianjun

2013-06-01

The ratio of osteoprotegerin ligand (OPGL) to osteoprotegerin (OPG) determines the delicate balance between bone resorption and synthesis. The main objective of the present study is to investigate the possible role of OPGL and OPG in the bone metabolism of rats exposed to fluoride and the protective or aggravating effect of calcium (Ca). In a 6-month study, 270 weanling male Sprague-Dawley rats weighing between 70 and 90 g were divided randomly into six groups of 45 rats in each group. Three groups (groups I, III, and V)served as controls and drank deionized water and were fed purified rodent diets containing either 1,000 mg Ca/kg (low Ca), 5,000 mg Ca/kg (normal Ca), or 20,000 mg Ca/kg (high Ca). The three experimental groups (groups II, IV, and VI) were given the same diets but they drank water containing 100 mg F ion/L (from NaF). Every 2 months 15 rats were randomly selected from each group and sacrificed for the study. The ratio of OPGL mRNA to OPG mRNA was significantly increased by the sixth month in the distal femur joints of the F-exposed rats. Serum tartrate-resistant acid phosphatase activity and serum calcitonin activity in the F-exposed groups was increased, although changes were not apparent in the serum alkaline phosphatase or Gla-containing proteins, especially in the low calcium and high calcium diet F-exposed groups. The results indicated that OPG and OPGL may play important roles in skeletal fluorosis, and that fluoride may enhance osteoclast formation and induce osteoclastic bone destruction. A high Ca diet did not play a protective role, but rather may aggravate the damage of fluoride.

DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component.

PubMed

Han, Xiaozhe; LaRosa, Karen B; Kawai, Toshihisa; Taubman, Martin A

2014-01-03

Porphyromonas gingivalis (Pg) is one of a constellation of oral organisms associated with human chronic periodontitis. While adaptive immunity to periodontal pathogen proteins has been investigated and is an important component of periodontal bone resorption, the effect of periodontal pathogen DNA in eliciting systemic and mucosal antibody and modulating immune responses has not been investigated. Rowett rats were locally injected with whole genomic Pg DNA in alum. Escherichia coli (Ec) genomic DNA, Fusobacterium nucleatum (Fn) genomic DNA, and saline/alum injected rats served as controls. After various time points, serum IgG and salivary IgA antibody to Ec, Fn or Pg were detected by ELISA. Serum and salivary antibody reactions with Pg surface antigens were determined by Western blot analyses and the specific antigen was identified by mass spectrometry. Effects of genomic DNA immunization on Pg bacterial colonization and experimental periodontal bone resorption were also evaluated. Sera from Pg DNA, Ec DNA and Fn DNA-injected rats did not react with Ec or Fn bacteria. Serum IgG antibody levels to Pg and Pg surface extracts were significantly higher in animals immunized with Pg DNA as compared to the control groups. Rats injected with Pg DNA demonstrated a strong serum IgG and salivary IgA antibody reaction solely to Pg fimbrillin (41kDa), the major protein component of Pg fimbriae. In the Pg DNA-immunized group, the numbers of Pg bacteria in oral cavity and the extent of periodontal bone resorption were significantly reduced after Pg infection. This study suggests that infected hosts may select specific genes from whole genomic DNA of the periodontal pathogen for transcription and presentation. The results indicate that the unique gene selected can initiate a host protective immune response to the parent bacterium. Copyright © 2013 Elsevier Ltd. All rights reserved.

Central and peripheral fat body mass have a protective effect on osteopenia or osteoporosis in adults and elderly?

PubMed

Freitas, P M S S; Garcia Rosa, M L; Gomes, A M; Wahrlich, V; Di Luca, D G; da Cruz Filho, R A; da Silva Correia, D M; Faria, C A; Yokoo, E M

2016-04-01

This cross-sectional study involves randomly selected men aged 50 to 99 years and postmenopausal women. Either central fat mass or peripheral fat mass were associated to osteoporosis or osteopenia independently from fat-free body mass and other confounding factors. Obesity and osteoporosis are public health problems that probably share common pathophysiological mechanisms. The question if body fat mass, central or peripheral, is protective or harmful for osteoporosis or osteopenia is not completely resolved. This study aims to investigate the association between osteoporosis or osteopenia, and fat body mass (central and peripheral) independently from fat-free body mass, in men aged 50 to 99 years old and postmenopausal women randomly selected in the community. This is a cross-sectional investigation with a random sample of registered population in Niterói Family Doctor Program (FDP), State of Rio de Janeiro, Brazil. Bone mineral density (BMD) and fat-free mass were assessed by dual X-ray absorptiometry (DXA). There was statistically significant bivariate association between bone loss with gender, age, skin color, alcohol consumption at risk dose, use of thiazide, fat-free body mass, and fat body mass (central and peripheral). In the multiple analysis of fat-free body mass, central and peripheral fat body mass showed an independent and protective effect on the presence of osteoporosis or osteopenia (p value <0.001). Since both obesity and osteoporosis are public health problems worldwide, strategies aimed at preventing both conditions should be encouraged during aging.

Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study.

PubMed

Prieto-Alhambra, Daniel; Servitja, Sonia; Javaid, M Kassim; Garrigós, Laia; Arden, Nigel K; Cooper, Cyrus; Albanell, Joan; Tusquets, Ignasi; Diez-Perez, Adolfo; Nogues, Xavier

2012-06-01

Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels ≥40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice.

PubMed

Adebayo, O O; Ko, F C; Wan, P T; Goldring, S R; Goldring, M B; Wright, T M; van der Meulen, M C H

2017-12-01

Animal models recapitulating post-traumatic osteoarthritis (OA) suggest that subchondral bone (SCB) properties and remodeling may play major roles in disease initiation and progression. Thus, we investigated the role of SCB properties and its effects on load-induced OA progression by applying a tibial loading model on two distinct mouse strains treated with alendronate (ALN). Cyclic compression was applied to the left tibia of 26-week-old male C57Bl/6 (B6, low bone mass) and FVB (high bone mass) mice. Mice were treated with ALN (26 μg/kg/day) or vehicle (VEH) for loading durations of 1, 2, or 6 weeks. Changes in articular cartilage and subchondral and epiphyseal cancellous bone were analyzed using histology and microcomputed tomography. FVB mice exhibited thicker cartilage, a thicker SCB plate, and higher epiphyseal cancellous bone mass and tissue mineral density than B6 mice. Loading induced cartilage pathology, osteophyte formation, and SCB changes; however, lower initial SCB mass and stiffness in B6 mice did not attenuate load-induced OA severity compared to FVB mice. By contrast, FVB mice exhibited less cartilage damage, and slower-growing and less mature osteophytes. In B6 mice, inhibiting bone remodeling via ALN treatment exacerbated cartilage pathology after 6 weeks of loading, while in FVB mice, inhibiting bone remodeling protected limbs from load-induced cartilage loss. Intrinsically lower SCB properties were not associated with attenuated load-induced cartilage loss. However, inhibiting bone remodeling produced differential patterns of OA pathology in animals with low compared to high SCB properties, indicating that these factors do influence load-induced OA progression. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Histone Deacetylases in Bone Development and Skeletal Disorders

PubMed Central

Bradley, Elizabeth W.; Carpio, Lomeli R.; van Wijnen, Andre J.; McGee-Lawrence, Meghan E.; Westendorf, Jennifer J.

2015-01-01

Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn2+ for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2+. Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering. PMID:26378079

Reduction of Dacarbazine cytogenetic effects on somatic cells in male mice using bee glue (Propolis) to manifest the scientific miracles in the Quran.

PubMed

Kurdi, Lina Abdul-Fattah; Aljeddani, Fatimah Aliyan

2016-09-01

This study was carried out to investigate the ability of Propolis to ameliorate the adverse cytogenetic effects of Dacarbazine on bone marrow cells. In this experimental in vivo study, 18 mice were used, divided into four groups: control group; Propolis-treated group (treated with 50mg/kg Propolis); and Dacarbazine-treated group (treated with 3.5mg/kg Dacarbazine). The fourth, fifth, and sixth were treated with Dacarbazine and Propolis as pre 2h, post 2h, and concomitant treatment. After five days, the Bone Marrow (BM) samples were obtained for cytogenetic investigation. The in vivo studies revealed that Dacarbazine induced an abnormalities in polychromatic erythrocytes cells (PECs) as increase of cell with micronuclei, while the dual treatment accompanied with improvement of this abnormalities. It could be concluded that there are protective effects of Propolis against the adverse effects of Dacarbazine. It could be recommended to use Propolis as an adjuvant with chemotherapeutic agents.

BMP-2-regenerated calvarial bone: a biomechanical appraisal in a large animal model.

PubMed

Cray, James; Henderson, Sarah E; Smith, Darren M; Kinsella, Christopher R; Bykowski, Michael; Cooper, Gregory M; Almarza, Alejandro J; Losee, Joseph E

2014-11-01

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is gaining popularity in craniofacial applications. Calvarial defects are, under normal circumstances, subjected to only minimal levels of the biomechanical stresses known to play an important role in osteogenesis, yet regenerated calvarial bone must be capable of withstanding traumatic forces such that the underlying neurocapsule is protected. The aim of this study is to, for the first time, assess the biomechanical properties of calvarial bone regenerated with derivations of a commercially available rhBMP-2-based system. Standardized calvarial defects were created in 23 adult male canines. These defects were treated with rhBMP-2 on one of several carriers. After 24 weeks, the biomechanical properties of the rhBMP-2-generated bone were compared to those of controls with a modified punch-out test (Bluehill 2; Instron, Norwood, Mass) and compared using a paired nonparametric analyses (SPSS, 17.0, Chicago, Ill). In a previously published report, defects across all the rhBMP-2 therapy groups were observed to have a mean rate of 99.5% radio-opacity at 24 weeks indicating nearly full bony coverage of the calvarial defect (compared to 32.7% in surgical controls). For ultimate load, ultimate energy, and first peak energy, there were significant differences (P<0.05) with the control native bone having more robust biomechanical properties than the rhBMP-2-generated bone. We conclude from these findings that rhBMP-2-generated calvarial bone is significantly less protective against trauma than native bone at 6 months. Further investigation is required to assess the efficacy of rhBMP-2 in healing calvarial defects in the longer term.

Proteoglycan 4: A Dynamic Regulator of Skeletogenesis and Parathyroid Hormone Skeletal Anabolism

PubMed Central

Novince, Chad M; Michalski, Megan N; Koh, Amy J; Sinder, Benjamin P; Entezami, Payam; Eber, Matthew R; Pettway, Glenda J; Rosol, Thomas J; Wronski, Thomas J; Kozloff, Ken M; McCauley, Laurie K

2014-01-01

Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure. PMID:21932346

Severely impaired bone material quality in Chihuahua zebrafish resembles classical dominant human osteogenesis imperfecta.

PubMed

Fiedler, Imke A K; Schmidt, Felix N; Wölfel, Eva M; Plumeyer, Christine; Milovanovic, Petar; Gioia, Roberta; Tonelli, Francesca; Bale, Hrishikesh A; Jähn, Katharina; Besio, Roberta; Forlino, Antonella; Busse, Björn

2018-04-17

Excessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Since the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how osteogenesis imperfecta manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/ +) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as suitable animal model of classical dominant OI, showing skeletal deformities, altered mineralization patterns and a smaller body size. This study assessed the bone quality properties of Chi/+ at multiple length scales using micro-computed tomography (micro-CT), histomorphometry, quantitative back-scattered electron imaging, Fourier transform infrared spectroscopy, nanoindentation and X-ray microscopy. At the skeletal level, Chi/+ display smaller body size, deformities and fracture calli in the ribs. Morphological changes at the whole bone level showed that the vertebrae in Chi/+ had a smaller size, smaller thickness and distorted shape. At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to WT. The alterations in the cellular, compositional and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties, which promote an increase in overall bone fragility in Chi/ +. The quantitative assessment of bone quality in Chi/+ thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant osteogenesis imperfecta. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair.

PubMed

Paiva, Katiucia B S; Granjeiro, José M

2017-01-01

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

Eyes, bones and teeth in the 16th century Statute law of Rijeka.

PubMed

Milovic, Dorde; Milovic Karic, Grozdana

2008-01-01

The 16th century statute law or the town of Rijeka treats the eye in two ways. First, it stipulates a severe punishment for deliberate "eye-plucking". Second, for those who commit this crime, it specifies "eye-plucking" as a corporeal punishment (following the eye-for-an-eye principle).The 1530 Statute of Rijeka also pays considerable attention to the bones. Bone breaking by means of intentional or unintentional blow was fined 25 libras (pounds) for the following bones: thighbone, forearm and hand bones, lower leg bone, and foot bone. A fine of 10 libras applied for all other intentional or unintentional bone breaking by a blow. Legal protection of teeth involved a fine of five libras for each of the teeth blown out, and half the fine for a broken tooth. Both fines applied whether the offence was done on purpose or not.

[Studies on chemical protectors against radiation. XXXII. Protective effects of methanol extracts of various Taiwan crude drugs on radiation injuries].

PubMed

Wang, C M; Ohta, S; Shinoda, M

1990-11-01

This study is to investigate radioprotective effects of 23 Taiwan crude drugs on X-ray induced bone marrow death and skin injury in mice. Each methanol extract of these Taiwan crude drugs was injected intraperitoneally into ICR male mice at 6 weeks of age before irradiation. Mice were whole-body irradiated with a soft X-ray generator. Radiation factors of the two screening tests used were as follows: 70 kVp, 10 mA, 10 mm acrylate filter, 70R/min, 2100R for survival test, and 30 kVp, 10 mA, 190R/min, 1100R for protective test on skin injury. As a result of these studies, the survival effect was recognized in Solani Incani Herba and Orthosiphi Aristati Herba. On the other hand, Mimosae Herba, Canarii Radix, Bombacis Radix, Arecae Fructus, Hedyotidis Diffusae Herba and Cynomorii Caulis were shown to have significant protective potency on skin injury.

Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy.

PubMed

Dufresne, Sébastien S; Boulanger-Piette, Antoine; Bossé, Sabrina; Argaw, Anteneh; Hamoudi, Dounia; Marcadet, Laetitia; Gamu, Daniel; Fajardo, Val A; Yagita, Hideo; Penninger, Josef M; Russell Tupling, A; Frenette, Jérôme

2018-04-24

Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANK mko ) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc represents an efficient alternative in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions.

Prevention of myelosuppression by combined treatment with enterosorbent and granulocyte colony-stimulating factor.

PubMed

Shevchuk, O O; Posokhova, К А; Todor, I N; Lukianova, N Yu; Nikolaev, V G; Chekhun, V F

2015-06-01

Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. Simultaneous administration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy.

Membrane estrogen receptor alpha is an important modulator of bone marrow C-Kit+ cells mediated cardiac repair after myocardial infarction

PubMed Central

Su, Feng; Zhang, Wentian; Liu, Jianfang

2015-01-01

It has been validated that c-kit positive (c-kit+) cells in infarcted myocardium are from bone marrow (BM). Given the recent study that in the heart, estrogen receptor alpha (ERα) is involved in adaptive mechanisms by supporting cardiomyocytes survival via post-infarct cardiac c-kit+ cells, we tested a novel hypothesis that membrane ERα (mERа) supports survival of BM c-kit+ cells and enhance protective paracrine function for cardiac repair. Our data showed that myocardial infarction (MI) leads to an increase in c-kit+ first in bone marrow and then specifically within the infarcted myocardium. Also up-regulated mERа in post-infarct BM c-kit+ cells was found in day 3 post MI. In vitro co-culture system, mERа+ enhances the beneficial effects of BM c-kit+ cells by increasing their viability and reducing apoptosis. Post-infarct c-kit+ mERа+ cells population expresses predominant ERα and holds self-renewal as well as cardiac differentiation potentials after MI. In vivo, BM c-kit+ cells reduced infarct size, fibrosis and improved cardiac function. In conclusion, BM c-kit+ mERа+ exerted significantly cardiac protection after MI. A potential important implication of this study is that the manipulation of BM c-kit+ stem cells with ERа-dependent fashion may be helpful in recovering functional performance after cardiac tissue injury. PMID:26191121

The relation between dietary protein, calcium and bone health in women: results from the EPIC-Potsdam cohort.

PubMed

Weikert, Cornelia; Walter, Dietmar; Hoffmann, Kurt; Kroke, Anja; Bergmann, Manuela M; Boeing, Heiner

2005-01-01

The role of dietary protein in bone health is controversial. The objective of the present study was to examine the association between protein intake, dietary calcium, and bone structure measured by broadband ultrasound attenuation (BUA). Our analysis includes 8,178 female study participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam Study. Ultrasound bone measurements were performed on the right os calcis, and BUA was determined. Dietary intake was assessed by a standardized food frequency questionnaire. We applied linear regression models to estimate the association between dietary protein and BUA. After multivariate adjustment, high intake of animal protein was associated with decreased BUA values (beta = -0.03; p = 0.010) whereas high vegetable protein intake was related to an increased BUA (beta = 0.11; p = 0.007). The effect of dietary animal protein on BUA was modified by calcium intake. High consumption of protein from animal origin may be unfavourable, whereas a higher vegetable protein intake may be beneficial for bone health. Our results strengthen the hypothesis that high calcium intake combined with adequate protein intake based on a high ratio of vegetable to animal protein may be protective against osteoporosis. Copyright (c) 2005 S. Karger AG, Basel.

Absence of genotoxic effects of the chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one) and its potential chemoprevention against DNA damage using in vitro and in vivo assays

PubMed Central

2017-01-01

The chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one), or 2HMC, displays antileishmanial, antimalarial, and antioxidant activities. The aim of this study was to investigate the cytotoxic, genotoxic, mutagenic, and protective effects of 2HMC using the Ames mutagenicity test, the mouse bone marrow micronucleus test, and the comet assay in mice. In the assessment using the Ames test, 2HMC did not increase the number of His+ revertants in Salmonella typhimurium strains, demonstrating lack of mutagenicity. 2HMC showed no significant increase in micronucleated polychromatic erythrocyte frequency (MNPCE) in the micronucleus test, or in DNA strand breaks using the comet assay, evidencing absence of genotoxicity. Regarding cytotoxicity, 2HMC exhibited moderate cytotoxicity in mouse bone marrow cells by micronucleus test. 2HMC showed antimutagenic action in co-administration with the positive controls, sodium azide (SA) and 4-nitroquinoline-1-oxide (4NQO), in the Ames test. Co-administered and mainly pre-administered with cyclophosphamide (CPA), 2HMC caused a decrease in the frequency of MNPCE using the micronucleus test and in DNA strand breaks using the comet assay. Thus, 2HMC exhibited antimutagenic and antigenotoxic effects, displaying a DNA-protective effect against CPA, SA, and 4NQO carcinogens. In conclusion, 2HMC presented antimutagenic, antigenotoxic and moderate cytotoxic effects; therefore it is a promising molecule for cancer prevention. PMID:28207781

Absence of genotoxic effects of the chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one) and its potential chemoprevention against DNA damage using in vitro and in vivo assays.

PubMed

Lima, Débora Cristina da Silva; Vale, Camila Regina do; Véras, Jefferson Hollanda; Bernardes, Aline; Pérez, Caridad Noda; Chen-Chen, Lee

2017-01-01

The chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one), or 2HMC, displays antileishmanial, antimalarial, and antioxidant activities. The aim of this study was to investigate the cytotoxic, genotoxic, mutagenic, and protective effects of 2HMC using the Ames mutagenicity test, the mouse bone marrow micronucleus test, and the comet assay in mice. In the assessment using the Ames test, 2HMC did not increase the number of His+ revertants in Salmonella typhimurium strains, demonstrating lack of mutagenicity. 2HMC showed no significant increase in micronucleated polychromatic erythrocyte frequency (MNPCE) in the micronucleus test, or in DNA strand breaks using the comet assay, evidencing absence of genotoxicity. Regarding cytotoxicity, 2HMC exhibited moderate cytotoxicity in mouse bone marrow cells by micronucleus test. 2HMC showed antimutagenic action in co-administration with the positive controls, sodium azide (SA) and 4-nitroquinoline-1-oxide (4NQO), in the Ames test. Co-administered and mainly pre-administered with cyclophosphamide (CPA), 2HMC caused a decrease in the frequency of MNPCE using the micronucleus test and in DNA strand breaks using the comet assay. Thus, 2HMC exhibited antimutagenic and antigenotoxic effects, displaying a DNA-protective effect against CPA, SA, and 4NQO carcinogens. In conclusion, 2HMC presented antimutagenic, antigenotoxic and moderate cytotoxic effects; therefore it is a promising molecule for cancer prevention.

In vivo osteoprotegerin gene therapy preventing bone loss induced by periodontitis.

PubMed

Tang, H; Mattheos, N; Yao, Y; Jia, Y; Ma, L; Gong, P

2015-08-01

The objective of this study was to investigate the effects of osteoprotegerin (OPG) gene therapy on alveolar bone resorption caused by experimental periodontitis in rats, thus forming a foundation for potential clinical applications of OPG gene therapy in the treatment of periodontitis and peri-implantitis. To study the effects of OPG on alveolar bone protection, an experimental periodontitis model was used by placing a bacterial plaque retentive silk ligature in the gingival sulcus around the maxillary second molar tooth, injection of Porphyromonas gingivalis and high carbohydrate diet. A total of 30 Sprague-Dawley rats were randomly divided into three groups, with 10 rats in each group: group I (control) was treated with 10 μL normal saline injection; group II with 10 μL mock vector; and group III with 10 μL local OPG gene transfer by transfection with in vitro constructed pcDNA3.1-human OPG (pcDNA3.1-hOPG). A subperiosteal injection was done adjacent to the second molars on days 0, 7, 14 and 21. Four weeks later, all animals were killed and radiographic, histological and immunohistochemical examinations were performed. Statistical analysis included ANOVA and LSD-Bonferroni test. Group III (OPG gene therapy) had significantly enhanced (p < 0.05) integrated optical density of OPG, had significantly decreased alveolar bone resorption volume and active osteoclast number (p < 0.05) through descriptive histological examination when compared with the other two groups at week 4. Local recombinant OPG plasmid-mediated gene therapy suppresses osteoclastogenesis in vivo and inhibits alveolar bone height reduction caused by experimental periodontitis in rats. OPG gene therapy may be beneficial in preventing progressive periodontal bone loss. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.

PubMed

Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J

2012-06-01

Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.

Anticancer Efficacy of Apo2L/TRAIL Is Retained in the Presence of High and Biologically Active Concentrations of Osteoprotegerin In Vivo

PubMed Central

Zinonos, Irene; Labrinidis, Agatha; Lee, Michelle; Liapis, Vasilios; Hay, Shelley; Ponomarev, Vladimir; Diamond, Peter; Findlay, David M; Zannettino, Andrew CW; Evdokiou, Andreas

2017-01-01

Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor (TNF) receptor superfamily that binds to the ligand for receptor activator of nuclear factor κB (RANKL) and inhibits bone resorption. OPG can also bind and inhibit the activity of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL), raising the possibility that the anticancer efficacy of soluble Apo2L/TRAIL may be abrogated in the bone microenvironment where OPG expression is high. In this study we used a murine model of breast cancer growth in bone to evaluate the efficacy of recombinant soluble Apo2L/TRAIL against intratibial tumors that were engineered to overexpress native full-length human OPG. In vitro, OPG-overexpressing breast cancer cells were protected from Apo2L/TRAIL-induced apoptosis, an effect that was reversed with the addition of soluble RANKL or neutralizing antibodies to OPG. In vivo, mice injected intratibially with cells containing the empty vector developed large osteolytic lesions. In contrast, OPG overexpression preserved the integrity of bone and prevented breast cancer–induced bone destruction. This effect was due primarily to the complete absence of osteoclasts in the tibias of mice inoculated with OPG-transfected cells, confirming the biologic activity of the transfected OPG in vivo. Despite the secretion of supraphysiologic levels of OPG, treatment with Apo2L/TRAIL resulted in strong growth inhibition of both empty vector and OPG-overexpressing intratibial tumors. While Apo2L/TRAIL-induced apoptosis may be abrogated in vitro by OPG overexpression, the in vivo anticancer efficacy of recombinant soluble Apo2L/TRAIL is retained in the bone microenvironment even in the presence of biologically active OPG at supraphysiologic concentrations. PMID:20818644

Glucocorticoid Signaling and Bone Biology.

PubMed

Komori, T

2016-11-01

Since glucocorticoids remain an effective therapeutic option for the treatment of many inflammatory and autoimmune diseases, glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Fractures may occur in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Under physiological conditions, glucocorticoids are required for normal bone development due to their regulation of osteoblast differentiation, possibly via the Wnt/β-catenin pathway and TSC22D3. However, serum levels of endogenous corticosterone are elevated in aged mice and glucocorticoids exert negative effects on the survival of osteoblasts and osteocytes as well as angiogenesis. Glucocorticoid treatments impair bone formation and enhance bone resorption. Excess glucocorticoids induce osteoblast and osteocyte apoptosis by increasing pro-apoptotic molecules, reactive oxygen species, and endoplasmic reticulum stress and suppressing the Wnt/β-catenin pathway. Autophagy protects osteocytes from glucocorticoid-induced apoptosis, but passed some threshold, the process of autophagy leads the cells to apoptosis. Excess glucocorticoids impair osteoblastogenesis by inducing Wnt antagonists, including Dkk1, Sost, and sFRP-1. However, the findings are controversial and the involvement of Wnt antagonists requires further study. Excess glucocorticoids reduce the phosphorylation of Akt and GSK3β, which enhances the degradation of β-catenin. Excess glucocorticoids have been shown to modulate the expression of miRNAs, including miR-29a, miR-34a-5p, and miR-199a-5p, which regulate the proliferation and differentiation of osteoblast lineage cells. Excess glucocorticoids also enhance bone resorption by reducing OPG expression, increasing Rankl expression and reactive oxygen species, and prolonging the life span of osteoclasts; however, they also suppress the bone-degrading capacity of osteoclasts by disturbing the organization of the cytoskeleton. © Georg Thieme Verlag KG Stuttgart · New York.

Osteoporosis and obesity: Role of Wnt pathway in human and murine models.

PubMed

Colaianni, Graziana; Brunetti, Giacomina; Faienza, Maria Felicia; Colucci, Silvia; Grano, Maria

2014-07-18

Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research. Although the onset of these two diseases can occur in a different way, recent studies have shown that obesity and osteoporosis share common genetic and environmental factors. Despite being a risk factor for health, obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading, exerted by high body mass, on bone formation. However, contrasting studies have not achieved a clear consensus, suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or, even worse, could be rather detrimental to bone. On the other hand, it is hitherto better established that, since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor, molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa. Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation, which are peroxisome proliferators activated receptor-γ and Wnts, respectively. In particular, we will focus on the role of both canonical and non-canonical Wnt signalling, involved in mesenchymal cell fate regulation. Moreover, at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis, although it is well known its role on bone metabolism. In addition, the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause. Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity, we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.

Intra-oral soft tissue expansion and volume stability of onlay bone grafts.

PubMed

Abrahamsson, Peter

2011-01-01

Insufficient regeneration of missing bone and soft-tissue may present aesthetic or functional problems in patients indicated for dental implant surgery. Several techniques such as bone grafts, bone substitutes and guided tissue regeneration (GTR) have been described to rebuild a compromised alveolar ridge. Adequate soft-tissue coverage of grafted bone and titanium-mesh is important to avoid exposure which may result in loss of the bone graft. The general aim of this thesis was to evaluate use of an osmotic tissue expander for expanding intra-oral soft tissue--creating a surplus of soft tissue-- in preparation for onlay bone grafting. An experimental rabbit model was used in studies (I), (II) and (III). In (I) an osmotic soft-tissue expander was placed bilaterally on the lateral wall of the mandible via an extra-oral approach. After two weeks of expansion the rabbits were killed and specimens were collected for histology. No inflammatory reaction and no resorbtion of the cortical bone occured. The periosteum was expanded and new bone formation was seen in the edges of the expander. In (II) and (III) the expander was placed under the periosteum in the same way as in (I): bilaterally in 13 rabbits in (II) and unilaterally in 11 rabbits in (III). After two weeks of expansion the expander was identified and removed. In (II) particulated bone was placed at the recipient site protected by a titanium mesh in one site and a bio-resorbable mesh on the other site. In (III), DBBM particles and bone particles collected from the lateral border of the mandible separated by a collagen membrane was placed at the recipient site. The graft was protected by a pre-bent titanium mesh covered by a collagen membrane. After a healing period of 3 months specimens were collected for histological and SEM examination. New bone was growing in direct contact with the titanium mesh and bio resorbable mesh. The newly formed bone had the same calcium content as the mature bone in the base of the mandible. In the clinical study (IV) 20 patients were consecutively recruited and randomised into two groups. The experimental group (ten patients) had an osmotic soft tissue expander implanted. After two weeks of expansion the expander was removed and a particulated bone graft protected by a titanium mesh and a collagen membrane was fixed to the recipient site. Titanium implants were installed after a healing period of 6 months. The patients in the reference group had a bone block grafted from the anterior ramus fixated to the recipient site with one or two titanium mini screws. Implants were installed after a healing period of 6 months. A three dimensional optical measuring device was used to measure alterations in the soft tissue profile before each surgical procedure. The three-dimensional changes were then analysed on a PC. The results from the clinical study in patients confirmed the results from the experimental rabbit studies. The osmotic tissue expander expanded the soft tissue. Expander perforations of the soft tissue occurred in two patients. The optical measurements demonstrated a positive volume gain after soft tissue expansion and bone grafting. The expanded tissue could be used to cover a bone graft. There still was a risk of mesh exposure, even after soft tissue expansion, which occurred in two patients. In both groups, implants could be installed in the grafted bone in positions that would allow the crowns to fit aesthetically into the dental arch.

Experimental-clinical validation of the use of amitetravit, ATP and autologous bone marrow in radiation injuries caused by prolonged radiation

NASA Technical Reports Server (NTRS)

Atamanova, O. M.; Vodyakova, L. M.; Gvozdeva, N. I.; Davydova, S. A.; Ignasheva, L. P.; Rogozkin, V. D.; Sbitneva, M. F.; Ostroumova, L. M.; Tikhomirova, M. V.; Fedotenkov, A. G.

1974-01-01

Experimental clinical studies show that early pathogenetic treatment against the effects of prolonged radiation includes amitetravit as a means of increasing natural radio resistance, ATP as protective therapeutic agent, and automyelotransplantation for early pathogenetic treatment. The high effectiveness of the combined use of ATP and amitetravit in tests on dogs indicates an ability to prevent primary damages to genetic structures and accelerated processes of reparation in the first stages of radiopathological processes.

Role of Semen on Vaginal HIV-1 Transmission and Maraviroc Protection

PubMed Central

Council, Olivia D.; Swanson, Michael D.; Spagnuolo, Rae Ann

2015-01-01

We used bone marrow/liver/thymus (BLT) humanized mice to establish the effect of semen on vaginal HIV infection and on the efficacy of topically applied maraviroc. Our results demonstrate that vaginal transmission of cell-free HIV occurs efficiently in the presence of semen and that topically applied maraviroc efficiently prevents HIV transmission in the presence of semen. We also show that semen has no significant effect on the transmission of transmitted/founder viruses or cell-associated viruses. PMID:26392489

Glabridin and glycyrrhizic acid show no beneficial effect on the chemical composition and mechanical properties of bones in ovariectomized rats, when administered in moderate dose.

PubMed

Kaczmarczyk-Sedlak, Ilona; Klasik-Ciszewska, Sylwia; Wojnar, Weronika

2016-10-01

One of the major causes of osteoporosis and bone fracture in postmenopausal women is estrogen deficiency. To prevent the fractures, and avoid the side effects of hormone replacement therapy, phytoestrogens including the isoflavonoids are used. In the presented study two constituents occurring in the licorice root-the isoflavane glabridin and triterpenoid saponin glycyrrhizic acid were examined on the skeletal system of ovariectomized rats. The female Wistar rats were divided into five groups: control group, ovariectomized group as well as three ovariectomized groups treated with estradiol (0.2mg/kg), glabridin (5mg/kg) or glycyrrhizic acid (15mg/kg). All substances were administered orally for 4 weeks. The estradiol served as a positive control. The mechanical properties of femoral diaphysis, tibial metaphysis and femoral neck were assessed using bending and compression tests. Moreover the chemical composition of the femur, tibia and L-4 vertebra - content of water, organic substances and minerals - was determined. Ovariectomy induced unfavorable changes in the skeletal system of the rats. Administration of glabridin and glycyrrhizic acid to the ovariectomized rats did not improve analyzed parameters of the bones. Obtained results indicate, that the tested substances revealed no beneficial effect on the mechanical properties and chemical composition of the tested bones, thus they cannot be used as the osteoporosis protective agents. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Protective effects of Tualang honey on bone structure in experimental postmenopausal rats

PubMed Central

Zaid, Siti Sarah Mohamad; Sulaiman, Siti Amrah; Othman, Nor Hayati; Soelaiman, Ima-Nirwana; Shuid, Ahmad Nazrun; Mohamad, Norazlina; Muhamad, Norliza

2012-01-01

OBJECTIVE: The objective of this study was to evaluate the effects of Tualang honey on trabecular structure and compare these effects with those of calcium supplementation in ovariectomized rats. METHODS: Forty female, Sprague-Dawley rats were randomly divided into five groups (n = 8): four controls and one test arm. The control arm comprised a baseline control, sham-operated control, ovariectomized control, and ovariectomized calcium-treated rats (receiving 1% calcium in drinking water ad libitum). The test arm was composed of ovariectomized, Tualang honey-treated rats (received 0.2 g/kg body weight of Tualang honey). Both the sham-operated control and ovariectomized control groups received vehicle treatment (deionized water), and the baseline control group was sacrificed without treatment. RESULTS: All rats were orally gavaged daily for six weeks after day one post-surgery. The bone structural analysis of rats in the test arm group showed a significant increase in the bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) and a significant decrease in inter-trabecular space (Tb.Sp) compared with the ovariectomized control group. The trabecular thickness (Tb.Th) in the test arm group was significantly higher compared with the ovariectomized-calcium treated group, and the inter-trabecular space (Tb.Sp) in the test arm group was significantly narrower compared with the ovariectomized-calcium treated group. CONCLUSION: In conclusion, ovariectomized rats that received Tualang honey showed more improvements in trabecular bone structure than the rats that received calcium. PMID:22892923

Protective effects of Tualang honey on bone structure in experimental postmenopausal rats.

PubMed

Zaid, Siti Sarah Mohamad; Sulaiman, Siti Amrah; Othman, Nor Hayati; Soelaiman, Ima-Nirwana; Shuid, Ahmad Nazrun; Mohamad, Norazlina; Muhamad, Norliza

2012-07-01

The objective of this study was to evaluate the effects of Tualang honey on trabecular structure and compare these effects with those of calcium supplementation in ovariectomized rats. Forty female, Sprague-Dawley rats were randomly divided into five groups (n =8): four controls and one test arm. The control arm comprised a baseline control, sham-operated control, ovariectomized control, and ovariectomized calcium-treated rats (receiving 1% calcium in drinking water ad libitum). The test arm was composed of ovariectomized, Tualang honey-treated rats (received 0.2 g/kg body weight of Tualang honey). Both the sham-operated control and ovariectomized control groups received vehicle treatment (deionized water), and the baseline control group was sacrificed without treatment. All rats were orally gavaged daily for six weeks after day one post-surgery. The bone structural analysis of rats in the test arm group showed a significant increase in the bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) and a significant decrease in inter-trabecular space (Tb.Sp) compared with the ovariectomized control group. The trabecular thickness (Tb.Th) in the test arm group was significantly higher compared with the ovariectomized-calcium treated group, and the inter-trabecular space (Tb.Sp) in the test arm group was significantly narrower compared with the ovariectomized-calcium treated group. In conclusion, ovariectomized rats that received Tualang honey showed more improvements in trabecular bone structure than the rats that received calcium.

L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC).

PubMed

Abd-Allah, Adel R A; Al-Majed, Abdulhakeem A; Al-Yahya, Abdulaziz A; Fouda, Soliman I; Al-Shabana, Othman A

2005-07-01

Carboplatin (CP), a second generation platinum compound, is effective against various types of cancers, producing less nephrotoxicity and ototoxicity but more myelotoxicity than cisplatinum. CP-myelosuppression is the rate-limiting step of its clinical use. Prevention of CP-myelosuppression is a major target in the field of chemotherapy. Therefore, the present study investigates the use of L-carnitine (LCR)-an antioxidant, cardioprotective, neuroprotective, and immunostimulant nontoxic natural compound-to protect against CP-induced myelosuppression. The viability of BMC was studied using a trypan blue exclusion technique following incubation with CP and/or LCR as a function of time and concentration. Apoptosis was tested for by detecting the amount of DNA fragmentation and the visualization of DNA ladders upon gel electrophoresis. Bone marrow progenitor cell function was examined by colony forming unit assay. Cellular contents of glutathione (GSH) and malondialdehyde (MDA) were also estimated. Results revealed that LC50 of CP is 4.7 mM and the highest safe concentration of LCR is 5 mM. Co-exposure of LCR+CP rescued BMC viability by 37% compared to the CP-treated cultures. The LCR halts CP-induced apoptosis and it significantly improves the function of the bone marrow progenitors by increasing the number of colony-forming units as a response to granulocyte/macrophage colony stimulating factors. Finally, LCR restores CP-induced GSH depletion and prevents MDA elevation in BMC. In summary, the results suggest that LCR is able to protect against CP-induced myelosuppression, which suggests its use as an adjuvant therapy. This finding merits further investigation into the mechanism(s) of such protection as well as its interaction with CP antitumor activity.

Bone resorption and remodeling in murine collagenase-induced osteoarthritis after administration of glucosamine

PubMed Central

2011-01-01

Introduction Glucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage. Glucosamine has been clinically introduced for the treatment of osteoarthritis but the data about its protective role in disease are insufficient. The goal of this study was to investigate the effect of long term administration of glucosamine on bone resorption and remodeling. Methods The effect of glucosamine on bone resorption and remodeling was studied in a model of collagenase-induced osteoarthritis (CIOA). The levels of macrophage-inflammatory protein (MIP)-1α, protein regulated upon activation, normal T-cell expressed, and secreted (RANTES), soluble receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, 4 and 10 in synovial fluid were measured by enzyme-linked immunosorbent assay (ELISA). Cell populations in synovial extracts and the expression of RANKL, of receptors for TNF-α (TNF-αR) and interferon γ (IFN-γR) on clusters of differentiation (CD) three positive T cells were analyzed by flow cytometry. Transforming growth factor (TGF)-β3, bone morphogenetic protein (BMP)-2, phosphorylated protein mothers against decapentaplegic homolog 2 (pSMAD-2), RANKL and Dickkopf-1 protein (DKK-1) positive staining in CIOA joints were determined by immunohistochemistry. Results The administration of glucosamine hydrochloride in CIOA mice inhibited loss of glycosaminoglycans (GAGs) and proteoglycans (PGs) in cartilage, bone erosion and osteophyte formation. It decreased the levels of soluble RANKL and IL-6 and induced IL-10 increase in the CIOA joint fluids. Glucosamine limited the number of CD11b positive Ly6G neutrophils and RANKL positive CD3 T cells in the joint extracts. It suppressed bone resorption via down-regulation of RANKL expression and affected bone remodeling in CIOA by decreasing BMP-2, TGF-β3 and pSMAD-2 expression and up-regulating DKK-1 joint levels. Conclusions Our data suggest that glucosamine hydrochloride inhibits bone resorption through down-regulation of RANKL expression in the joints, via reduction of the number of RANKL positive CD3 T cells and the level of sRANKL in the joints extracts. These effects of glucosamine appear to be critical for the progression of CIOA and result in limited bone remodeling of the joints. PMID:21410959

Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation.

PubMed

Chavolla-Calderón, Mara; Bayer, Meggan K; Fontán, J Julio Pérez

2003-04-01

Neurogenic inflammation is believed to originate with the antidromic release of substance P, and of other neurokinins encoded by the preprotachykinin A (PPT-A) gene, from unmyelinated nerve fibers (C-fibers) following noxious stimuli. Consistent with this concept, we show here that selective sensory-fiber denervation with capsaicin and targeted deletion of the PPT-A gene protect murine lungs against both immune complex-mediated and stretch-mediated injuries. Reconstitution of PPT-A gene-deleted mice with WT bone marrow does not abrogate this protection, demonstrating a critical role for PPT-A gene expression by sensory neurons in pulmonary inflammation. Surprisingly, reconstitution of WT mice with PPT-A gene-deficient bone marrow also confers protection against pulmonary injury, revealing that PPT-A gene expression in hemopoietic cells has a previously unanticipated essential role in tissue injury. Taken together, these findings demonstrate a critical synergy between capsaicin-sensitive sensory fibers and hemopoietic cells in neurokinin-mediated inflammation and suggest that such synergy may be the basis for a stereotypical mechanism of response to injury in the respiratory tract.

Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation

PubMed Central

Chavolla-Calderón, Mara; Bayer, Meggan K.; Fontán, J. Julio Pérez

2003-01-01

Neurogenic inflammation is believed to originate with the antidromic release of substance P, and of other neurokinins encoded by the preprotachykinin A (PPT-A) gene, from unmyelinated nerve fibers (C-fibers) following noxious stimuli. Consistent with this concept, we show here that selective sensory-fiber denervation with capsaicin and targeted deletion of the PPT-A gene protect murine lungs against both immune complex–mediated and stretch-mediated injuries. Reconstitution of PPT-A gene–deleted mice with WT bone marrow does not abrogate this protection, demonstrating a critical role for PPT-A gene expression by sensory neurons in pulmonary inflammation. Surprisingly, reconstitution of WT mice with PPT-A gene–deficient bone marrow also confers protection against pulmonary injury, revealing that PPT-A gene expression in hemopoietic cells has a previously unanticipated essential role in tissue injury. Taken together, these findings demonstrate a critical synergy between capsaicin-sensitive sensory fibers and hemopoietic cells in neurokinin-mediated inflammation and suggest that such synergy may be the basis for a stereotypical mechanism of response to injury in the respiratory tract. PMID:12671046

Fluoride effects: the two faces of janus.

PubMed

Gazzano, E; Bergandi, L; Riganti, C; Aldieri, E; Doublier, S; Costamagna, C; Bosia, A; Ghigo, D

2010-01-01

The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.

Roles of Zinc and Iron on Bone Health in a Rat Model of Osteoporosis

NASA Astrophysics Data System (ADS)

Yan, Danhua

Bone is one of the most vital organs in animals, serving as both structural and protective functions. Remodeling of bone is an important indicator of bone health, and disorders in bone remodeling may lead to bone diseases such as osteoporosis. Osteoporosis increases risk of bone fracture and even death, and much more preferable to be happened in postmenopausal women due to great changes in hormones. Micronutrients, such as Zinc (Zn) and Iron (Fe), would as well influence bone health in different manners. That Zn would promote bone health is widely accepted, for the reasons Zn increases osteoblast cell proliferation and differentiation, inhibits osteoclast cell activities, and forms alkaline phosphatase that does help to maintain bone metabolism. Diseases caused by Fe overload is usually related to osteoporosis. Ferric ion could facilitate osteoclast differentiation, inhibit osteoblast and alkaline phosphatase activities, and interfere with hydroxyapatite crystal growth and depositions. However, changes of concentrations and distributions for Zn and Fe in osteoporotic bones are seldom studied. In this thesis, ovariectomized rat femur bones are used as a model of postmenopausal osteoporosis. Rats from different ages and health conditions are categorized as 6 AM (6-month age matched control), 6 OVX (6-month ovariectomized control), 12 AM (12-month age matched control), 12 OVX (12-month ovariectomized control). The trace elements Zn and Fe is studied through Synchrotron Radiation X-Ray Fluorescence (SRXRF). Elemental maps are used to observe changes in distribution, and further quantitative analysis is used to discover changes in concentration among different animal groups. Both the decrease of Zn and the increase of Fe are significant from healthy to osteoporotic bones (p<0.05). In the meanwhile, accumulation of Zn (p<0.05) and Fe (p>0.1) is also observed over age in healthy groups. Both elements show changes in distribution, that healthy animals present a more even distribution while in OVX groups the tendency of aggregation is observed. These results agree with most of the predictions and add evidence for effects of Zn and Fe on bone health. Hypothesis is further made to rationalize the changing trend observed and explain mechanisms behind.

[Guided bone regeneration: general survey].

PubMed

Cosyn, Jan; De Bruyn, Hugo

2009-01-01

The principle of 'guided bone regeneration' was first described in 1988 on the basis of animal-experimental data. Six weeks after transmandibular defects had been created and protected by non-resorbable teflonmembranes, complete bone regeneration was found. The technique was based on the selective repopulation of the wound: every infiltration of cells outside the neighbouring bone tissue was prevented by the application of the membrane. Additional animal experiments showed that guided bone regeneration was a viable treatment option for local bone defects surrounding dental implants. Clinical practice, however, showed that premature membrane exposure was a common complication, which was responsible for a tremendous reduction in regenerated bone volume. In addition, a second surgical intervention was always necessary to remove the membrane. As a result, resorbable alternatives were developed. Since these are less rigid, bone fillers are usually used simultaneously. These comprise autogenous bone chips and bone substitutes from allogenic or xenogenic origine. Also alloplastic materials could be used for this purpose. Based on their characteristics this article provides an overview of the biomaterials that could be considered for guided bone regeneration. Specific attention goes to their application in clinical practice.

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight.

PubMed

Morey-Holton, E R; Globus, R K

1998-05-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight

NASA Technical Reports Server (NTRS)

Morey-Holton, E. R.; Globus, R. K.

1998-01-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Serum 25-hydroxyvitamin D and bone turnover markers in Palestinian postmenopausal osteoporosis and normal women.

PubMed

Kharroubi, Akram; Saba, Elias; Smoom, Riham; Bader, Khaldoun; Darwish, Hisham

2017-12-01

This study evaluated the association of vitamin D and bone markers with the development osteoporosis in Palestinian postmenopausal women. Even though vitamin D deficiency was very high for the recruited subjects, it was not associated with osteoporosis except for bones of the hip. Age and obesity were the strongest determining factors of the disease. The purpose of this study was to investigate the association of bone mineral density (BMD) with serum vitamin D levels, parathyroid hormone (PTH), calcium, obesity, and bone turnover markers in Palestinian postmenopausal women. Three hundred eighty-two postmenopausal women (≥45 years) were recruited from various women clinics for BMD assessment (131 women had osteoporosis and 251 were normal and served as controls). Blood samples were obtained for serum calcium, PTH, 25(OH)D, bone formation (N-terminal propeptide (PINP)), and bone resorption (serum C-terminal telopeptide of type I collagen (CTX1)) markers. Women with osteoporosis had statistically significant lower mean weight, height, body mass index (BMI), and serum calcium (p < 0.05) compared to controls. No significant differences were detected between the mean values of bone turnover markers (CTX and PINP), 25(OH)D, and PTH of the two groups. Women with vitamin D deficiency (severe and insufficiency) represented 85.9% of the study subjects. Multiple and logistic regression showed that age and BMI significantly affected BMD and vitamin D had a significant association with BMD only at the lumbar spine. BMI was positively correlated with BMD and PTH but negatively correlated with vitamin D. Logistic regression showed that the odds ratio (OR) for having osteoporosis decreased with increasing BMI (overweight OR = 0.11, p = 0.053; obese OR = 0.05, p = 0.007). There was no direct correlation between BMD and PTH, bone turnover markers, and vitamin D except at the lumbar spine. A negative correlation between BMD and age and a positive correlation with BMI were observed. The protective effect of obesity on osteoporosis was complicated by the effect of obesity on vitamin D and PTH.

Bone: from a reservoir of minerals to a regulator of energy metabolism

PubMed Central

Confavreux, Cyrille B

2011-01-01

Besides locomotion, organ protection, and calcium–phosphorus homeostasis, the three classical functions of the skeleton, bone remodeling affects energy metabolism through uncarboxylated osteocalcin, a recently discovered hormone secreted by osteoblasts. This review traces how energy metabolism affects osteoblasts through the central control of bone mass involving leptin, serotoninergic neurons, the hypothalamus, and the sympathetic nervous system. Next, the role of osteocalcin (insulin secretion, insulin sensitivity, and pancreas β-cell proliferation) in the regulation of energy metabolism is described. Then, the connections between insulin signaling on osteoblasts and the release of uncarboxylated osteocalcin during osteoclast bone resorption through osteoprotegerin are reported. Finally, the understanding of this new bone endocrinology will provide some insights into bone, kidney, and energy metabolism in patients with chronic kidney disease. PMID:21346725

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

PubMed

Hartwell, Kimberly A; Miller, Peter G; Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2013-12-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

Polydatin induces bone marrow stromal cells migration by activation of ERK1/2.

PubMed

Chen, ZhenQiu; Wei, QiuShi; Hong, GuoJu; Chen, Da; Liang, Jiang; He, Wei; Chen, Mei Hui

2016-08-01

Bone marrow stromal cells (BMSCs) have proven to be useful for the treatment of numerous human diseases. However, the reparative ability of BMSCs is limited by their poor migration. Polydatin, widely used in traditional Chinese remedies, has proven to exert protective effects to BMSCs. However, little is known about its role in BMSCs migration. In this study, we studied the effects of polydatin on rat BMSCs migration using the scratch wound healing and transwell migration assays. Our results showed polydatin could promote BMSCs migration. Further experiments showed activation of ERK 1/2, but not JNK, was required for polydatin-induced BMSCs migration, suggesting that polydatin may promote BMSCs migration via the ERK 1/2 signaling pathways. Taken together, our results indicate that polydatin might be beneficial for stem cell replacement therapy by improving BMSCs migration. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

PubMed Central

Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2014-01-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone-marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on-target, via inhibition of HMGCoA reductase. These results illustrate the power of merging physiologically-relevant models with high-throughput screening. PMID:24161946

Melatonin prevents radiation-induced oxidative stress and periodontal tissue breakdown in irradiated rats with experimental periodontitis.

PubMed

Köse, O; Arabaci, T; Kizildag, A; Erdemci, B; Özkal Eminoğlu, D; Gedikli, S; Özkanlar, S; Zihni, M; Albayrak, M; Kara, A; Kermen, E

2017-06-01

The aim of this study was to analyze the biochemical and histochemical effects of radiation therapy and protective melatonin administration on periodontal tissues in rats with experimental periodontitis. Sixty male Sprague Dawley rats were divided into six groups, as follows: control; experimental periodontitis (Ped); radiotherapy administration (Rt); experimental periodontitis and exposure to irradiation (Ped-Rt); radiotherapy and protective melatonin administration (Rt-Mel); and periodontitis, radiation therapy and protective melatonin administration (Ped-Rt-Mel). The rats were killed at the end of the experimental procedure, and the oxidative stress level and periodontal destruction were compared among the groups. The oxidative stress index and the levels of 8-hydroxy-2'-deoxyguanosine, malondialdehyde and C-terminal telopeptide of type I collagen were found to be significantly higher in the Ped-Rt group compared with the Ped group (p < 0.05), and the levels were lower in the Ped-Rt-Mel group than in the Ped-Rt group (p < 0.05). Alveolar bone destruction and attachment level were also significantly lower in the Ped-Rt-Mel group than in the Ped-Rt group (p < 0.05). It was found that radiotherapy increased oxidative stress, the periodontal attachment level and alveolar bone loss, and protective melatonin administration significantly reduced the oxidative parameters and prevented periodontal damage in irradiated rats with experimental periodontitis. Further research is needed regarding the use of systemic melatonin administration before radiation therapy. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Histological Observation of the Retinacula of Weitbrecht and Its Clinical Significance: A cadaveric study.

PubMed

Dou, Bang; Mei, Jiong; Wang, Zhiyuan; Ni, Ming; Jia, Guangyao; Liu, Shiwei

2018-01-01

The retinacular arteries provide major supply to the femoral head, their injuries may lead to the femoral head necrosis (FHN) in femoral neck fractures. Although the femoral neck fracture was seriously displaced in some patients, FHN did not occur, which suggests that the blood supply is not fully blocked. This study was aimed to find the association between the structure of the retinacula of Weitbrecht and the mechanism of protecting retinacular arteries from being injured. Fourteen formalin-fixed cadaveric specimens (in 28 hips) with no significant vascular disease were observed. The retinacula were cut longitudinally and then cut into three parts: medial, middle, and lateral. These specimens were stained using hematoxylin and eosin and improved Masson Trichrome stain. The microstructure and tightness of the retinacula fixed to the bone and the distribution of vessels were examined under a stereoscope, an optical microscope, and a scanning electron microscope. The microstructure and compactness in each part of retinacula were different, and the tightness of the fibers of the retinacula fixed to the bone in each part were different. A particular structure which resembled a Sandwich panels was observed, and it may be an effective mechanism of protecting retinacular arteries. The Sandwich panels structure existed generally in the retinacula of Weitbrecht, and this sandwich panelture may play very important role in protecting the retinaculum artery from being injured, which show the importance of protecting the retinacular artery in the treatment of femoral neck fractures.

Surface modification of biodegradable porous Mg bone scaffold using polycaprolactone/bioactive glass composite.

PubMed

Yazdimamaghani, Mostafa; Razavi, Mehdi; Vashaee, Daryoosh; Tayebi, Lobat

2015-04-01

A reduction in the degradation rate of magnesium (Mg) and its alloys is in high demand to enable these materials to be used in orthopedic applications. For this purpose, in this paper, a biocompatible polymeric layer reinforced with a bioactive ceramic made of polycaprolactone (PCL) and bioactive glass (BG) was applied on the surface of Mg scaffolds using dip-coating technique under low vacuum. The results indicated that the PCL-BG coated Mg scaffolds exhibited noticeably enhanced bioactivity compared to the uncoated scaffold. Moreover, the mechanical integrity of the Mg scaffolds was improved using the PCL-BG coating on the surface. The stable barrier property of the coatings effectively delayed the degradation activity of Mg scaffold substrates. Moreover, the coatings induced the formation of apatite layer on their surface after immersion in the SBF, which can enhance the biological bone in-growth and block the microcracks and pore channels in the coatings, thus prolonging their protective effect. Furthermore, it was shown that a three times increase in the concentration of PCL-BG noticeably improved the characteristics of scaffolds including their degradation resistance and mechanical stability. Since bioactivity, degradation resistance and mechanical integrity of a bone substitute are the key factors for repairing and healing fractured bones, we suggest that PCL-BG is a suitable coating material for surface modification of Mg scaffolds. Published by Elsevier B.V.

α7 Nicotinic Acetylcholine Receptor (α7nAChR) Expression in Bone Marrow–Derived Non–T Cells Is Required for the Inflammatory Reflex

PubMed Central

Olofsson, Peder S; Katz, David A; Rosas-Ballina, Mauricio; Levine, Yaakov A; Ochani, Mahendar; Valdés-Ferrer, Sergio I; Pavlov, Valentin A; Tracey, Kevin J; Chavan, Sangeeta S

2012-01-01

The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the α7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of α7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and α7nAChR-deficient mice. Deficiency of α7nAChR in bone marrow–derived cells significantly impaired vagus nerve–mediated regulation of tumor necrosis factor (TNF), whereas α7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell α7nAChR, we adoptively transferred α7nAChR-deficient or WT T cells to nude mice. Transfer of WT and α7nAChR-deficient T cells restored function, indicating that α7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that α7nAChR expression in bone marrow–derived non–T cells is required for the integrity of the inflammatory reflex. PMID:22183893

Intraarticular injection autologous platelet-rich plasma and bone marrow concentrate in a goat osteoarthritis model.

PubMed

Wang, Zhen; Zhai, Chenjun; Fei, Hao; Hu, Junzheng; Cui, Weiding; Wang, Zhen; Li, Zeng; Fan, Weimin

2018-02-21

To evaluate the effects of intraarticular injections of autologous platelet-rich plasma (PRP) or bone marrow concentrate (BMC) on osteoarthritis (OA), 24 adult goats were equally divided into control (Ctrl), saline (NS), PRP, and BMC groups, and OA was induced by surgery in NS, PRP, and BMC groups. Autologous PRP and BMC were obtained from whole blood and bone marrow aspirates, respectively. The data revealed, platelets were increased in BMC by 1.8-fold, monocytes by 5.6-fold, TGF-β1 by 7.7-fold, and IGF-1 by 3.6-fold (p < 0.05), and platelets were increased in PRP by 2.9-fold, and TGF-β1 by 3.3-fold (p < 0.05). From the sixth week post-operation, saline, PRP, and BMC were administered by intraarticular injection once every 4 weeks, three consecutive times. After the animals were sacrificed, inflammatory cytokines in the synovial fluid was measured, and bone and cartilage degeneration progression was observed by macroscopy, histology, and immunohistochemistry. Compared with the NS group, the level of inflammatory cytokines was reduced in the PRP and BMC groups (p < 0.05). Histologically, delayed cartilage degeneration and higher levels of extracellular matrix (ECM) were observed in both PRP and BMC treated groups (p < 0.05). Furthermore, the BMC group showed greater cartilage protection and less ECM loss than the PRP group (p < 0.05). In summary, this study showed that intraarticular injection of autologous PRP and BMC has therapeutic efficacy in a goat osteoarthritis model, with the greater benefit in terms of cartilage protection being observed in the BMC-treated group than PRP. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Effect of preparation and processing conditions on UV absorbing properties of hydroxyapatite-Fe2O3 sunscreen.

PubMed

C Teixeira, M A; Piccirillo, C; Tobaldi, D M; Pullar, R C; Labrincha, J A; Ferreira, M O; L Castro, P M; E Pintado, M M

2017-02-01

The development of innovative, safe and non-photocatalytic sunscreens is urgently needed, as it is essential to have sunscreen filters offering appropriate UV protection without damaging the environment and/or generating free radicals when in contact with the skin. Hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 , HAp) when substituted with iron has UV protection properties and is not photocatalytic; HAp was used to make a sunscreen filter by treating cod fish bones in an iron-containing solution, and then calcining them at 700°C. Here we present a systematic and advanced study on this material, to obtain a sunscreen with improved UV absorbing properties. Bones were treated with three different iron salts - Fe(II) chloride, Fe(II) lactate and Fe(III) nitrate - under various pH conditions. Results showed that Fe(II) chloride in basic pH led to the most effective iron inclusion. High energy ball milling or ultrasound were investigated to increase surface area and corresponding UV absorption; high energy ball milling treatment led to the best optical properties. The optimum powders were used to formulate UV protection creams, which showed Sun Protection Factor (SPF) values significantly superior to the control cream (up to 4.1). Moreover the critical wavelength (λ crit ) was >370nm (388-389nm) and UVA/UVB ratios were very close to 1. With these properties these sunscreens can be classified as broad UV protectors. Results also showed that combining these powders with other sunscreens (i.e. titanium dioxide), a synergic effect between the different components was also observed. This investigation showed that HAp-based sunscreens of marine origin are a valid alternative to commercial products, safe for the health of the customers and, being non-photocatalytic, do not pose a threat to the environment. Copyright © 2016 Elsevier B.V. All rights reserved.

Detoxification of rats subjected to nickel chloride by a biomaterial-based carbonated orthophosphate.

PubMed

Boulila, S; El Feki, A; Oudadesse, H; Kallel, C; El Feki, H

2014-09-01

Recently, the therapeutic approaches of the detoxification against the metals (nickel) in the body are the use of biomaterials such as carbonated hydroxyapatite. The aim of this study is therefore to analyze the physiological and physicochemical parameters of strain white rats "Wistar" receiving nickel chloride and to study the protective associative of apatite against adverse effects of this metal, and this in comparison with control rats. Our results showed that the nickel induced in rats an oxidative stress objectified by elevated levels of thiobarbituric acid-reactive substances and conjugated dienes associated with inhibition of the activity of the antioxidant defense system such as glutathione peroxidase, superoxide dismutase and catalase in the liver, kidney, spleen and erythrocyte. Disorders balances of ferric, phosphocalcic, a renal failure and a liver toxicity were observed in rats exposed to nickel. As well as a significant increase in the rate of nickel in the bones and microcytic anemia was revealed. However, the implantation of carbonated hydroxyapatite in capsule form protects rats intoxicated by the nickel against the toxic effects of this metal by lowering the levels of markers of lipid peroxidation and improving the activities of defense enzymes. Our implantation technique is effective to correct ferric balance and phosphocalcic equilibrium, to protect liver and kidney function, to reduce the rate of bone nickel and to correct anemia. They clearly explain the beneficial and protective of our biomaterial which aims the detoxification of rats receiving nickel by substituting cationic (Ca(2+) by Ni(2+)) and anionic (OH(-) by Cl(-)) confirmed by physicochemical characterization like the IR spectroscopy and X-ray diffraction. These techniques have shown on the one hand a duplication of OH(-) bands (IR) and on the other hand the increase of the volume of the apatite cell after these substitutions (X-ray diffraction). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Efficacy of the bone injection gun in the treatment of organophosphate poisoning.

PubMed

Eisenkraft, Arik; Gilat, Eran; Chapman, Shira; Baranes, Shlomo; Egoz, Inbal; Levy, Aharon

2007-04-01

Immediate administration of antidotal treatment is crucial in severe organophosphate (OP) poisoning and the use of an open intravenous (i.v.) line might also be required. The state of casualties might prevent getting access to their veins. The bone injection gun (BIG) was established as a simple method for introducing an intraosseous (i.o.) line and could be applied while wearing a protective suit. The present study followed the pharmacokinetics of the anticonvulsive drug midazolam after i.o. administration in pigs compared with i.v. and the common intramuscular (i.m.) administration. A new method for monitoring midazolam concentrations in plasma was developed. Plasma concentrations following both i.v. and i.o. administrations peaked at 2 min post injection and only at 10 min following the i.m. route. In an antidotal treatment study against paraoxone poisoning, the anticonvulsive effect of midazolam appeared immediately following i.o. administration, while it took 5-10 min to exhibit a similar effect following i.m. administration. This study indicates that the use of i.o. administration after OP poisoning might provide the necessary fast response for rapid termination of convulsions. The BIG might offer a convenient method for treating casualties in the chemical arena by teams wearing full protective gear. Copyright (c) 2007 John Wiley & Sons, Ltd.

Time dependent loss of trabecular bone in human tibial plateau fractures.

PubMed

Solomon, Lucian Bogdan; Kitchen, David; Anderson, Paul Hamill; Yang, Dongqing; Starczak, Yolandi; Kogawa, Masakazu; Perilli, Egon; Smitham, Peter Jonathan; Rickman, Mark Sean; Thewlis, Dominic; Atkins, Gerald James

2018-05-22

We investigated if time between injury and surgery affects cancellous bone properties in patients suffering tibial plateau fractures (TPF), in terms of structural integrity and gene expression controlling bone loss. A cohort of 29 TPF, operated 1-17 days post-injury, had biopsies from the fracture and an equivalent contralateral limb site, at surgery. Samples were assessed using micro-computed tomography and real-time RT-PCR analysis for the expression of genes known to be involved in bone remodeling and fracture healing. Significant decreases in the injured vs control side were observed for bone volume fraction (BV/TV, -13.5 ± 6.0%, p = 0.011), trabecular number (Tb.N, -10.5 ± 5.9%, p = 0.041) and trabecular thickness (Tb.Th, -4.6 ± 2.5%, p = 0.033). Changes in these parameters were more evident in patients operated 5-17 days post-injury, compared to those operated in the first 4 days post injury. A significant negative association was found between Tb.Th (r = -0.54, p < 0.01) and BV/TV (r = -0.39, p < 0.05) in relation to time post-injury in the injured limb. Both BV/TV and Tb.Th were negatively associated with expression of key molecular markers of bone resorption, CTSK, ACP5 and the ratio of RANKL:OPG mRNA. These structure/gene expression relationships did not exist in the contralateral tibial plateau of these patients. This study demonstrated that there is a significant early time-dependent bone loss in the proximal tibia after TPF. This bone loss was significantly associated with altered expression of genes typically involved in the process of osteoclastic bone resorption but possibly also by osteocytes. The mechanism of early bone loss in such fractures should be a subject of further investigation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

An extremely sensitive species-specific ARMS PCR test for the presence of tiger bone DNA.

PubMed

Wetton, Jon H; Tsang, Carol S F; Roney, Chris A; Spriggs, Adrian C

2002-04-18

The survival of the tiger (Panthera tigris) is seriously threatened by poaching to provide raw materials for traditional Chinese medicines (TCMs). Most highly prized are the tiger's bones, which are used in combination with other animal and plant derivatives in pills and plasters for the treatment of rheumatism and other ailments. Hundreds of patent remedies have been produced which claim to contain tiger bone, but proof of its presence is needed if legislation prohibiting the trade in endangered species is to be enforced.A highly sensitive tiger-specific real-time PCR assay has been developed to address this problem. Using primers specific to the tiger mitochondrial cytochrome b gene, successful amplification has been reliably achieved from blood, hair and bone as well as from a range of TCMs spiked with 0.5% tiger bone. Although capable of detecting fewer than 10 substrate molecules, the seven varieties of TCM pills and plasters tested showed no detectable trace of tiger DNA before spiking. Furthermore, sequencing several "tiger bone" fragments seized from TCM shops has shown that they actually originated from cattle and pigs. The potential effects of traditional bone preparation methods, evidence that much lower concentrations are used than alleged on TCM packaging, and substitution of bones from other species all suggest a low likelihood of detecting tiger DNA in patent medicines. Despite this, the basic methods have been thoroughly proven and can be readily applied to derivatives from other Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) protected species, providing a rapid and highly sensitive forensic test for species of origin. Potential applications to the monitoring of wild populations are demonstrated by the successful identification of shed hairs and faecal samples.

Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women

NASA Technical Reports Server (NTRS)

Ettinger, B.; Genant, H. K.; Steiger, P.; Madvig, P.

1992-01-01

With the use of a double-blind, randomized, dose-ranging design, we tested during an 18-month period the degree of protection against postmenopausal bone loss afforded by micronized 17 beta-estradiol in dosages of 0.5, 1.0, and 2.0 mg. All subjects received supplementation to ensure a minimum of 1500 mg calcium daily. Fifty-one subjects completed at least 1 year of follow-up bone density measurements by quantitative computed tomography and by single- and dual-photon absorptiometry. In the placebo group spinal trabecular bone density decreased 4.9% annually (p less than 0.001), whereas in those taking micronized 17 beta-estradiol bone density tended to increase (annual increases of 0.3% in the 0.5 mg micronized 17 beta-estradiol group, 1.8% in the 1.0 mg micronized 17 beta-estradiol group, and 2.5% in the 2.0 mg micronized 17 beta-estradiol group). After completing the double-blind phase, 41 subjects completed an additional 18 months of follow-up while taking 1.0 mg micronized 17 beta-estradiol. During this time one third of the subjects were randomly assigned to discontinue calcium supplements. Among those who previously received placebo, trabecular bone density increased 4.3% annually, whereas among those who had used micronized 17 beta-estradiol, trabecular bone density response was inversely related to the dosage previously used. Additionally and independently, the level of calcium intake showed a statistically significant correlation with the change in spinal trabecular bone density (r = 0.37, p = 0.02). We conclude that micronized 17 beta-estradiol has a continuous skeletal dose-response effect in the range of 0.5 to 2.0 mg and that calcium intake positively modifies the skeletal response to 1.0 mg micronized 17 beta-estradiol.

Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice.

PubMed

Bhattacharjee, Arin; Basu, Abhishek; Ghosh, Prosenjit; Biswas, Jaydip; Bhattacharya, Sudin

2014-08-01

Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Myocardial protective effect of extracellular superoxide dismutase gene modified bone marrow mesenchymal stromal cells on infarcted mice hearts.

PubMed

Pan, Qiao; Qin, Xing; Ma, Sai; Wang, Haichang; Cheng, Kang; Song, Xinxing; Gao, Haokao; Wang, Qiang; Tao, Rannie; Wang, Yabin; Li, Xiujuan; Xiong, Lize; Cao, Feng

2014-01-01

Extracellular superoxide dismutase (ecSOD) is a unique scavenger of superoxide anions and a promising target of gene therapy for ischemia/reperfusion injury (I/R). However, conventional gene therapies have limitation in effectiveness and efficiency. This study aimed to investigate the protective effects of ecSOD gene modified bone marrow mesenchymal stromal cells (BMSCs) on cardiac function improvement in mice infarcted heart. BMSCs were isolated from Fluc(+) transgenic mice (Tg FVB[Fluc(+)]) and transfected by adenovirus combined with human ecSOD gene. ELISA was performed to determine ecSOD protein level. Female syngeneic FVB mice were randomized into 5 groups: (1) Sham group (sham); (2) MI group (MI); (3) MI+BMSCs group (BMSC); (4) MI+BMSCs-vector group (BMSC-vector); (5) MI+ BMSCs-ecSOD group (BMSC-ecSOD). MI was accomplished by ligation of the left anterior descending artery. BMSCs (2 x 10(6)) were injected into the border zone of infarction. In vivo bioluminescence imaging (BLI) was performed to monitor transplanted BMSCs viability. Echocardiography and histological staining revealed that BMSCs-ecSOD significantly reduced myocardial infarction size and improved cardiac function. Lucigenin chemiluminescence, DHE and TUNEL staining demonstrated that BMSCs-ecSOD delivery reduced ROS level and cell apoptosis both in vivo and in vitro. Western blot assay revealed that ecSOD supplementation increased FoxO3a phosphorylation in cardiomyocytes. Moreover, quantitative real-time PCR showed that pro-apoptotic factors (bim and bax) were decreased while the anti-apoptotic factor mir-21 expression was increased after ecSOD intervention. Intra-myocardial transplantation of adenovirus-ecSOD transfected BMSCs could exert potential cardiac protection against MI, which may be partly through reduction of oxidative stress and improvement of BMSCs survival.

Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial.

PubMed

Amstrup, Anne Kristine; Sikjaer, Tanja; Heickendorff, Lene; Mosekilde, Leif; Rejnmark, Lars

2015-09-01

Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

1,25-Dihydroxyvitamin D deficiency accelerates alveolar bone loss independent of aging and extracellular calcium and phosphorus.

PubMed

Gong, Aixiu; Chen, Jie; Wu, Jun; Li, Jing; Wang, Lin; Goltzman, David; Miao, Dengshun

2018-04-10

Vitamin D is critical for bone homeostasis and immunomodulation. We therefore assessed whether 1,25-dihydroxyvitamin D (1,25(OH) 2 D) deficiency in mice with targeted deletion of the gene encoding 25-hydroxyvitaminD-1αhydroxylase [1α(OH)ase] (1αOH)ase -/- mice) results in alveolar bone loss and periodontal inflammation in vivo. 10-week-old and 12-month-old 1α(OH)ase -/- mice and wild-type littermates were fed a normal diet or a rescue diet, and the phenotype of the periodontium was then analyzed using micro-computed tomography, histology, immunohistochemistry and real-time RT-PCR. Alveolar bone loss was increased and maxillary bone mineral density (BMD), osteoblast numbers and the number of osterix-positive cells were decreased significantly in 1α(OH)ase -/- mice compared with wild-type mice. Although aging from 10 weeks to 12 months accentuated these changes, and a rescue diet reduced them, the alterations in the 1α(OH)ase -/- mice exceeded the effects of aging and diet change. Nuclear factor kappa light-chain-enhancer of activated B cells (NF-кB) p65 and CD3 positive cells, and the gene expression levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP) -3 and -8 were all increased significantly in periodontal tissues of 1α(OH)ase -/- mice compared with wild-type mice. Aging from 10 weeks to 12 months also accentuated these changes, and a rescue diet reduced them, however, the alterations in the 1α(OH)ase -/- mice exceeded the effects of aging and diet change. 1,25(OH) 2 D deficiency in the 1α(OH)ase -/- mice accelerated alveolar bone loss by inhibiting osteoblastic bone formation and enhancing periodontal tissue degeneration in a calcium and phosphorus as well as age independent manner. This article is protected by copyright. All rights reserved. © 2018 American Academy of Periodontology.

Use of piezoelectric bone scalpel in hand and reconstructive microsurgery.

PubMed

Arnez, Z; Papa, G; Renzi, N; Ramella, V; Panizzo, N; Toffanetti, F

2009-01-01

Performing osteotomies with piezoelectric bone scalpel is also possible with bones of larger diameter/thickness. At the same time, adjacent soft tissues are not in danger from cutting or thermal damage, reducing the risk of damaging neurovascular structures - which is of primary importance in hand and reconstructive microsurgery. These features contribute to the safety and easy execution of the procedure. The resulting bony cut is precise and permits immediate and safe bone fixation. Osteotomy of bones of >1 cm thickness takes 20-30% longer than when using a conventional oscillating saw, though the increased safety of the procedure more than compensates for this. Three cases are presented, illustrating of the use of Genera Ultrasonic for cutting bones of major thickness (metacarpal, fibula and rib) without any complication. Because of its selectivity for bony tissue, precision and ability to protect soft tissues we also advocate the use of the Genera piezoelectric bone scalpel in hand and reconstructive microsurgery.

Nandrolone slows hindlimb bone loss in a rat model of bone loss due to denervation.

PubMed

Cardozo, Christopher P; Qin, Weiping; Peng, Yuanzhen; Liu, Xuan; Wu, Yong; Pan, Jiangping; Bauman, William A; Zaidi, Mone; Sun, Li

2010-03-01

Nandrolone is an anabolic steroid that has been demonstrated to reduce the loss of bone and muscle from hindlimb unweighting and to slow muscle atrophy after nerve transection. To determine whether nandrolone has the ability to protect bone against loss due to disuse after denervation, male rats underwent sciatic nerve transaction, followed 28 days later by treatment with nandrolone or vehicle for 28 days. Bone mineral density (BMD) was determined 28 days later or 56 days after nerve transection. Denervation led to reductions in BMD of 7% and 12% for femur and tibia, respectively. Nandrolone preserved 80% and 60% of BMD in femur and tibia, respectively, demonstrating that nandrolone administration significantly reduced loss of BMD from denervation. This study offers a potential novel pharmacological strategy for use of nandrolone to reduce bone loss in severe disuse- and denervation-related bone loss, such as that which occurs after spinal cord injury.

Treatment of collagenase-induced osteoarthritis with a viral vector encoding TSG-6 results in ectopic bone formation.

PubMed

Broeren, Mathijs G A; Di Ceglie, Irene; Bennink, Miranda B; van Lent, Peter L E M; van den Berg, Wim B; Koenders, Marije I; Blaney Davidson, Esmeralda N; van der Kraan, Peter M; van de Loo, Fons A J

2018-01-01

Tumor necrosis factor-inducible gene 6 (TSG-6) has anti-inflammatory and chondroprotective effects in mouse models of inflammatory arthritis. Because cartilage damage and inflammation are also observed in osteoarthritis (OA), we determined the effect of viral overexpression of TSG-6 in experimental osteoarthritis. Bone marrow-derived cells were differentiated to multinucleated osteoclasts in the presence of recombinant TSG-6 or after transduction with a lentiviral TSG-6 expression vector. Multi-nucleated osteoclasts were analyzed after tartrate resistant acid phosphatase staining and resorption activity was determined on dentin slices. Collagenase-induced osteoarthritis (CIOA) was induced in C57BL/6 mice after intra-articular injection of an adenoviral TSG-6 or control luciferase expression vector. Inflammation-related protease activity was measured using bioluminescent Prosense probes. After a second adenovirus injection, cartilage damage was assessed in histological sections stained with Safranin-O. Ectopic bone formation was scored in X-ray images of the affected knees. TSG-6 did not inhibit the formation of multi-nucleated osteoclasts, but caused a significant reduction in the resorption activity on dentin slices. Adenoviral TSG-6 gene therapy in CIOA could not reduce the cartilage damage compared to the luciferase control virus and no significant difference in inflammation-related protease activity was noted between the TSG-6 and control treated group. Instead, X-ray analysis and histological analysis revealed the presence of ectopic bone formation in the TSG-6 treated group. Gene therapy based on the expression of TSG-6 could not provide cartilage protection in experimental osteoarthritis, but instead resulted in increased ectopic bone formation.

Impact of air pollution on vitamin D deficiency and bone health in adolescents.

PubMed

Feizabad, Elham; Hossein-Nezhad, Arash; Maghbooli, Zhila; Ramezani, Majid; Hashemian, Roxana; Moattari, Syamak

2017-12-01

The association between air pollution and bone health was evaluated in adolescents in the city of Tehran. This study is essentially ecological. Vitamin D deficiency among adolescents has been reported at higher rates in polluted areas than in non-polluted areas. Additionally, residence in polluted areas is associated with lower levels of bone alkaline phosphatase. The aim of this study was to evaluate the association between ambient air pollution and bone turnover in adolescents and to compare the prevalence of vitamin D deficiency between polluted and non-polluted areas of Tehran. This cross-sectional population-based study was conducted on 325 middle- and high-school students (both girls and boys) in Tehran in the winter. During the study period, detailed daily data on air pollution were obtained from archived data collected by Tehran Air Quality Control Company (AQCC). Serum levels of calcium, phosphorus, parathyroid hormone (PTH), bone-specific alkaline phosphatase, 25(OH) vitamin D, osteocalcin, cross-linked C-telopeptide (CTX), total protein, albumin, and creatinine were obtained from the study group. Vitamin D deficiency was more prevalent in polluted areas than in non-polluted areas. After adjustment for age and sex, residence in the polluted area showed a statistically significant positive association with vitamin D deficiency and a statistically significant negative association with bone turnover. Interestingly, high calcium intake (>5000 mg/week) protects against the effects of air pollution on bone turnover. Air pollution is a chief factor determining the amount of solar UVB that reaches the earth's surface. Thus, atmospheric pollution may play a significant independent role in the development of vitamin D deficiency.

Carprofen simultaneously reduces progression of morphological changes in cartilage and subchondral bone in experimental dog osteoarthritis.

PubMed

Pelletier, J P; Lajeunesse, D; Jovanovic, D V; Lascau-Coman, V; Jolicoeur, F C; Hilal, G; Fernandes, J C; Martel-Pelletier, J

2000-12-01

To examine the effect of a nonsteroidal antiinflammatory drug, carprofen, on the structure and metabolism of cartilage and subchondral bone in the experimental osteoarthritic (OA) canine model. Experimental Groups 1 and 2 received a sectioning of the anterior cruciate ligament (ACL) of the right stifle joint, and were administered carprofen (2.2 and 4.4 mg/kg/twice daily/po, respectively) for 8 weeks beginning 4 weeks postsurgery. Group 3 received ACL sectioning and no treatment. Group 4 was composed of unoperated normal dogs. Cartilage macroscopic lesions were assessed, and their histological severity was graded. Specimens of subchondral bones were fixed, decalcified, and stained with hematoxylin/eosin. The level of metalloprotease (MMP) activity in cartilage was measured. Osteoblast cells were prepared from the subchondral bone. The level of synthesis of osteoblast biomarkers (osteocalcin, alkaline phosphatase), as well as urokinase plasminogen activator (uPA) activity and insulin-like growth factor (IGF-1) in the culture medium, was estimated. Carprofen treatment decreased the width of osteophytes (p < 0.01), the size of cartilage lesions, and the histologic severity of cartilage lesions (p < 0.008). There was no difference in the levels of MMP activity in cartilage between OA and carprofen treated groups. In OA dogs, the subchondral bone plate was thinner and was the site of an extensive remodeling process with numerous lacunae. Dogs treated with carprofen showed a marked decrease in the remodeling activity with normal plate thickness, and subchondral bone morphology resembling that of normal dogs. Osteoblasts from untreated OA dogs showed slightly higher alkaline phosphatase activities and osteocalcin release that reverted back to normal upon carprofen treatment. Moreover, uPA activity and IGF-1 levels were increased in OA dogs and were significantly reduced in carprofen treated dogs. Under therapeutic conditions, treatment with carprofen could reduce the progression of early structural changes in experimental OA. Carprofen treatment also delays and/or prevents the abnormal metabolism of subchondral osteoblasts in this model. The hypothesis of a possible link between the protective effect of carprofen and its effect on subchondral bone is of interest in the context of therapeutic intervention.

Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation

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

Ming, Wei, E-mail: weiming@xiyi.edu.cn; Department of Pharmacology, Xi’an Medical University, Xi’an 710021; Lu, Gan, E-mail: leonming99@163.com

Therapeutic targeting bone loss has been the focus of the study in osteoporosis. The present study is intended to evaluate whether MOTS-c, a novel mitochondria related 16 aa peptide, can protect mice from ovariectomy-induced osteoporosis. After ovary removal, the mice were injected with MOTS-c at a dose of 5 mg/kg once a day for 12 weeks. Our results showed that MOTS-c treatment significantly alleviated bone loss, as determined by micro-CT examination. Mechanistically, we found that the receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclast differentiation was remarkably inhibited by MOTS-c. Moreover, MOTS-c increased phosphorylated AMPK levels, and compound C, anmore » AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis. Thus, our findings provide evidence that MOTS-c may exert as an inhibitor of osteoporosis via AMPK dependent inhibition of osteoclastogenesis. -- Highlights: •MOTS-c decreases OVX-induced bone loss in vivo. •MOTS-c inhibits RANKL-induced osteoclast formation. •MOTS-c inhibits RANKL-induced osteoclast-specific gene expression. •MOTS-c represses osteoclast differentiation via the activation of AMPK.« less

[Effects of smoking on the thyroid gland, digestive system, kidney and bone].

PubMed

Underner, M; Hadjadj, S; Beauchant, M; Bridoux, F; Debiais, F; Meurice, J-C

2008-12-01

In addition to being a major cardiovascular risk factor, smoking promotes or worsens thyroid, digestive, renal and bone diseases. Smoking is positively associated with hyperthyroidism. It is associated with Graves' disease and it especially increases the risk of the development of severe exophthalmos. In contrast, smoking might exert a protective action for thyroid carcinoma. Smoking increases the severity of hepatic lesions in patients with chronic hepatitis C. Smoking accelerates the progression of primary biliary cirrhosis and increases the risk of hepatocellular carcinoma. Smoking increases risk of both hyperplastic and adenomatous polyps. While Crohn's disease is associated with smoking, ulcerative colitis is largely a disease of non smokers. Smoking increases risk of development of both renal cell carcinoma and chronic nephropathies, particularly in types 1 and 2 diabetes. Smoking is a risk factor for decreased bone density and is associated with a significantly increased risk of fracture. Smoking is related to the development of rheumatoid arthritis and may adversely influence its severity. Smoking might be considered a risk factor for the development of several thyroid, digestive, renal and bone diseases. Consequently, smoking prevention and cessation programs must be strongly encouraged among the patients concerned.

Supplementation with green tea polyphenols improves bone microstructure and quality in aged, orchidectomized rats

USDA-ARS?s Scientific Manuscript database

Recent studies show that green tea polyphenols (GTP) attenuate bone loss and microstructure deterioration in ovariectomized aged female rats, a model of postmenopausal osteoporosis. However, it is not known if such an osteo-protective role of GTP is demonstrable in androgen-deficient aged rats, a mo...

Antiosteoporotic effect of Petroselinum crispum, Ocimum basilicum and Cichorium intybus L. in glucocorticoid-induced osteoporosis in rats.

PubMed

Hozayen, Walaa G; El-Desouky, Mohamed A; Soliman, Hanan A; Ahmed, Rasha R; Khaliefa, Amal K

2016-06-02

Glucocorticoid-induced osteoporosis (GIO) is one of the serious side effects which have become the most common secondary osteoporosis. The purpose of this study is to evaluate the effect of aqueous extract of parsley, basil and chicory on glucocorticoid-induced osteoporosis in rats. Fifty Female rats were divided into five groups and treated for 8 weeks as follow: group 1 served as control; group (2) subcutaneously injected with 0.1 mg/kg b. wt. dexamethasone dissolved in saline; group 3 received similar dose of dexamethasone together with aqueous parsley extract in a dose of 2 g/kg b. wt.; group 4 received similar dose of dexamethasone together with 400 mg/kg b. wt. aqueous basil extract and group 5 received similar dose of dexamethasone together with 100 mg/kg b. wt. aqueous chicory extract. The dexamethasone group showed a significant decrease in serum E2, Ca, P levels and significant decrease in total BMD, BMC and a significant increase in serum PTH, ALP and ACP. Bone TBARs was significantly increased while GSH, antioxidant enzymes were significantly decreased. These changes were attenuated by parsley, basil and chicory extracts in the group 3, 4 and 5 respectively. Aqueous extracts of parsley, basil and chicory showed bone protection against glucocorticoid-induced in rats. From our results, we concluded that chicory has a potent protective effect more than parsley and basil due to containing flavonoids and inulin.

Using stable isotope tracers to study bone metabolism in children.

PubMed

O'Brien, Kimberly O; Abrams, Steven A

2018-06-05

Skeletal mineralization is initiated in utero and continues throughout childhood and adolescence. During these key periods of the life cycle calcium retention must increase significantly to provide sufficient mineral for bone deposition and skeletal growth. Stable calcium isotopes have served as a fundamental tool to non-invasively characterize the dynamic changes in calcium physiology that occur from infancy through adolescence. These approaches have helped define the dynamics of calcium absorption and utilization in healthy children and in children with chronic diseases. As data in this area have accumulated, new areas of emphasis are beginning to characterize the determinants of variability in mineral retention, the genetic determinants of bone turnover and calcium flux and the impact of the gut microbiome on whole body and niche specific calcium dynamics. Advances in these areas will help define calcium utilization in pediatric populations and provide information that may be useful in maximizing bone acquisition across this critical phase of the life cycle. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Periodontal regeneration via chemo-attractive constructs.

PubMed

Cai, Xinjie; Yang, Fang; Walboomers, X Frank; Wang, Yining; Jansen, John A; van den Beucken, Jeroen J J P; Plachokova, Adelina S

2018-05-19

Chemo-attractants, such as stromal cell-derived factor-1α (SDF-1α), can offer an advantage for periodontal regeneration by recruiting the patient's own stem cells to stimulate self-repair. We here developed a chemo-attractive construct for periodontal regeneration using SDF-1α and evaluated its efficacy in vivo. SDF-1α was loaded on gelatin sponge and tested in vitro for SDF-1α release. Subsequently, SDF-1α constructs were implanted into rat periodontal defects for 1 and 6 weeks, with unloaded materials and empty defects as controls. The regenerative efficacy was evaluated by micro-CT, histological and histomorphometrical analyses. In vitro results showed limited SDF-1α release up to 35 days. In contrast, SDF-1α constructs significantly improved periodontal defect regeneration in terms of alveolar bone height, new bone area, and functional ligament length. Additionally, SDF-1α constructs decreased the inflammatory response at week 6. Chemo-attractive constructs significantly improved periodontal regeneration in terms of alveolar bone height, new bone area, and functional ligament length. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of fenoterol on the skeletal system depend on the androgen level.

PubMed

Śliwiński, Leszek; Cegieła, Urszula; Pytlik, Maria; Folwarczna, Joanna; Janas, Aleksandra; Zbrojkiewicz, Małgorzata

2017-04-01

The role of sympathetic nervous system in the osseous tissue remodeling is not clear enough. The effects of fenoterol, a selective β 2 -adrenomimetic drug, on the skeletal system of normal and androgen deficient (orchidectomized) rats were studied in vivo. Osteoclastogenesis and mRNA expression in osteoblasts were investigated in vitro in mouse cell cultures. Fenoterol administered to animals with physiological androgen level unfavorably affected the skeletal system, damaging the bone microarchitecture. Androgen deficiency induced osteoporotic changes, and fenoterol protected the osseous tissue from consequences of androgen deficiency. The results of in vitro studies correlated with the in vivo observations. A significantly increased number of osteoclasts in bone marrow cell cultures to which testosterone and fenoterol were added simultaneously was demonstrated. In cultures without the addition of testosterone, fenoterol significantly inhibited osteoclastogenesis in comparison with control cultures. The results indicate the favorable action of fenoterol in conditions of testosterone deficiency, and its destructive influence upon the skeleton in the presence of androgens. The results confirm the key role of sympathetic nervous system in the regulation of bone remodeling. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Effect of tocopherol-monoglucoside (TMG), a water-soluble glycosylated derivate of vitamin E, on hematopoietic recovery in irradiated mice.

PubMed

Cherdyntseva, Nadezda; Shishkina, Anna; Butorin, Ivan; Murase, Hironobu; Gervas, Polina; Kagiya, Tsutomu V

2005-03-01

A preparation of alpha-tocopherol monoglucoside (TMG) administered i.p. at a dose of 600 mg/kg immediately after whole body gamma irradiation was examined for its radioprotective efficacy towards bone marrow and peripheral blood nucleated cells. When mice received X-rays at a dose of 5,6 Gy, a marked decrease in bone marrow karyocytes and a reduction of peripheral leukocytes within the early post-irradiated period were observed. However these changes were attenuated in TMG-treated mice. Significant protection of blood lymphocytes was found for the TMG group of mice. The return to normal value of the reduced blood leukocyte count starting from the 8th day was more rapid in TMG-treated mice than in untreated irradiated mice. TMG administration was found to enhance hematopoietic recovery, as measured by the exceeded nucleated bone marrow cell count due to elevated amount of both lymphoid and granulocytic elements in the TMG-group, in comparison with that of both control irradiated and non-irradiated animals. These findings indicate that the radioprotective effect of TMG is apparently realized through its influence on hematopoietic system.

Space flight and bone formation.

PubMed

Doty, St B

2004-12-01

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

Space flight and bone formation

NASA Technical Reports Server (NTRS)

Doty, St B.

2004-01-01

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

Modification of radiobiological effects of 171 MeV protons by elements of physical protection

NASA Astrophysics Data System (ADS)

Bulinina, Taisia; Shurshakov, Vyacheslav; Ivanov, Alexander; Molokanov, Alexander

2016-07-01

Space radiation includes protons of various energies. Physical protection is effective in the case of low energy protons (50-100 MeV) and becomes insufficient for radiation with a high part of high-energy protons. In the experiment performed on outbred mice, the purpose of the study was to evaluate the radiobiological effect of 171 MeV protons and protons modified by elements of physical protection of the spacecraft, on a complex of indicators of the functional condition of the system hematopoiesis and the central nervous system in 24 hours after irradiation at 20 cGy dose. The spacecraft radiation protection elements used in the experiment were a construction of wet hygiene wipes called a «protective curtain», and a glass plate imitating an ISS window. Mass thickness of the " protective curtain" in terms of water equivalent was ̴ 6,2 g/cm2. Physical shielding along the path of 171 MeV protons increases their linear energy transfer leading to the absorbed dose elevation and strengthening of the radiobiological effect. In the experiment, the two types of shielding together raised the absorbed dose from 20 to 23.2 cGy. Chemically different materials (glass and water in the wipes) were found to exert unequal modifying effects on physical and biological parameters of the proton-irradiated mice. There was a distinct dose-dependent reduction of bone marrow cellularity within the dose range from 20 cGy to 23.2 cGy in 24 hours after exposure. No modifying effect of the radiation protection elements on spontaneous motor activity was discovered when compared with entrance protons. The group of animals protected by the glass plate exhibited normal orientative-trying reactions and weakened grip with the forelimbs. The effects observed in the experiment indicate the necessity to carry out comprehensive radiobiological researches (physical, biological and mathematical) in assessing the effects of physical protection, that are actual for ensuring radiation safety of crews in interplanetary flights.

The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation.

PubMed

Chen, W; Gao, B; Hao, L; Zhu, G; Jules, J; MacDougall, M J; Wang, J; Han, X; Zhou, X; Li, Y-P

2016-10-01

Periodontitis is a severe chronic inflammatory disease and one of the most prevalent non-communicable chronic diseases that affects the majority of the world's adult population. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno-associated virus (AAV) expressing cathepsin K (Ctsk) small hairpin (sh)RNA (AAV-sh-Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease. We used a known mouse model of periodontitis, in which wild-type BALB/cJ mice were infected with Porphyromonas gingivalis W50 in the maxillary and mandibular periodontium to induce the disease. AAV-sh-Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess progression of the disease. AAV-mediated Ctsk silencing drastically protected mice (> 80%) from P. gingivalis-induced bone resorption by osteoclasts. In addition, AAV-sh-Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T-cell and dendritic cell numbers in periodontal lesions. AAV-mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV-sh-Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV-mediated local silencing of Ctsk as an important therapeutic strategy for effectively treating periodontal disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bone-to-bone Fixation Enhances Functional Healing of the Porcine Anterior Cruciate Ligament Using a Collagen-Platelet Composite

PubMed Central

Murray, Martha M.; Magarian, Elise; Zurakowski, David; Fleming, Braden C.

2010-01-01

Purpose The purpose of this study was to determine if providing bony stabilization between the tibia and femur would improve the structural properties of an “enhanced” ACL repair using a collagen-platelet composite when compared to the traditional (Marshall) suture technique. Methods Twelve pigs underwent unilateral ACL transection and were treated with sutures connecting the bony femoral ACL attachment site to the distal ACL stump (LIGAMENT group), or to the tibia via a bone tunnel (TIBIA group). A collagen-platelet composite was placed around the sutures to enhance the biologic repair in both groups. Anteroposterior (AP) knee laxity and the graft structural properties were measured after 15 weeks of healing in both the ACL-repaired and contralateral ACL-intact joints. Results Enhanced ACL repair with bone-to-bone fixation significantly improved yield load and linear stiffness of the ACL repairs (p<0.05) after 15 weeks of healing. However, laxity values of the knees were similar in both groups of repaired knees (p>0.10). Conclusions Using an enhanced ACL suture repair technique that includes bone-to-bone fixation to protect the repair in the initial healing stages resulted in an ACL with improved structural properties after 15 weeks in the porcine model. Clinical Relevance The healing response of an ACL suture repair using a collagen-platelet composite can be enhanced by providing bony stabilization between the tibia and femur to protect the graft during the initial healing process in a translational model. PMID:20810092

Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells

PubMed Central

Gao, B; Han, Y-H; Wang, L; Lin, Y-J; Sun, Z; Lu, W-G; Hu, Y-Q; Li, J-Q; Lin, X-S; Liu, B-H; Jie, Q; Yang, L; Luo, Z-J

2016-01-01

Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse. PMID:27228350

Non-canonical Wnt4 prevents skeletal aging and inflammation by inhibiting NF-κB

PubMed Central

Yu, Bo; Chang, Jia; Liu, Yunsong; Li, Jiong; Kevork, Kareena; Al-Hezaimi, Khalid; Graves, Dana T; Park, No-Hee; Wang, Cun-Yu

2014-01-01

Aging-related bone loss and osteoporosis affect millions of patients worldwide. Chronic inflammation associated with aging and arthritis promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuated bone loss in osteoporosis and skeletal aging by inhibiting nuclear factor-kappa B (NF-κB) via non-canonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 could inhibit osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited transforming growth factor beta-activated kinase 1-mediated NF-κB activation in macrophages and osteoclast precursors independent of β-catenin. Moreover, recombinant Wnt4 proteins were able to alleviate osteoporotic bone loss and inflammation by inhibiting NF-κB in vivo. Taken together, our results suggest that Wnt4 might be used as a therapeutic agent for treating osteoporosis by attenuating NF-κB. PMID:25108526

Effect of heme oxygenase-1 transduced bone marrow mesenchymal stem cells on damaged intestinal epithelial cells in vitro.

PubMed

Cao, Yi; Wu, Ben-Juan; Zheng, Wei-Ping; Yin, Ming-Li; Liu, Tao; Song, Hong-Li

2017-07-01

In this study, we explored the effects of mesenchymal stem cells (MSCs) from bone marrow overexpressing heme oxygenase-1 (HO-1) on the damaged human intestinal epithelial barrier in vitro. Rat MSCs were isolated from bone marrow and transduced with rat HO-1 recombinant adenovirus (HO-MSCs) for stable expression of HO-1. Colorectal adenocarinoma 2 (Caco2) cells were treated with tumor necrosis factor-α (TNF-α) to establish a damaged colon epithelial model. Damaged Caco2 were cocultured with MSCs, Ad-MSCs, Ad-HO + MSCs or HO-MSCs. mRNA and protein expression of Zona occludens-1 (ZO-1) and human HO-1 and the release of cytokines were measured. ZO-1 and human HO-1 in Caco2 were significantly decreased after treatment with TNF-α; and this effect was reduced when coculture with MSCs from bone marrow. Expression of ZO-1 was not significantly affected by Caco2 treatment with TNF-α, Ad-HO, and MSCs. In contrast, ZO-1 and human HO-1 increased significantly when the damaged Caco2 was treated with HO-MSCs. HO-MSCs showed the strongest effect on the expression of ZO-1 in colon epithelial cells. Coculture with HO-MSCs showed the most significant effects on reducing the expression of IL-2, IL-6, IFN-γ and increasing the expression of IL-10. HO-MSCs protected the intestinal epithelial barrier, in which endogenous HO-1 was involved. HO-MSCs play an important role in the repair process by reducing the release of inflammatory cytokines and increasing the release of anti-inflammatory factors. These results suggested that HO-MSCs from bone marrow were more effective in repairing the damaged intestinal epithelial barrier, and the effectiveness of MSCs was improved by HO-1 gene transduction, which provides favorable support for the application of stem cell therapy in the intestinal diseases. © 2017 The Authors. Cell Biology International Published by John Wiley & Sons Ltd on behalf of International Federation of Cell Biology.

Short communication: Effect of commercial or depurinized milk diet on plasma advanced oxidation protein products, cardiovascular markers, and bone marrow CD34+ stem cell potential in rat experimental hyperuricemia.

PubMed

Kocic, Gordana; Sokolovic, Dusan; Jevtovic, Tatjana; Cvetkovic, Tatjana; Veljkovic, Andrej; Kocic, Hristina; Stojanovic, Svetlana; Jovanovic, Aneta; Jovanovic, Jelena; Zivkovic, Petar

2014-11-01

Cardiovascular repair and myocardial contractility may be improved by migration of bone marrow stem cells (BMSC) and their delivery to the site of injury, a process known as BMSC homing. The aim of our study was to examine the dietary effect of a newly patented depurinized milk (DP) that is almost free of uric acid and purine and pyrimidine compounds compared with a standard commercial 1.5% fat UHT milk diet or allopurinol therapy in rat experimental hyperuricemia. Bone marrow stem cell potential (BMCD34(+), CD34-postive bone marrow cells), plasma oxidative stress parameters [advanced oxidation protein products, AOPP) and thiobarbituric acid reactive substances (TBARS)], myocardial damage markers [creatine phosphokinase (CPK), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)], plasma cholesterol, and high-density lipoprotein cholesterol were investigated. The DP milk diet significantly increased the number of BMCD34(+) stem cells compared with commercial UHT milk. Allopurinol given alone also increased the number of BMCD34(+). Hyperuricemia caused a significant increase in all plasma enzyme markers for myocardial damage (CPK, LDH, and AST). A cardioprotective effect was achieved with allopurinol but almost equally with DP milk and more than with commercial milk. Regarding plasma AOPP, TBARS, and cholesterol levels, the most effective treatment was DP milk. In conclusion, the protective role of a milk diet on cardiovascular function may be enhanced through the new depurinized milk diet, which may improve cardiovascular system function via increased bone marrow stem cell regenerative potential, decreased plasma oxidative stress parameters, and decreased levels of myocardial damage markers and cholesterol. New dairy technology strategies focused on eliminating harmful milk compounds should be completely nontoxic. Novel milk products should be tested for their ability to improve tissue repair and function. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Massive elimination of multinucleated osteoclasts by eupatilin is due to dual inhibition of transcription and cytoskeletal rearrangement.

PubMed

Kim, Ju-Young; Lee, Myeung Su; Baek, Jong Min; Park, Jongtae; Youn, Byung-Soo; Oh, Jaemin

2015-12-01

Osteoporosis is an aging-associated disease requiring better therapeutic modality. Eupatilin is a major flavonoid from Artemisia plants such as Artemisia princeps and Artemisia argyi which has been reported to possess various beneficial biological effects including anti-inflammation, anti-tumor, anti-cancer, anti-allergy, and anti-oxidation activity. Complete blockade of RANK-dependent osteoclastogenesis was accomplished upon stimulation prior to the receptor activator of nuclear factor κB (RANK)-ligand (RANKL) treatment or post-stimulation of bone marrow macrophages (BMCs) in the presence of RANKL with eupatilin. This blockade was accompanied by inhibition of rapid phosphorylation of Akt, GSK3β, ERK and IκB as well as downregulation of c-Fos and NFATc1 at protein, suggesting that transcriptional suppression is a key mechanism for anti-osteoclastogenesis. Transient reporter assays or gain of function assays confirmed that eupatilin was a potent transcriptional inhibitor in osteoclasts (OC). Surprisingly, when mature osteoclasts were cultured on bone scaffolds in the presence of eupatilin, bone resorption activity was also completely blocked by dismantling the actin rings, suggesting that another major acting site of eupatilin is cytoskeletal rearrangement. The eupatilin-treated mature osteoclasts revealed a shrunken cytoplasm and accumulation of multi-nuclei, eventually becoming fibroblast-like cells. No apoptosis occurred. Inhibition of phosphorylation of cofilin by eupatilin suggests that actin may play an important role in the morphological change of multinucleated cells (MNCs). Human OC similarly responded to eupatilin. However, eupatilin has no effects on osteoblast differentiation and shows cytotoxicity on osteoblast in the concentration of 50 μM. When eupatilin was administered to LPS-induced osteoporotic mice after manifestation of osteoporosis, it prevented bone loss. Ovariectomized (OVX) mice remarkably exhibited bone protection effects. Taken together, eupatilin is an effective versatile therapeutic intervention for osteoporosis via; 1) transcriptional suppression of c-Fos and NFATc1 of differentiating OC and 2) inhibition of actin rearrangement of pathogenic MNCs.

The Effects of Aging and Sex Steroid Deficiency on the Murine Skeleton Are Independent and Mechanistically Distinct

PubMed Central

Ucer, Serra; Iyer, Srividhya; Kim, Ha-Neui; Han, Li; Rutlen, Christine; Allison, Kelly; Thostenson, Jeff D; de Cabo, Rafael; Jilka, Robert L; O’Brien, Charles; Almeida, Maria; Manolagas, Stavros C

2017-01-01

Old age and sex steroid deficiency are the two most critical factors for the development of osteoporosis. It remains unknown, however, whether the molecular culprits of the two conditions are similar or distinct. We show herein that at 19.5 months of age —a time by which the age-dependent decline of cortical and cancellous bone mass and cortical porosity were fully manifested in C57BL/6J mice—these animals remained functionally estrogen sufficient. Transgenic mice with conditional expression of mitochondria-targeted catalase—a potent H2O2 inactivating enzyme—in cells of the myeloid lineage (mitoCAT;LysM-Cre mice) were protected from the loss of cortical, but not cancellous, bone caused by gonadectomy in either sex. Consistent with these findings, in vitro studies with ERα-deficient Prx1+ cells and gonadectomized young adult mice showed that in both sexes decreased ERα signaling in Prx1+ cells leads to an increase in SDF1, a.k.a. CXCL12, an osteoclastogenic cytokine whose effects were abrogated in macrophages from mitoCAT;LysM-Cre mice. In contrast to sex steroid deficiency, the adverse effects of aging on either cortical or cancellous bone were unaffected in mitoCAT;LysM-Cre mice. On the other hand, attenuation of H2O2 generation in cells of the mesenchymal lineage targeted by Prx1-Cre partially prevented the loss of cortical bone caused by old age. Our results suggest the effects of sex steroid deficiency and aging on the murine skeleton are independent and result from distinct mechanisms. In the former, the prevailing mechanism of the cortical bone loss in both sexes is increased osteoclastogenesis caused by estrogen deficiency; this is likely driven, at least in part, by mesenchymal/stromal cell–derived SDF1. Decreased osteoblastogenesis, owing in part to increased H2O2, combined with increased osteoclastogenesis caused by aging mechanisms independent of estrogen deficiency, are the prevailing mechanisms of the loss of cortical bone with old age. PMID:27714847

Influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats exposed to sodium fluoride in drinking water.

PubMed

Błaszczyk, Iwona; Birkner, Ewa; Gutowska, Izabela; Romuk, Ewa; Chlubek, Dariusz

2012-06-01

Increased exposure to fluorine-containing compounds leads to accumulation of fluorides in hard tissues of bones and teeth, which may result in numerous skeletal and dental disorders. This study evaluates the influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats subjected to long-term exposure to sodium fluoride in drinking water. The study was conducted in 30 3-month-old female Wistar FL rats. The animals were divided into five groups, six rats per group. The control group consisted of rats receiving only distilled water as drinking water. All other groups received NaF in the amount of 10 mg/kg of body mass/day in their drinking water. In addition, respective animal groups received: NaF + Met group--10 mg of methionine/kg of body mass/day, NaF + Met + E group--10 mg of methionine/kg of body mass/day and 3 mg of vitamin E (tocopheroli acetas)/rat/day and NaF + E group--3 mg of vitamin E/rat/day. Femoral bones and incisor teeth were collected for the study, and the fluoride concentration was determined using a fluoride ion-selective electrode. Fluoride concentration in both bones and teeth was found to be higher in the NaF and NaF + Met groups compared to the control group. In groups NaF + Met + E and NaF + E, the study material contained much lower fluoride concentration compared to the NaF group, while the effect was more prominent in the NaF + E group. The results of the studies indicate that methionine and vitamin E have opposite effects on accumulation of fluorides in hard tissue in rats. By stimulating fluoride accumulation, methionine reduces the adverse effect of fluorides on soft tissue, while vitamin E, which prevents excessive accumulation of fluorides in bones and teeth, protects these tissues from fluorosis. Therefore, it seems that combined application of both compounds would be optimal for the prevention of the adverse effects of chronic fluoride intoxication.

Fingers to the Bone: United States Failure To Protect Child Farmworkers.

ERIC Educational Resources Information Center

Tucker, Lee

Agricultural work is the most hazardous and grueling area of employment open to U.S. children and is also the least protected. Adolescent farmworkers labor under more dangerous conditions than their peers working in nonagricultural settings and also face persistent wage exploitation and fraud. These adolescent workers are protected less under U.S.…

Spinacia oleracea extract attenuates disease progression and sub-chondral bone changes in monosodium iodoacetate-induced osteoarthritis in rats.

PubMed

Choudhary, Dharmendra; Kothari, Priyanka; Tripathi, Ashish Kumar; Singh, Sonu; Adhikary, Sulekha; Ahmad, Naseer; Kumar, Sudhir; Dev, Kapil; Mishra, Vijay Kumar; Shukla, Shubha; Maurya, Rakesh; Mishra, Prabhat R; Trivedi, Ritu

2018-02-20

Spinacia oleracea is an important dietary vegetable in India and throughout the world and has many beneficial effects. It is cultivated globally. However, its effect on osteoarthritis that mainly targets the cartilage cells remains unknown. In this study we aimed to evaluate the anti-osteoarthritic and chondro-protective effects of SOE on chemically induced osteoarthritis (OA). OA was induced by intra-patellar injection of monosodium iodoacetate (MIA) at the knee joint in rats. SOE was then given orally at 250 and 500 mg.kg - 1  day - 1 doses for 28 days to these rats. Anti-osteoarthritic potential of SOE was evaluated by micro-CT, mRNA and protein expression of pro-inflammatory and chondrogenic genes, clinically relevant biomarker's and behavioural experiments. In vitro cell free and cell based assays indicated that SOE acts as a strong anti-oxidant and an anti-inflammatory agent. Histological analysis of knee joints at the end of the experiment by safranin-o and toluidine blue staining established its protective effect. Radiological data corroborated the findings with improvement in the joint space and irregularity of the articular and atrophied femoral condyles and tibial plateau. Micro-CT analysis of sub-chondral bone indicated that SOE had the ability to mitigate OA effects by increasing bone volume to tissue volume (BV/TV) which resulted in decrease of trabecular pattern factor (Tb.Pf) by more than 200%. SOE stimulated chondrogenic marker gene expression with reduction in pro-inflammatory markers. Purified compounds isolated from SOE exhibited increased Sox-9 and Col-II protein expression in articular chondrocytes. Serum and urine analysis indicated that SOE had the potential to down-regulate glutathione S-transferase (GST) activity, clinical markers of osteoarthritis like cartilage oligometric matrix protein (COMP) and CTX-II. Overall, this led to a significant improvement in locomotion and balancing activity in rats as assessed by Open-field and Rota rod test. On the basis of in vitro and in vivo experiments performed with Spinacea oleracea extract we can deduce that SOE has the ability to alleviate the MIA induced deleterious effects.

In vivo antigenotoxic activity of watercress juice (Nasturtium officinale) against induced DNA damage.

PubMed

Casanova, Natalia A; Ariagno, Julia I; López Nigro, Marcela M; Mendeluk, Gabriela R; de los A Gette, María; Petenatti, Elisa; Palaoro, Luis A; Carballo, Marta A

2013-09-01

The present study was carried out to investigate the genotoxicity as well as possible protective activity against damage induced by cyclophosphamide (CP) of the aqueous juice of watercress (Nasturtium officinale, W.T. Aiton) in vivo. Male and female Swiss mice 7-8 weeks old (N = 48) were treated by gavage with 1 g kg(-1) body weight and 0.5 g kg(-1) body weight of watercress juice during 15 consecutive days. Genotoxicity and its possible protective effect were tested by the comet assay in peripheral blood cells and the micronucleus test in bone marrow. In addition, biopsies of the bladder, epididymis and testicles of mice were performed to extend the experimental design. Watercress juice per se did not induce genetic damage according to the comet assay and micronucleus study, exhibiting a protective activity against CP (P < 0.05 and P < 0.001, respectively). The comparative analysis of bladder histological changes obtained in the watercress plus CP group against those treated with CP alone suggests a probable protective effect. Further studies are needed in order to establish the protective role of watercress juice against DNA damage. Copyright © 2012 John Wiley & Sons, Ltd.

Stem cell factor (SCF) protects osteoblasts from oxidative stress through activating c-Kit-Akt signaling

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

Yang, Lei; Wu, Zhong; Yin, Gang

2014-12-12

Highlights: • SCF receptor c-Kit is functionally expressed in primary and transformed osteoblasts. • SCF protects primary and transformed osteoblasts from H{sub 2}O{sub 2}. • SCF activation of c-Kit in osteoblasts, required for its cyto-protective effects. • c-Kit mediates SCF-induced Akt activation in cultured osteoblasts. • Akt activation is required for SCF-regulated cyto-protective effects in osteoblasts. - Abstract: Osteoblasts regulate bone formation and remodeling, and are main target cells of oxidative stress in the progression of osteonecrosis. The stem cell factor (SCF)-c-Kit pathway plays important roles in the proliferation, differentiation and survival in a range of cell types, but littlemore » is known about its functions in osteoblasts. In this study, we found that c-Kit is functionally expressed in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. Its ligand SCF exerted significant cyto-protective effects against hydrogen peroxide (H{sub 2}O{sub 2}). SCF activated its receptor c-Kit in osteoblasts, which was required for its cyto-protective effects against H{sub 2}O{sub 2}. Pharmacological inhibition (by Imatinib and Dasatinib) or shRNA-mediated knockdown of c-Kit thus inhibited SCF-mediated osteoblast protection. Further investigations showed that protection by SCF against H{sub 2}O{sub 2} was mediated via activation of c-Kit-dependent Akt pathway. Inhibition of Akt activation, through pharmacological or genetic means, suppressed SCF-mediated anti-H{sub 2}O{sub 2} activity in osteoblasts. In summary, we have identified a new SCF-c-Kit-Akt physiologic pathway that protects osteoblasts from H{sub 2}O{sub 2}-induced damages, and might minimize the risk of osteonecrosis caused by oxidative stress.« less

Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial.

PubMed

Shen, Chwan-Li; Mo, Huanbiao; Yang, Shengping; Wang, Shu; Felton, Carol K; Tomison, Michael D; Soelaiman, Ima Nirwana

2016-12-23

Osteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal women show the bone-protective effect of tocotrienols (TTs) with antioxidant capability. We aim to access the safety and efficacy of TT consumption for bone health in postmenopausal women. In this 12-week randomised double-blinded placebo-controlled trial for the effects of dietary TT supplementation in postmenopausal women, postmenopausal women aged 45 years and older with at least 1 year after menopause and bone mineral density T-score at the spine and/or hip 2.5 or more below the reference values will be randomly assigned to 3 daily supplements: (1) placebo group receiving 860 mg olive oil, (2) low TT group receiving 430 mg of 70% pure TTs (containing 300 mg TT) and (3) high TT group receiving 860 mg of 70% pure TTs (600 mg TT). The primary outcome measure will be urinary N-terminal telopeptide. The secondary outcome measures will be serum bone-specific alkaline phosphatase, receptor activator of nuclear factor-κB ligand, osteoprotegerin, urinary 8-hydroxy-2'-deoxyguanosine and quality of life. At 0, 6 and 12 weeks, the following will be assessed: (1) primary and secondary outcome measures; (2) serum TT and tocopherol concentrations; (3) physical activity and food frequency questionnaires. Liver function will be monitored every 6 weeks for safety. 'Intent-to-treat' principle will be employed for data analysis. A model of repeated measurements with random effect error terms will be applied. Analysis of covariance, χ 2 analysis and regression will be used for comparisons. This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center. The findings of this trial will be submitted to a peer-reviewed journal in the areas of bone or nutrition and international conferences. NCT02058420; results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Adiponectin improves the osteointegration of titanium implant under diabetic conditions by reversing mitochondrial dysfunction via the AMPK pathway in vivo and in vitro.

PubMed

Hu, Xiao-Fan; Wang, Lin; Lu, Yi-Zhao; Xiang, Geng; Wu, Zi-Xiang; Yan, Ya-Bo; Zhang, Yang; Zhao, Xiong; Zang, Yuan; Shi, Lei; Lei, Wei; Feng, Ya-Fei

2017-10-01

Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat-derived adipocytokine with strong antioxidant, mitochondrial-protective and anti-diabetic efficacies. We hypothesized that mitochondrial dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM+APN, DM+AICAR (AMPK activator) and DM+APN+Compound C (AMPK inhibitor). In vivo, APN or APN+Compound C were administered to diabetic db/db mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterial-engineering to improve clinical performance of TI in diabetic patients. The loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients. Copyright © 2017. Published by Elsevier Ltd.