Browsing by Subject "bone remodeling"
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Item Bisphosphonate Treatment Modifies Canine Bone Mineral and Matrix Properties and their Heterogeneity(2010-03) Gourion-Arsiquaud, Samuel; Allen, Matthew R.; Burr, David B.; Vashishth, Deepak; Tang, Simon Y; Boskey, Adele LBone loss and alterations in bone quality are major causes leading to bone fragility in postmenopausal women. Although bisphosphonates are well known to reduce bone turnover and prevent bone loss in postmenopausal osteoporosis, their effects on other bone properties are not fully characterized. Changes in bone mineral and matrix properties may contribute to the anti-fracture efficacy observed with bisphosphonate treatments. The aim of this work was to analyze the effect of a 1-year treatment with either alendronate or risedronate, at low and high doses, on spatially resolved bone material and compositional properties that could contribute to the fracture efficacy of these agents. Distal tibias from 30 normal beagles that had been treated daily for 1 year with oral doses of vehicle (Veh), alendronate (Aln) at 0.2 or 1 mg/kg, and risedronate (Ris) at 0.1 or 0.5 mg/kg were analyzed by Fourier Transform Infrared imaging (FTIRI) to assess the changes in both mineral and matrix properties in discrete bone areas. The widths at half maximum of the pixel histograms for each FTIRI parameter were used to assess the heterogeneity of the bone tissue. Aln and Ris increased the mineral content and the collagen maturity mainly in cancellous bone and at the endocortical surface. Significant differences were observed in the mineral content and in the hydroxyapatite crystallinity distribution in bone tissue, which can contribute to reduced ductility and micro-crack accumulation. No significant differences were observed between low and high dose nor between Aln and Ris treatments. These results show that pharmacologic suppression of bone turnover increases the mineral and matrix bone tissue maturity in normal cancellous and endocortical bone areas where bone turnover is higher. These positive effects for decreased fracture risk are also associated with a loss of bone heterogeneity that could be one factor contributing to increased bone tissue brittleness and micro-crack accumulation.Item Bone development and remodeling in metabolic disorders(Wiley, 2020-01) Serra-Vinardell, Jenny; Roca-Ayats, Neus; De-Ugarte, Laura; Vilageliu, Lluïsa; Balcells, Susanna; Grinberg, Daniel; Anatomy and Cell Biology, School of MedicineThere are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre‐existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.Item Exploring the Bone Proteome to Help Explain Altered Bone Remodeling and Preservation of Bone Architecture and Strength in Hibernating Marmots(University of Chicago Press, 2016-09) Doherty, Alison H.; Roteliuk, Danielle M.; Gookin, Sara E.; McGrew, Ashley K.; Broccardo, Carolyn J.; Condon, Keith W.; Prenni, Jessica E.; Wojda, Samantha J.; Florant, Gregory L.; Donahue, Seth W.; Department of Anatomy & Cell Biology, IU School of MedicinePeriods of physical inactivity increase bone resorption and cause bone loss and increased fracture risk. However, hibernating bears, marmots, and woodchucks maintain bone structure and strength, despite being physically inactive for prolonged periods annually. We tested the hypothesis that bone turnover rates would decrease and bone structural and mechanical properties would be preserved in hibernating marmots (Marmota flaviventris). Femurs and tibias were collected from marmots during hibernation and in the summer following hibernation. Bone remodeling was significantly altered in cortical and trabecular bone during hibernation with suppressed formation and no change in resorption, unlike the increased bone resorption that occurs during disuse in humans and other animals. Trabecular bone architecture and cortical bone geometrical and mechanical properties were not different between hibernating and active marmots, but bone marrow adiposity was significantly greater in hibernators. Of the 506 proteins identified in marmot bone, 40 were significantly different in abundance between active and hibernating marmots. Monoaglycerol lipase, which plays an important role in fatty acid metabolism and the endocannabinoid system, was 98-fold higher in hibernating marmots compared with summer marmots and may play a role in regulating the changes in bone and fat metabolism that occur during hibernation.Item In vivo reference point indentation reveals positive effects of raloxifene on mechanical properties following six months of treatment in skeletally mature beagle dogs.(Published article can be found at: http://www.sciencedirect.com/science/article/pii/S8756328213002718 doi: 10.1016/j.bone.2013.07.009, 2013) Aref, Mohammad; Gallant, Maxime A.; Organ, Jason M.; Wallace, Joseph M.; Newman, Christopher L.; Burr, David B.; Brown, Drew M.; Allen, Matthew R.Raloxifene treatment has been shown previously to positively affect bone mechanical properties following one year of treatment in skeletally mature dogs. Reference point indentation (RPI) can be used for in vivo assessment of mechanical properties and has been shown to produce values that are highly correlated with properties derived from traditional mechanical testing. The goal of this study was to use RPI to determine if raloxifene-induced alterations in mechanical properties occurred after 6 months of treatment. Twelve skeletally mature female beagle dogs were treated for 6 months with oral doses of saline vehicle (VEH, 1 ml/kg/day) or a clinically relevant dose of raloxifene (RAL, 0.5 mg/kg/day). At six months, all animals underwent in vivo RPI (10 N force, 10 cycles) of the anterior tibial midshaft. RPI data were analyzed using a custom MATLAB program, designed to provide cycle-by-cycle data from the RPI test and validated against the manufacturer-provided software. Indentation distance increase (IDI), a parameter that is inversely related to bone toughness, was significantly lower in RAL-treated animals compared to VEH (-16.5%) suggesting increased bone toughness. Energy absorption within the first cycle was significantly lower with RAL compared to VEH (-21%). These data build on previous work that has documented positive effects of raloxifene on material properties by showing that these changes exist after 6 months.Item Issues in modern bone histomorphometry(2011-11) Recker, Robert R; Kimmel, DB; Dempster, D; Weinstein, RS; Wronski, TJ; Burr, David B.This review reports on proceedings of a bone histomorphometry session conducted at the Fortieth International IBMS Sun Valley Skeletal Tissue Biology Workshop held on August 1, 2010. The session was prompted by recent technical problems encountered in conducting histomorphometry on bone biopsies from humans and animals treated with anti-remodeling agents such as bisphosphonates and RANKL antibodies. These agents reduce remodeling substantially, and thus cause problems in calculating bone remodeling dynamics using in vivo fluorochrome labeling. The tissue specimens often contain few or no fluorochrome labels, and thus create statistical and other problems in analyzing variables such as mineral apposition rates, mineralizing surface and bone formation rates. The conference attendees discussed these problems and their resolutions, and the proceedings reported here summarize their discussions and recommendations.Item Mechanotransduction in Living Bone: Effects of the Keap1-Nrf2 Pathway(2019-08) Priddy, Carlie; Li, Jiliang; Dai, Guoli; Wallace, Joseph M.The Keap1-Nrf2 pathway regulates a wide range of cytoprotective genes, and has been found to serve a protective and beneficial role in many body systems. There is limited information available, however, about its role in bone homeostasis. While Nrf2 activation has been suggested as an effective method of increasing bone mass and quality, there have been conflicting reports which associate Keap1 deficiency with detrimental phenotypes. As Keap1 deletion is a common method of Nrf2 activation, further study should address the impacts of various methods of regulating Nrf2 expression. Also, little research has been conducted on the specific pathways by which Nrf2 activation improves bone quality. In this study, the effects of alterations to Nrf2 activation levels were explored in two specific and varied scenarios. In the first experiment, moderate Nrf2 activation was achieved via partial deletion of its sequestering protein, Keap1, in an aging mouse model. The hypothesis tested here is that moderate Nrf2 activation improves bone quality by affecting bone metabolism and response to mechanical loading. The results of this first experiment suggest a subtle, sex-specific effect of moderate Nrf2 activation in aging mice which improves specific indices of bone quality to varying degrees, but does not affect loading-induced bone formation. It is likely that the overwhelming phenotypic impacts associated with aging or the systemic effects of global Keap1 deficiency may increase the difficulty in parsing out significant effects that can be attributed solely to Nrf2 activation. In the second experiment, a cell-specific knockout of Nrf2 in the osteocytes was achieved using a Cre/Lox breeding system. The hypothesis tested here is that osteocyte-specific deletion of Nrf2 impairs bone quality by affecting bone metabolism and response to mechanical loading. The results of this experiment suggest an important role of Nrf2 in osteocyte function which improves certain indices of bone quality, which impacts male and female bones in different 7 ways, but did not significantly impact loading-induced bone formation. Further studies should modify the method of Nrf2 activation in an effort to refine the animal model, allowing the effects of Nrf2 to be isolated from the potential systemic effects of Keap1 deletion. Future studies should also utilize other conditional knockout models to elucidate the effects of Nrf2 in other specific cell types.Item Osteocitos y la regulación de la formación ósea(2016) Bellido, Teresita; Pelegrini, Gretel; Department of Anatomy and Cell Biology, School of MedicineFor many years, osteocytes have been the forgotten bone cells and considered as inactive spectators buried in the bone matrix. We now know that osteocytes detect and respond to mechanical and hormonal stimuli to coordinate bone resorption and bone formation. Osteocytes are currently considered a major source of molecules that regulate the activity of osteoclasts and osteoblasts, such as RANKL and sclerostin; and genetic and pharmacological manipulations of either molecule markedly affect bone homeostasis. This article summarizes recent findings demonstrating the mechanisms by which osteocytes regulate the number and activity of osteoblasts and thus affect bone formation.Item The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data.(2009-05) Allen, Matthew R.; Burr, David B.Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great interest in the medical and research communities yet remains an enigma, given its unknown pathogenesis. The goal of this review is to summarize the various proposed hypotheses underlying BRONJ. Although a role of the oral mucosa has been proposed, the bone is likely the primary tissue of interest for BRONJ. The most popular BRONJ hypothesis-manifestation of necrotic bone resulting from bisphosphonate--induced remodeling suppression--is supported mostly by indirect evidence, although recent data have shown that bisphosphonates significantly reduce remodeling in the jaw. Remodeling suppression would be expected, and has been shown, to allow accumulation of nonviable osteocytes, whereas a more direct cytotoxic effect of bisphosphonates on osteocytes has also been proposed. Bisphosphonates have antiangiogenic effects, leading to speculation that this could contribute to the BRONJ pathogenesis. Compromised angiogenesis would most likely be involved in post-intervention healing, although other aspects of the vasculature (eg, blood flow) could contribute to BRONJ. Despite infection being present in many BRONJ patients, there is no clear evidence as to whether infection is a primary or secondary event in the pathophysiology. In addition to these main factors proposed in the pathogenesis, numerous cofactors associated with BRONJ (eg, diabetes, smoking, dental extraction, concurrent medications) could interact with bisphosphonates and affect remodeling, angiogenesis/blood flow, and/or infection. Because our lack of knowledge concerning BRONJ pathogenesis results from a lack of data, it is only through the initiation of hypothesis-driven studies that significant progress will be made to understand this serious and debilitating condition.Item Theoretical analysis of alendronate and risedronate effects on canine vertebral remodeling and microdamage(2009-05) Wang, Xiang; Erickson, Antonia M; Allen, Matthew R.; Burr, David B.; Martin, R Bruce; Hazelwood, Scott JBisphosphonates suppress bone remodeling activity, increase bone volume, and significantly reduce fracture risk in individuals with osteoporosis and other metabolic bone diseases. The objectives of the current study were to develop a mathematical model that simulates control and 1 year experimental results following bisphosphonate treatment (alendronate or risedronate) in the canine fourth lumbar vertebral body, validate the model by comparing simulation predictions to 3 year experimental results, and then use the model to predict potential long term effects of bisphosphonates on remodeling and microdamage accumulation. To investigate the effects of bisphosphonates on bone volume and microdamage, a mechanistic biological model was modified from previous versions to simulate remodeling in a representative volume of vertebral trabecular bone in dogs treated with various doses of alendronate or risedronate, including doses equivalent to those used for treatment of post-menopausal osteoporosis in humans. Bisphosphonates were assumed to affect remodeling by suppressing basic multicellular unit activation and reducing resorption area. Model simulation results for trabecular bone volume fraction, microdamage, and activation frequency following 1 year of bisphosphonate treatment are consistent with experimental measurements. The model predicts that trabecular bone volume initially increases rapidly with 1 year of bisphosphonate treatment, and continues to slowly rise between 1 and 3 years of treatment. The model also predicts that microdamage initially increases rapidly, 0.5–1.5-fold for alendronate or risedronate during the first year of treatment, and reaches its maximum value by 2.5 years before trending downward for all dosages. The model developed in this study suggests that increasing bone volume fraction with long term bisphosphonate treatment may sufficiently reduce strain and damage formation rate so that microdamage does not accumulate above that which is initiated in the first two years of treatment.Item Type 1 diabetes mellitus leads to gingivitis and an early compensatory increase in bone remodeling(Wiley, 2023-02) Yuan, Xue; Amin, Vedanshi; Zhu, Tianli; Kittaka, Mizuho; Ueki, Yasuyoshi; Bellido, Teresita M.; Turkkahraman, Hakan; Orthodontics and Oral Facial Genetics, School of DentistryBackground Type 1 diabetes mellitus (T1DM) and periodontitis have long been thought to be biologically connected. Indeed, T1DM is a risk factor for periodontal disease. With the population of diabetic individuals growing, it is more important than ever to understand the negative consequences of diabetes on the periodontium and the mechanisms. The aim of this study was to find out the early effects of T1DM on the periodontium without any experimentally induced periodontitis. Methods We established the streptozotocin (STZ)-induced diabetic mouse model and examined the periodontium 8 weeks later by histology, molecular and cellular assays. Microcomputed tomographic (𝜇CT) imaging and in vivo fluorochrome labeling were also used to quantify bone volume and mineral apposition rates (MAR). Results The histologic appearance of epithelium tissue, connective tissue, and periodontal ligament in the diabetic condition was comparable with that of control mice. However, immune cell infiltration in the gingiva was dramatically elevated in the diabetic mice, which was accompanied by unmineralized connective tissue degeneration. Bone resorption activity was significantly increased in the diabetic mice, and quantitative 𝜇CT demonstrated the bone volume, the ratio of bone volume over tissue volume, and cemento-enamel junction to alveolar bone crest (CEJ-ABC) in the diabetic condition were equivalent to those in the control group. In vivo fluorochrome labeling revealed increased MAR and bone remodeling in the diabetic mice. Further investigation found the diabetic mice had more osteoprogenitors recruited to the periodontium, allowing more bone formation to balance the enhanced bone resorption. Conclusions STZ-induced T1DM mice, at an early stage, have elevated gingival inflammation and soft tissue degeneration and increased bone resorption; but still the alveolar bone was preserved by recruiting more osteoprogenitor cells and increasing the rate of bone formation. We conclude that inflammation and periodontitis precede alveolar bone deterioration in diabetes.