Recent advances in bone biology provide insight into the pathogenesis of bone diseases.
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Keywords:
Endochondral ossification
Bone sialoprotein
Bone remodeling
Bone cell
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Endochondral ossification
Bone sialoprotein
Bone remodeling
Bone cell
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Abstract Chronic stress and depression are associated with alterations in the hypothalamic–pituitary–adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro–computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.
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The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget's disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.
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Bone remodeling
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Abstract Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice. Given that high systemic triiodothyronine (T3) levels in Mct8 knockout (KO) mice are still able to cause trabecular bone loss, alternative TH transporters must substitute for MCT8 function in bone. In this study, we analyzed the skeletal phenotypes of male Oatp1c1 KO and Mct10 KO mice, which are euthyroid, and male Mct8/Oatp1c1 and Mct8/Mct10 double KO mice, which have elevated circulating T3 levels, to unravel the role of TH transport in bone. MicroCT analysis showed no significant trabecular bone changes in Oatp1c1 KO mice at 4 weeks and 16 weeks of age compared with wild-type littermate controls, whereas 16-week-old Mct8/Oatp1c1 double KO animals displayed trabecular bone loss. At 12 weeks, Mct10 KO mice, but not Mct8/Mct10 double KO mice, had decreased trabecular femoral bone volume with reduced osteoblast numbers. By contrast, lack of Mct10 in 24-week-old mice led to trabecular bone gain at the femur with increased osteoblast numbers and decreased osteoclast numbers whereas Mct8/Mct10 double KO did not alter bone mass. Neither Mct10 nor Mct8/Mct10 deletion affected vertebral bone structures at both ages. In vitro, osteoblast differentiation and activity were impaired by Mct10 and Mct8/Mct10-deficiency. These data demonstrate that MCT10, but not OATP1C1, is a site- and age-dependent regulator of bone mass and turnover in male mice.
Bone remodeling
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Glucocorticoids therapy is the most common cause of secondary iatrogenic osteoporosis.The bone loss occurs predominantly due to a decrease in bone formation, although increased bone resorption also occurs. Insulin resistance is the key pathology in type 2 diabetes negatively influence bone remodeling and leads to reduced bone strength. Loss of sex steroids, particularly oestradiol, as in ovariectomized rats,leads to increased skeletal remodeling over and above the age-related increment, together with excessive osteoclast activity. In this study, ovariectomy DEX group has highly significant increase in relative cortical resorptioncompared to ovaiectomy and sham DEX groups, also ovariectomy and DEX group has highly significant decrease in bone thickness compared to ovariectomy and sham DEX groups. The consequent increase in remodeling activation increases the overall resorption rate without a compensatory increase in formation, leading to rapid bone loss.This negative effect on bone which is due to the glucocorticoid excess is also mediated by indirect mechanisms such as the calcium malabsorption and hypercalciuria. In response to the enhanced supply of calcium from the skeleton, PTH secretion tends to be diminished, thereby reducing vitamin D [1,25(OH)2 cholecalciferol] concentration with a consequent reduction in calcium absorption.
Bone remodeling
Osteopenia
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Gastrointestinal hormones including gastric inhibitory polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 are secreted immediately after meal ingestion, and GIP and GLP-2 have been shown to regulate bone turnover. We hypothesize that endogenous GLP-1 may also be important for control of skeletal homeostasis. We investigated the role of GLP-1 in the regulation of bone metabolism using GLP-1 receptor knockout (Glp-1r−/−) mice. A combination of bone density and histomorphometry, osteoclast activation studies, biochemical analysis of calcium and PTH, and RNA analysis was used to characterize bone and mineral homeostasis in Glp-1r−/− and Glp-1r+/+ littermate controls. Glp-1r−/− mice have cortical osteopenia and bone fragility by bone densitometry as well as increased osteoclastic numbers and bone resorption activity by bone histomorphometry. Although GLP-1 had no direct effect on osteoclasts and osteoblasts, Glp-1r−/− mice exhibited higher levels of urinary deoxypyridinoline, a marker of bone resorption, and reduced levels of calcitonin mRNA transcripts in the thyroid. Moreover, calcitonin treatment effectively suppressed urinary levels of deoxypyridinoline in Glp-1r−/−, mice and the GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wild-type mice. These findings establish an essential role for endogenous GLP-1 receptor signaling in the control of bone resorption, likely through a calcitonin-dependent pathway.
Deoxypyridinoline
Bone remodeling
Calcitonin receptor
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Human bones are formed through intramembranous and endochondral ossification followed by a period of appositional growth. Skeletal homeostasis of cancellous/trabecular and cortical bone tissue is sustained through a lifelong biological process known as bone remodeling. Bone remodeling is the balanced-integrated function of osteocyte signaling, osteoblast bone formation, and osteoclast bone resorption. In this review, the autocrine and paracrine factors that control the rate of bone synthesis and resorption as they attribute to osteogenic cell differentiation, localization, and function are reviewed. These factors direct the transition between each phase of the remodeling process: activation, resorption, reversal, formation, and mineralization. The five primary intracellular signaling pathways that regulate osteogenic gene expression, cell function, localization, and survival include: Wnt/βcatenin, transforming growth factor-β, bone morphogenetic protein, arachidonic acid metabolism/prostaglandin synthesis, and receptor activator of nuclear factor κ B are also discussed. Several diseases are associated with dysregulated bone remodeling and aberrant signaling in osteogenic cells. Some hereditable and acquired genetic mutations result in skeletal diseases, like craniometaphyseal dysplasia, osteogenesis imperfecta, osteopetrosis, and myeloma bone disease. Other skeletal disorders are attributed to endogenous and exogenous induced hormonal imbalances, like postmenopausal osteoporosis or glucocorticoid steroid use, or cytokine imbalances that exacerbate inflammatory diseases, like rheumatoid arthritis. The role of excessive resorption and inadequate bone formation have in these diseases that may result in overall decreased skeletal tissue integrity, chronic pain, pathological bone fractures, and mortality are also examined.
Bone remodeling
Bone cell
Bone remodeling period
Osteopetrosis
Endochondral ossification
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