The Experts below are selected from a list of 13329 Experts worldwide ranked by ideXlab platform
Roland Baron - One of the best experts on this subject based on the ideXlab platform.
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molecular regulation of Osteoclast Activity
Reviews in Endocrine & Metabolic Disorders, 2007Co-Authors: Angela Bruzzaniti, Roland BaronAbstract:Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Paget's disease, bone resorption by Osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of Osteoclastic bone resorption is regulated either at the level of differentiation of Osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature Osteoclast control its attachment, migration and resorption. Thus, reducing Osteoclast numbers and/or decreasing the bone resorbing Activity of Osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of Osteoclast Activity will be discussed.
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dynamin forms a src kinase sensitive complex with cbl and regulates podosomes and Osteoclast Activity
Molecular Biology of the Cell, 2005Co-Authors: Angela Bruzzaniti, Lynn Neff, Archana Sanjay, William C Horne, Pietro De Camilli, Roland BaronAbstract:Podosomes are highly dynamic actin-containing adhesion structures found in Osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases Osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of Osteoclasts and that dynamin forms a complex with Cbl in Osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in Osteoclasts was decreased by Src tyrosine kinase Activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased Osteoclast bone resorbing Activity and migration, whereas overexpression of dynK44A decreased Osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in Osteoclast adhesion, migration, and resorption.
Angela Bruzzaniti - One of the best experts on this subject based on the ideXlab platform.
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pyk2 deficiency potentiates osteoblast differentiation and mineralizing Activity in response to estrogen or raloxifene
Molecular and Cellular Endocrinology, 2018Co-Authors: Sumana Posritong, Jung Min Hong, Pierre P Eleniste, Patrick W Mcintyre, Evan R Himes, Vruti Patel, Melissa A Kacena, Angela BruzzanitiAbstract:Abstract Bone remodeling is controlled by the actions of bone-degrading Osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on Osteoclast Activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced Osteoclast Activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) Activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.
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molecular regulation of Osteoclast Activity
Reviews in Endocrine & Metabolic Disorders, 2007Co-Authors: Angela Bruzzaniti, Roland BaronAbstract:Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Paget's disease, bone resorption by Osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of Osteoclastic bone resorption is regulated either at the level of differentiation of Osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature Osteoclast control its attachment, migration and resorption. Thus, reducing Osteoclast numbers and/or decreasing the bone resorbing Activity of Osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of Osteoclast Activity will be discussed.
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dynamin forms a src kinase sensitive complex with cbl and regulates podosomes and Osteoclast Activity
Molecular Biology of the Cell, 2005Co-Authors: Angela Bruzzaniti, Lynn Neff, Archana Sanjay, William C Horne, Pietro De Camilli, Roland BaronAbstract:Podosomes are highly dynamic actin-containing adhesion structures found in Osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases Osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of Osteoclasts and that dynamin forms a complex with Cbl in Osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in Osteoclasts was decreased by Src tyrosine kinase Activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased Osteoclast bone resorbing Activity and migration, whereas overexpression of dynK44A decreased Osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in Osteoclast adhesion, migration, and resorption.
Robert J Moore - One of the best experts on this subject based on the ideXlab platform.
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changes in osteocyte density correspond with changes in osteoblast and Osteoclast Activity in an osteoporotic sheep model
Osteoporosis International, 2012Co-Authors: Mohammad Reza Zarrinkalam, A Mulaibrahimovic, Gerald J Atkins, Robert J MooreAbstract:Histomorphometric assessment of trabecular bone in osteoporotic sheep showed that bone volume, osteoid surface area, bone formation rate, and osteocyte density were reduced. In contrast, eroded surface area and empty lacunae density were increased. Changes in osteocyte density correlated with changes in osteoblast and Osteoclast Activity. Osteocytes contribute to the regulation of the Activity of Osteoclasts and osteoblasts that together control bone mass. Osteocytes therefore likely play a role in the loss of bone mass associated with osteoporosis. The purpose of this study was to investigate the relationships between osteocyte lacunar density and other bone histomorphometric parameters in the iliac crest (IC) and lumbar spine (LS) of osteoporotic sheep. Osteoporosis was induced in ten mature ewes by an established protocol involving a combination of ovariectomy, dexamethasone injection, and low calcium diet for 6 months. Five ewes were used as controls. Post-mortem IC and LS biopsies were collected and processed for further histomorphometric assessment. Bone volume, osteoid surface, and bone formation rate in the IC and LS of osteoporotic sheep were reduced compared to those of the controls. In contrast, eroded surface area was increased in osteoporotic sheep. In the osteoporotic group, osteocyte density was reduced in the LS region and to a greater extent in the IC region. The empty osteocyte lacunae were increased 1.7-fold in LS and 2.1-fold in IC in the osteoporotic group. The osteocyte density correlated positively with markers of osteoblast Activity and negatively with those of Osteoclast Activity. Depletion of osteocytes and an increase in the empty lacunae could be important factors contributing to bone loss in this model since they may adversely affect intercellular communication between osteoblasts and Osteoclasts. The regional differences in histology suggest that there may be different pathological mechanisms operating at different anatomical sites.
Cheng Wang - One of the best experts on this subject based on the ideXlab platform.
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analysis of early stage osteonecrosis of the human femoral head and the mechanism of femoral head collapse
International Journal of Biological Sciences, 2018Co-Authors: Cheng Wang, Haoye Meng, Yu Wang, Bin Zhao, Chenyang Zhao, Weijia Sun, Yun Zhu, Bingxing Han, Xueling Yuan, Ruoxi LiuAbstract:We explored the mechanism of early stage osteonecrotic femoral head collapse by analyzing and comparing different regions in human osteonecrotic femoral head samples. Eight osteonecrotic femoral heads (ARCO II-III) were obtained from patients undergoing total hip arthroplasty. Bone structure was observed and evaluated by micro-computed tomography (CT) scans and pathology. Osteoblast and Osteoclast activities were detected by tartrate-resistant acid phosphatase, alkaline phosphatase, and immunofluorescent staining. Some trabeculae had microfractures in the subchondral bone and necrotic region, which had lower bone mineral density, as well as trabecular thickness and number, but greater Osteoclast Activity. A sclerotic band had already appeared in certain samples which had greater trabecular thickness and number, bone mineral density, and osteoblast Activity. The appearance of the femoral head did not change significantly in the early stage of osteonecrosis of the femoral head. However, osteoblast and Osteoclast activities had already changed in different regions of the osteonecrotic femoral head, which may lead to eventual collapse of the femoral head. Therefore, osteonecrosis of the femoral head must be treated during the early stage. In addition, osteoblast Activity should be promoted and Osteoclast Activity inhibited as early as possible to prevent collapse of an osteonecrotic femoral head.
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bone microstructure and regional distribution of osteoblast and Osteoclast Activity in the osteonecrotic femoral head
PLOS ONE, 2014Co-Authors: Cheng Wang, Xueling Yuan, Xin Wang, Wenlong Gou, Aiyuan Wang, Quanyi Guo, Jiang PengAbstract:Objective To detect and compare the bone microstructure and osteoblast and Osteoclast Activity in different regions of human osteonecrotic femoral heads.
Stuart H Ralston - One of the best experts on this subject based on the ideXlab platform.
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NATURE MEDICINE ADVANCE ONLINE PUBLICATION Regulation of bone mass, bone loss and Osteoclast Activity by cannabinoid receptors A R T I C L E S
2020Co-Authors: Ayme I Idris, Iai R Greig, Susa A Ridge, Ruth A Ross, Robert J Van &apos, David Baker, Stuart H RalstonAbstract:Accelerated Osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate Osteoclast Activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB 1 ) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB 1 and CB 2 receptors prevented ovariectomy-induced bone loss in vivo and caused Osteoclast inhibition in vitro by promoting Osteoclast apoptosis and inhibiting production of several Osteoclast survival factors. These studies show that the CB 1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB 1 -and CB 2 -selective cannabinoid receptor antagonists are a new class of Osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases. Osteoclasts are cells derived from the monocyte-macrophage lineage that have an important role in modeling bone during skeletal growth and in remodeling bone during adult life 1 . Increased Osteoclast Activity or uncoupling of Osteoclastic bone resorption from bone formation results in focal or generalized bone loss and is a characteristic feature of bone diseases such as osteoporosis, Paget disease of bone and cancer-associated bone disease 2 . The importance of Osteoclastic bone resorption in the pathogenesis of these diseases is reflected by the fact that the most successful drug treatments for bone disease work by inhibiting bone resorption 3 . Osteoclastic bone resorption is regulated by a complex interplay between circulating calciotropic hormones like parathyroid hormone, calcitriol and sex hormones, and local regulators of bone cell Activity like receptor activator of nuclear factor κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF) and osteoprotegerin 4 . Recent work has shown that neuroendocrine pathways and neurotransmitters also have a key role in the regulation of bone remodeling RESULTS Skeletal phenotype of CB 1 knockout mice We found that CB 1 knockout mice had significantly increased bone mineral density (BMD) when compared with wild-type littermates. For example, the levels of BMD assessed by dual X-ray absorptiometry at the femur were 18% higher (P < 0.001) in CB 1 knockout animals than wild-type and values at the spine were 10% higher (P < 0.02
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cytokine induced nitric oxide inhibits bone resorption by inducing apoptosis of Osteoclast progenitors and suppressing Osteoclast Activity
Journal of Bone and Mineral Research, 1997Co-Authors: Rob Vant Hof, Stuart H RalstonAbstract:Interferon-g (IFN-g) has been shown to inhibit interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a) stimulated bone resorption by strongly stimulating nitric oxide (NO) synthesis. Here we studied the mechanisms underlying this inhibition. Osteoclasts were generated in 10-day cocultures of mouse osteoblasts and bone marrow cells and the effect of cytokine-induced NO on Osteoclast formation and Activity was determined. Stimulation of the cocultures with IL-1b, TNF-a and IFN-g markedly enhanced NO production by 50- to 70-fold, and this was found to be derived predominantly from the osteoblast cell layer. When high levels of NO were induced by cytokines during early stages of the coculture, Osteoclast formation was virtually abolished and bone resorption markedly inhibited. Cytokine stimulation during the latter stages of coculture also resulted in inhibition of bone resorption, but here the effects were mainly due to an inhibitory effect on Osteoclast Activity. At all stages, however, the inhibitory effects of cytokines on Osteoclast formation and Activity were blocked by the NO-synthase inhibitor L-NMMA. Further investigations suggested that the NO-mediated inhibition of Osteoclast formation was due in part to apoptosis of Osteoclast progenitors. Cytokine stimulation during the early stage of the culture caused a large increase in apoptosis of bone marrow cells, and these effects were blocked by L-NMMA and enhanced by NO donors. We found no evidence of apoptosis in osteoblasts exposed to high levels of cytokine-induced NO at any stage in the culture, however, or of apoptosis affecting mature Osteoclasts exposed to high levels of NO, suggesting that immature cells in the bone marrow compartment are most sensitive to NO-induced apoptosis. In summary, these studies identify NO as a potentially important osteoblast-Osteoclast coupling factor which has potent inhibitory effects on bone resorption. These actions, in turn, are mediated by inhibition of Osteoclast formation probably due to NO-induced apoptosis of Osteoclast progenitors and by inhibition of the resorptive Activity of mature Osteoclasts. (J Bone Miner Res 1997;12:1797‐1804)
