Calcium Regulation in Osteoclasts

破骨细胞中的钙调节

• 批准号: 8628387
• 负责人: Mary Beth Humphrey
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628387
• 关键词: Affect; Amino Acids; Animal Model; Animals; Automobile Driving; Binding; Biochemical; Biological; Bone Marrow; Bone Resorption; Bone remodeling; Calcium; Cell Proliferation; Cell Surface Receptors; Cells; Coculture Techniques; Complex; Critical Pathways; Cytokine Signaling; Cytoplasmic Protein; Data; Defect; Development; Diet; Disease; Equilibrium; Event; Frequencies; Genes; Hematopoietic stem cells; In Vitro; Inositol; Ion Channel; Knock-out; Knockout Mice; Lead; Life; Macrophage Colony-Stimulating Factor; Mediating; Methods; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Nuclear; Obstruction; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; Paget' s Disease; Pathway interactions; Periodontitis; Phenotype; Process; Protein Binding; Protein Isoforms; Proteins; RNA Splicing; Recruitment Activity; Regulation; Rheumatoid Arthritis; Role; Series; Signal Transduction; Staging; Stromal Cells; TNFSF11 gene; Testing; Therapeutic; Up-Regulation; Variant; Work; base; bone; bone loss; design; improved; in vivo; inhibitor/antagonist; novel therapeutic intervention; osteoclastogenesis; prevent; progenitor; programs; public health relevance; receptor; receptor coupling; research study; response; stoichiometry

Healthy bone maintains a balance of bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Many disease states, including chronic periodontitis, osteoporosis, rheumatoid arthritis, Paget's disease, and cancer metastases develop when osteoclasts are excessively recruited or inappropriately activated. Osteoclasts are constantly made throughout life from hematopoietic stem cells residing in the bone marrow through a series of complex events involving cytokine signaling and the microenvironment. Ca2+ signaling has an essential role in the regulation of osteoclastogenesis. Ca2+ channels activated in response to the depletion of intracellular Ca2+ stores have been suggested to mediate Ca2+ signaling in early stages of osteoclast formation. However, the exact molecules and the mechanism by which these channels control Ca2+ signaling in osteoclastogenesis are largely unknown. Using a combination of molecular, cell biological and whole animal studies, we show that the Transient Receptor Potential channel, TRPC1, enhances osteoclastogenesis at an early stage, whereas its inhibitor, the small cytosolic protein, I-mfa has an opposite effect. Enhanced osteoclastogenesis in I-mfa-null mice is corrected in mice lacking both genes indicating that TRPC1-mediated Ca2+ signaling has a dominant effect over I-mfa in osteoclast formation. Therefore, we propose that TRPC1 and I-mfa are essential for osteoclastogenesis by regulating Ca2+ signaling. This hypothesis will be tested by an integrated approach at the molecular, biophysical, cellular, and organismal levels by asking whether and how TRPC1 and I-mfa affect proliferation and "priming" of early osteoclast progenitors (specific aim 1), how TRPC1 and I-mfa modulate Ca2+ signaling in osteoclasts (specific aims 2 and 3), and whether TRPC1 and I-mfa affect osteoclastogenesis in a cell-autonomous fashion in vivo and in vitro and further, whether they affect osteoclast recruitment in experimentally induced animal models of osteoclastogenesis (specific aim 4). Our studies will lead to further understanding of critical pathways in the regulation of osteoclast development and function, which is needed to identify and develop new therapeutic interventions to control osteoclastogenesis and prevent bone loss.

健康的骨保持骨形成的平衡，由成骨细胞和由骨吸收介导 破骨细胞。许多疾病状态，包括慢性牙周炎，骨质疏松症，类风湿关节炎，Paget的 疾病和癌症转移发生过度募集或不适当 活性。骨细胞在骨骼中不断地制造出造血干细胞的生命 通过一系列涉及细胞因子信号传导和微环境的复杂事件骨髓。 Ca2+ 信号在调节破骨细胞生成中具有至关重要的作用。响应于 已经提出细胞内Ca2+存储的耗竭来介导Ca2+信号传导。 破骨细胞形成。但是，这些通道控制Ca2+的精确分子和机制 破骨细胞生成中的信号传导在很大程度上未知。结合分子，细胞生物学和 整个动物研究，我们表明瞬态受体电位通道TRPC1增强了 在早期阶段的破骨细胞生成，而其抑制剂，小的胞质蛋白，i-MFA的相反 影响。在缺乏这两个基因的小鼠中，校正了I-MFA-NULL小鼠中的破骨细胞生成，表明表明这两个基因 TRPC1介导的Ca2+信号传导在破骨细胞形成中与I-MFA具有显着作用。因此，我们 提出TRPC1和I-MFA通过调节Ca2+信号传导而对破骨细胞生成至关重要。这 假设将通过分子，生物物理，细胞和生物的综合方法进行检验 通过询问TRPC1和I-MFA是否影响早期破骨细胞的增殖和“启动”来通过 祖细胞（特定目标1），trpc1和i-MFA如何在破骨细胞中调节Ca2+信号传导（特定的目标2和 3），以及trpc1和i-MFA是否在体内和体外以细胞自主的方式影响破骨细胞发生。 此外，它们是否影响实验诱导的动物模型的破骨细胞募集 破骨细胞生成（特定目标4）。我们的研究将导致对关键途径的进一步理解 识别和开发新的治疗性所需的破骨细胞开发和功能的调节 控制破骨细胞生成并防止骨质流失的干预措施。