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.

健康的骨骼维持由成骨细胞介导的骨形成和由成骨细胞介导的骨吸收的平衡 破骨细胞。许多疾病状态，包括慢性牙周炎、骨质疏松症、类风湿性关节炎、佩吉特氏病 当破骨细胞过度募集或不当时，疾病和癌症转移就会发生 活性。破骨细胞在整个生命过程中不断由骨骼中的造血干细胞产生 骨髓通过涉及细胞因子信号传导和微环境的一系列复杂事件来发挥作用。钙离子 信号传导在破骨细胞生成的调节中具有重要作用。 Ca2+ 通道响应激活 细胞内 Ca2+ 储备的耗尽被认为在早期阶段介导 Ca2+ 信号传导 破骨细胞形成。然而，这些通道控制 Ca2+ 的确切分子和机制 破骨细胞生成中的信号传导在很大程度上是未知的。结合分子、细胞生物学和 在整个动物研究中，我们发现瞬时受体电位通道 TRPC1 可以增强 破骨细胞生成处于早期阶段，而其抑制剂，小胞质蛋白 I-mfa 则具有相反的作用 影响。 I-mfa 缺失小鼠中增强的破骨细胞生成在缺乏这两种基因的小鼠中得到纠正，表明 TRPC1 介导的 Ca2+ 信号传导在破骨细胞形成中比 I-mfa 具有主导作用。因此，我们 提出 TRPC1 和 I-mfa 通过调节 Ca2+ 信号传导对于破骨细胞生成至关重要。这 假设将通过分子、生物物理、细胞和有机体的综合方法进行检验 通过询问 TRPC1 和 I-mfa 是否以及如何影响早期破骨细胞的增殖和“启动”来了解 TRPC1 和 I-mfa 的水平 祖细胞（具体目标 1），TRPC1 和 I-mfa 如何调节破骨细胞中的 Ca2+ 信号传导（具体目标 2 和 3），以及TRPC1和I-mfa是否在体内和体外以细胞自主方式影响破骨细胞生成 此外，它们是否影响实验诱导的动物模型中破骨细胞的募集 破骨细胞生成（具体目标 4）。我们的研究将导致对关键途径的进一步了解 破骨细胞发育和功能的调节，这是识别和开发新治疗方法所必需的 控制破骨细胞生成和预防骨质流失的干预措施。