Calcium Regulation in Osteoclasts

破骨细胞中的钙调节

• 批准号: 8913682
• 负责人: Mary Beth Humphrey
• 金额: $ 41.1万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913682
• 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; Health; Hematopoietic stem cells; In Vitro; Inositol; Ion Channel; Knock-out; Knockout Mice; Lead; Life; Macrophage Colony-Stimulating Factor; Mediating; 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; biophysical techniques; bone; bone loss; design; improved; in vivo; inhibitor/antagonist; novel therapeutic intervention; osteoclastogenesis; prevent; progenitor; programs; receptor; receptor coupling; research study; response; stoichiometry

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：健康的骨骼保持了骨形成的平衡，由成骨细胞和由骨细胞介导的骨吸收。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疾病和癌症转移，当骨细胞被过度募集或不适当地激活时。整骨细胞是通过涉及细胞因子信号传导和微环境的一系列复杂事件，从造血干细胞中不断制造。 Ca2+信号传导在破骨细胞生成的调节中具有至关重要的作用。已经提出，在破骨细胞形成的早期阶段中，已提出对细胞内Ca2+存储的耗竭响应的Ca2+通道。然而，这些通道在破骨细胞生成中控制Ca2+信号传导的确切分子和机制在很大程度上未知。通过结合分子，细胞生物学和全动物研究，我们表明瞬态受体电位通道TRPC1在早期阶段增强了骨质核层的发生，而其抑制剂，小的胞质蛋白I-MFA具有相反的作用。在缺少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TRPC1介导的Ca2+信号传导在破骨细胞形成中对I-MFA具有显着作用。因此，我们建议通过调节Ca2+信号传导，TRPC1和I-MFA对于破骨细胞生成至关重要。该假设将通过询问TRPC1和I-MFA是否以及如何影响骨质骨祖细胞的增殖和“启动”（特定的目标1）（特定的AIM 1），TRPC1和I-MFA如何调节ca2+信号的ost-eSts and ost-2和3 trpa（特定的目标），是否如何影响TRPC1和IM-MFA在分子，生物物理，细胞和有机水平上进行的综合方法来测试。在体内和体外和进一步的细胞自主方式上影响破骨细胞的形成，是否影响骨细胞造成的骨质核切状发生动物模型，它们是否影响破骨细胞的募集（特定的目标4）。我们的研究将进一步了解破骨细胞发育和功能的关键途径，这是鉴定和开发新的治疗干预措施以控制破骨细胞发生并防止骨质流失所需的。