Calcium Regulation in Osteoclasts

健康的骨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、佩吉特病 当破骨细胞过度募集或不适当地募集时， 激活破骨细胞在人的一生中不断地由骨骼中的造血干细胞产生 骨髓通过一系列复杂的事件，涉及细胞因子信号和微环境。Ca2+ 信号传导在破骨细胞生成的调节中具有重要作用。Ca 2+通道响应于 细胞内Ca 2+储存的耗尽已经被认为介导了早期阶段的Ca 2+信号传导。 破骨细胞形成。然而，这些通道控制Ca 2+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。使用分子、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TRPC 1， 破骨细胞生成的早期阶段，而其抑制剂，小胞质蛋白，I-mfa有相反的作用 效果I-mfa缺失小鼠中破骨细胞生成的增强在缺乏这两种基因的小鼠中得到纠正，表明 TRPC 1介导的Ca 2+信号传导在破骨细胞形成中具有超过I-mfa的主导作用。所以我们 提示TRPC 1和I-mfa通过调节Ca 2+信号对破骨细胞的生成是必需的。这 假设将通过分子、生物物理、细胞和生物体的综合方法进行检验。 通过询问TRPC 1和I-mfa是否以及如何影响早期破骨细胞的增殖和“启动”， 祖细胞（具体目标1），TRPC 1和I-mfa如何调节破骨细胞中的Ca 2+信号传导（具体目标2和 3），以及TRPC 1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的发生 此外，它们是否影响破骨细胞在实验诱导的动物模型中的募集， 破骨细胞生成（具体目标4）。我们的研究将导致进一步了解的关键途径， 调节破骨细胞的发育和功能，这是鉴定和开发新的治疗方法所需要的。 控制破骨细胞生成和预防骨质流失的干预措施。

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.