Calcium Regulation in Osteoclasts

健康骨维持成骨细胞介导的骨形成和骨吸收的平衡 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、Paget‘s 当破骨细胞被过度招募或不当招募时，疾病和癌症转移就会发生 激活了。在整个生命过程中，破骨细胞都是由驻留在骨骼中的造血干细胞不断产生的。 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+ 信号转导在破骨细胞生成的调控中起着至关重要的作用。激活的钙通道响应于 细胞内钙库的耗竭被认为在早期阶段介导了钙信号转导。 破骨细胞形成。然而，这些通道控制钙离子的确切分子和机制 破骨细胞形成的信号在很大程度上是未知的。使用分子、细胞生物学和 整个动物研究表明，瞬时受体电位通道TRPC1增强 破骨细胞发生在早期，而其抑制物小细胞浆蛋白I-MFA则相反 效果。缺乏这两个基因的I-MFA缺失小鼠的增强破骨细胞生成得到纠正，这表明 TRPC1介导的Ca~(2+)信号在破骨细胞形成中比I-MFA起主导作用。因此，我们 提示TRPC1和I-MFA通过调节钙信号对破骨细胞的形成起重要作用。这 假说将通过分子、生物物理、细胞和生物体的综合方法进行检验 通过询问TRPC1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(特异性目标1)，TRPC1和I-MFA如何调节破骨细胞中的钙信号(特异性目标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的形成 此外，在实验诱导的动物模型中，它们是否影响破骨细胞的募集 破骨细胞生成(特定目标4)。我们的研究将使我们进一步了解人类免疫缺陷的关键途径 破骨细胞发育和功能的调节，这是识别和开发新的治疗方法所必需的 控制破骨细胞生成和防止骨丢失的干预措施。

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.