NFAT Negatively Regulates Osteoblast differentiation & Bone Formation

骨质流失和骨质疏松症是老年人的主要公共卫生问题。成骨细胞分化是一种 骨形成和重塑的一个重要方面，这是骨质疏松症中严重受损的过程。 新骨形成的过程涉及骨祖细胞的募集， 适当的刺激，进行增殖和分化为前成骨细胞，然后进入成熟 合成无机基质并最终形成矿化骨的成骨细胞。环孢素A（CsA），a 广泛用于免疫抑制和治疗同种异体移植排斥反应的药物。报告的影响 在人类和动物研究中，CsA对骨的作用是相互矛盾的， 由于破骨细胞和成骨细胞分化的增加， vivo. CsA通过抑制钙调神经磷酸酶/ NFAT（活化T细胞核因子）来激发其反应 信号通路NFAT最近已被证明在破骨细胞分化中起关键作用， 骨吸收其在成骨细胞分化和骨形成中的作用尚不清楚，并且是 这个提议。我们的初步数据表明，CsA增加成骨细胞分化和骨 通过抑制成骨细胞中的NFAT信号通路，在体外和体内形成。所以基于 我们的工作和其他人的工作，我们假设，Cn/NFAT信号通路负 调节成骨细胞分化。 具体目标是： I.分析成骨细胞中Cn和NFAT的表达，并确定它们在成骨细胞中的作用。 分化 二.描述NFAT调节成骨细胞分化的分子机制。 三.在动物模型中表征Cn/NFAT通路在骨形成中的作用。 尽管NFAT信号传导在调节破骨细胞分化中的重要性，但其在破骨细胞分化中的作用仍有待进一步研究。 成骨细胞的发育和骨形成仍然没有研究。我们的研究结果将提供 第一个文件的一种新的分子机制来解释的作用，Cn/NFAT在调节 成骨细胞分化从而为合成代谢新靶点的开发提供基础。 治疗骨质疏松症和骨质流失的药物。

Bone loss and osteoporosis are major public health problems in the elderly. Osteoblast differentiation is a crucial aspect of bone formation and remodeling, a process that is severely compromised in osteoporosis. The process of new bone formation involves the recruitment of osteoprogenitors which, with the appropriate stimulation, undergo proliferation and differentiate into preosteoblasts and then into mature osteoblasts that synthesize inorganic matrix and eventually form mineralized bone. Cyclosporin A (CsA), a widely used drug for immunosuppression and the treatment of allograft rejection. The reported effects of CsA on bone are contradictory both in human and animal studies with a common consensus that CsA causes a high turnover bone loss due to an increase in both osteoclast and osteoblast differentiation in vivo. CsA elicits its response by inhibiting the calcineurin/ NFAT (Nuclear Factor of Activated T Cells) signaling pathway. NFAT has recently been shown to play a critical role in osteoclast differentiation and bone resorption. Its role in osteoblast differentiation and bone formation is not known and is the subject of this proposal. Our preliminary, data demonstrate that CsA increases osteoblast differentiation and bone formation in vitro and in vivo by inhibiting the NFAT signaling pathway in osteoblasts. Therefore, based on our work and the work of others we hypothesize that the Cn/NFAT signaling pathway negatively regulates osteoblast differentiation. The Specific Aims are: I. Characterize the expression of Cn and NFAT in osteoblasts and determine their role in osteoblast differentiation. II. Characterize the molecular mechanisms by which NFAT regulates osteoblast differentiation. III. Characterize the role of Cn/NFAT pathway in bone formation in animal models. Despite the importance of NFAT signaling in regulating osteoclast differentiation, its role in the development of osteoblasts and bone formation remains unstudied. Findings from our studies will provide the first documentation of a novel molecular mechanism to explain the role of Cn/NFAT in regulating osteoblast differentiation. A basis will thereby be provided for the development of new targets for anabolic drugs to treat osteoporosis and bone loss.