NFAT Negatively Regulates Osteoblast differentiation & Bone Formation

骨丢失和骨质疏松症是老年人的主要公共健康问题。成骨细胞分化是一种 骨形成和重塑的关键方面，这一过程在骨质疏松症中严重受损。 新骨形成的过程涉及骨祖细胞的招募，这与 适当刺激，进行增殖，分化为成骨前细胞，再分化为成熟细胞 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同种异体移植排斥反应的治疗。已报道的影响 CsA在骨骼上的作用在人类和动物研究中都是矛盾的，人们普遍认为CsA 由于破骨细胞和成骨细胞分化的增加，导致高周转性骨丢失 活着。CsA通过抑制钙调神经磷酸酶/NFAT(活化T细胞核因子)诱导其应答 信号通路。NFAT最近被证明在破骨细胞分化和分化中发挥关键作用。 骨吸收。它在成骨细胞分化和骨形成中的作用尚不清楚，是 这项提议。我们的初步数据显示，CsA可促进成骨细胞分化和成骨 通过抑制成骨细胞中的NFAT信号通路在体外和体内形成。因此，基于 我们的工作和其他人的工作我们假设CN/NFAT信号通路是负面的 调节成骨细胞分化。 具体目标是： I.CN和NFAT在成骨细胞中的表达特征及其在成骨细胞中的作用 差异化。 研究NFAT调控成骨细胞分化的分子机制。 研究CN/NFAT通路在动物模型骨形成中的作用。 尽管NFAT信号在调节破骨细胞分化中很重要，但它在破骨细胞分化中的作用 成骨细胞的发育和骨形成仍未被研究。我们的研究结果将提供 首次用新的分子机制解释CN/NFAT在调节中的作用 成骨细胞分化。从而为开发合成代谢的新靶点提供了依据 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.