纤维结构不良（FD）病因为GNAS突变，特征为编织骨由纤维组织化生形成，破骨细胞过度激活。前期研究发现，GNAS突变上调MSCs中IL6和RANKL表达和激活单核巨噬细胞Ca2+-calmodulin-calcineurin和RANK-TRAF6-TAB2/TAK1通路而促进破骨细胞分化。因此本项目以“FD破骨细胞过度激活”为线索，以MSCs和单核巨噬细胞中GNAS突变为切入点，从成骨细胞-破骨细胞相互作用和破骨细胞本身两个角度研究“MSCs中GNAS突变如何上调IL6和RANKL的表达从而促进破骨细胞分化”和“单核巨噬细胞中GNAS突变如何通过Ca2+-calmodulin-calcineurin和RANK-TRAF6-TAB2/TAK1通路促进破骨细胞分化”等问题，探索FD中破骨细胞过度激活的机制。并构建破骨细胞和MSCs特异的GNAS突变敲入小鼠对结果进行验证并对FD表型进行挽救。

Fibrous dysplasia (FD), caused by GNAS mutation, is one of common diseases in orthopaedic clinic, which is characterized by the replacement of normal bone with abnormal fibro-osseous tissue. Excessive activation of osteoclasts is observed in FD lesion, which is believed to be one of the most important histological manifestations of FD absolutely. The results from our preliminary research showed that osteoclasts differentiation from mononuclear macrophage was significantly improved by GNAS mutation (R201H), in which the up-regulation of IL6 and RANKL in MSCs and the activation of Ca2+-calmodulin-calcineurin and RANK-TRAF6-TAB2/TAK1 signaling pathways in mononuclear macrophage were involved. Therefore, this project is designed to elucidate the molecular mechanisms underlying how MSCs with GNAS mutation could improve osteoclasts differentiation through the up-regulation of IL6 and RANKL in osteoblasts-osteoclasts interaction mode and why osteoclasts differentiation is improved in response to GNAS mutation in mononuclear macrophage through the activation of Ca2+-calmodulin-calcineurin and RANK-TRAF6-TAB2/TAK1 signaling pathways. Transgenic mouse model with MSCs- and osteoclasts-specific conditional GNAS mutation (R201H) knock-in will be constructed, by which we make an attempt to confirm the in vitro data and rescue the FD phenotype. This study provides useful insight into the signaling pathways involved in the FD phenotype and facilitates dissection of the molecular pathogenesis of FD and testing of novel therapies.