骨破坏是类风湿关节炎主要特征和患者致残的重要原因。破骨细胞在其中发挥至关重要作用。RANKL是调节破骨细胞分化的主要因子，但其确切机制尚不清楚。研究认为小G蛋白Rac在RANKL诱导破骨细胞分化过程中作用显著。Rac在GPCR信号通路中受ELMO/DOCK复合物调节,但ELMO1在破骨细胞分化中的作用尚无报道。我们发现Elmo1基因敲除小鼠破骨细胞分化能力显著降低,且其类风湿关节炎骨破坏程度也明显减轻。本课题将在此基础上，利用Elmo1基因敲除小鼠建立骨破坏模型，从分子、细胞、动物整体水平等多个层次开展以下研究：1）明确ELMO1对破骨细胞分化的影响；2）研究ELMO1调控破骨细胞分化的分子机制；3）探讨ELMO1与类风湿关节炎骨破坏的关系。本课题旨在通过研究ELMO1调控破骨细胞分化的机制，揭示其在类风湿关节炎骨破坏中所起的作用，为骨代谢失衡相关疾病的治疗提供新的靶点和研究思路。

Rheumatoid arthritis (RA) is characterized by the presence of inflammatory synovitis accompanied by destruction of joint cartilage and bone, in which osteoclasts play a critical role.Receptor activator of NF-κB ligand (RANKL) is the major cytokine that induces osteoclast differentiation. However, the exact molecular mechanism and signaling pathways involved remain unclear. RANKL-induced osteoclast differentiation is regulated by small GTPase Rac, which is the downstream of ELMO/DOCK complex in GPCR signaling. It is not clear whether ELMO1 functions in osteoclast differentiation. Our preliminary studies showed that Elmo1-deficient osteoclast precursors exhibited a defect in differentiation. In addition, bone destruction is dramatically reduced in Elmo1 knockout (KO) mice with serum transfer arthritis, which displays the characteristic features of RA. In the present study, we set out to investigating the following fundamental questions: 1) What is the role of ELMO1 in osteoclast differentiation? 2) What is the molecular mechanism underlying the ELMO1-involved osteoclast differentiation? 3) Does ELMO1-mediated osteoclast differentiation affect the bone destruction of RA? The proposed studies are designed to elucidate the function and molecular mechanism of Elmo1 signaling pathway in osteoclast differentiation, as well as its involvement in the bone destruction of RA. These studies may lead to new therapeutic strategies and targets for the treatment of diseases related with the disturbed bone metabolism.