转录因子SOX5调控骨髓破骨细胞分化微环境参与类风湿关节炎骨侵蚀的研究

大量证据表明骨髓水肿是最强预测类风湿关节炎(RA)骨侵蚀的危险因素，炎症导致骨髓微环境异常，引起破骨细胞过度分化激活是主要解释，迄今确切机制尚不明确。申请人近5年来大量原创性工作证明新转录因子SOX5参与调控破骨细胞分化关键基因- - RANKL表达，近期发现胶原诱导关节炎鼠骨髓细胞中SOX5表达增高16倍。为此，申请人提出假说：SOX5是调节RA骨髓破骨细胞分化微环境的关键因子。本研究将利用造血干细胞和髓系细胞（破骨前体细胞）条件性SOX5基因敲除鼠为工具，从分子、细胞以及动物层次揭示SOX5对骨髓破骨细胞分化微环境- - 上游：造血干细胞向破骨细胞谱系分化；下游：炎症介导的RANKL表达的影响。本研究不仅是申请人既往研究的延续和深入，更重要的是，骨髓水肿代表RA骨侵蚀的早期事件，以骨髓"破骨细胞分化微环境"为切入点，将有助于全面揭示RA骨侵蚀分子机制，并可能为探索新的早期干预靶标奠定基础。

Accumulated evidences have proved that the bone marrow edema is the strongest predictor of bone erosion for Rheumatoid arthritis (RA). The accelerated osteoclast activation in bone marrow caused by inflammation-mediated microenvironment might be an explanation, but the exact mechanism remains unclear. We previously identified a novel transcriptional factor of SOX5 involved in regulation the expression of RANKL, a central mediator of osteoclast development and osteoclast function. Our recently data indicated that the expression of SOX5 is 16-fold higher in the bone marrow cells from collagen induced mice arthritis than those in normal mice, which prompt us to hypothesize that SOX5 play a critical in regulation the microenvironment of osteoclast differentiation. Here, we will study the role of SOX5 on the differentiation of hematopoietic stem cell to osteoclast and the interaction of inflammatory cytokines and RANKL by conditional SOX5 knockout mice. Given bone marrow edema presents the early event of inflammation- mediated bone erosion, our proposal will not only help to fully understand the molecular mechanism of bone erosion in RA, most importantly, facilitate the identification a novel target to suppress bone lose in early stage.