BMPR1a的SUMO化修饰通过调控BMP受体寡聚化促进类风湿关节炎破骨细胞分化活化的机制研究

破骨细胞分化和活化异常是导致类风湿关节炎（RA）关节破坏的关键。BMP信号在维持破骨和成骨细胞分化平衡中起着重要作用。我们前期研究显示，SENP1缺失引起的外周血单核细胞BMPR1a受体SUMO化及细胞膜定位增加，与破骨细胞生成呈正相关。在此基础上，本项目首先明确SENP1在RA单核细胞中的低表达及临床意义；然后体外诱导单核细胞分化为破骨细胞，通过SENP1活性调控、单核细胞特异SENP1敲除和SUMO位点突变技术，探讨BMPR1a的SUMO化修饰对RA破骨细胞分化和骨吸收功能的调控，以及BMPR1a膜表达做为RA破骨细胞前体细胞分型标志的可行性；继而利用质粒共转染、免疫共沉淀和免疫荧光技术，检测RA破骨细胞分化过程中BMPR1a-BMPRII受体聚合方式、内吞途径及下游信号通路；最后我们将构建RA模型小鼠，验证干预上述信号对关节破坏进程的影响。本项目将为RA治疗和药物开发提供理论依据。

Rheumatoid arthritis (RA) is characterized by progressive cartilage destruction and focal bone erosion. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Small ubiquitin-like modifier (SUMO) can post-translationally conjugate to cellular proteins (SUMOylation) and modulate their biological functions. Our previous study shown that RA peripheral blood CD14+ monocytes were more prone to osteoclastogenesis than in healthy controls. Our recent preliminary data also suggested that SENP1 protein expression was negatively correlated with radiographic joint destruction. Moreover, we found that SUMOylation targets BMPR1a, a receptor for BMP ligands known to regulate osteoclast. SENP1 deletion and enzyme activity inhibition induced BMPR1a signaling, correlating with increased osteoclastogenesis. Based on these preliminary findings, we hypothesize that SUMO modification of BMPR1a promotes osteoclastogenesis. Here, we propose the following specific aims and studies: 1) To define the deficiency of SENP1 in circulating osteoclast precursors is associated with bone destruction in RA and its clinical significance; 2) To clarify SENP1 regulates RA osteoclastogensis and bone resorption through BMPR1a SUMOylation and membrane distribution; 3) To define the mechanism by which SUMOylation of BMPR1a influences the imbalance of osteoclast differentiation through BMP receptor oligomerization and following clathrin-dependent endocytosis; 4) Using RA mouse models to determine how downregulation of SENP1 in monocyte promotes osteoclastogenesis and triggers following bone destruction. Our proposed studies will provide insights into the role of protein SUMOylation and BMP receptor oligomerization in the process of osteoclastogenesis and define previously unrecognized mechanism regulating the onset and progression of bone destruction. This may provide a new way for RA management and may identify SENP1-BMPR1a as a therapeutic target to combat bone destruction in RA.