SNX10介导的囊泡转运在类风湿关节炎骨侵蚀中的作用及分子机制

破骨细胞活性增强是导致类风湿关节炎（RA）骨侵蚀的关键因素，而破骨细胞必须依赖囊泡转运实施骨吸收功能。我们前期研究发现，在活化的破骨细胞中内体囊泡转运蛋白SNX10高表达，SNX10基因敲除不影响破骨细胞的分化，但明显抑制了破骨细胞的骨侵蚀活性；免疫共沉淀研究发现SNX10可以同骨基质的降解酶MMP9共沉淀；在SNX10基因缺失的破骨细胞中，MMP9 mRNA的表达未出现改变，但培养液中的MMP9活性显著降低，提示MMP9的分泌被抑制。这些结果提示SNX10很可能通过其介导的囊泡运输调控了破骨细胞骨侵蚀活性。本项目将在前期研究基础上，以SNX10基因敲除小鼠为研究对象，从in vitro的细胞实验和in vivo的RA疾病模型入手，探讨SNX10介导的囊泡运输的物质基础和调控机制，明确其在破骨细胞活化和关节炎骨侵蚀中的重要作用。本项目的实施有可能为RA的治疗提供新的靶点。

Articular bone erosions are a central clinical feature of rheumatoid arthritis (RA). Enhanced osteoclast activity is the key factor in bone erosion in RA. Bone-resorbing osteoclasts are highly dependent on vesicular trafficking pathways. Our previous study found that SNX10, a protein for endosomal vesicle transport, was highly expressed in activated osteoclasts. SNX10 knockout did not affect differentiation of osteoclasts, but significantly inhibited the resorptive activity of osteoclasts. We further found that SNX10 co-precipitated with MMP9, one of bone matrix degrading enzymes. The expression of MMP9 mRNA in SNX10 deficient osteoclasts was not altered, but the activity of MMP9 in culture medium was significantly decreased indicating a suppressed secretion of MMP9. These results suggested that SNX10 may regulate the activity of osteoclasts and bone erosion via mediating vesicle transport. In the current study, cellular experiments and animal model of RA based on the SNX10 knockout mice will be conducted to explore the fundamental components and regulatory mechanisms of SNX10 mediated vesicle transport, and also to elucidate the important roles of SNX10 in activity of osteoclasts and bone erosion. Our study will provide a new target for RA treatment.