HLA-B27介导强直性脊柱炎骨病变的分子机制及潜在药靶发现

强直性脊柱炎（简称AS）是一种具有高度遗传的自身免疫性脊柱关节炎，具有炎症与新骨生成两大特征，但两者之间的关系仍知之甚少。我们前期发现CD4-Cre介导的软骨细胞中SHP2条件性敲除会导致骨骺生长板紊乱，继而骺软骨中不均衡软骨内成骨导致强直样骨病变。本项目拟在此基础上，通过引入AS关键致病基因HLA-B27构建HLA-B27;B2M;CD4-Cre;SHP2f/f多重转基因小鼠，在此小鼠中使用人关节软骨蛋白聚糖诱导的小鼠脊柱关节炎，探索炎症对于软骨内成骨过程及异位骨化过程的影响，阐明AS中炎症对于新骨生成的影响及其分子机制。利用HLA-B27识别的病原菌肽诱导关节炎模型，探究HLA-B27调控T细胞活化的分子机制。本项目首次构建了同时含有炎症和骨稳态失衡因素的AS疾病模型，为探索抑制AS新骨生成的新靶标以及评价药物减缓AS骨病变的疗效提供理想平台。

Ankylosing spondylitis is a type of inherited autoimmune spondyloarthritis characterized by immune-mediated arthritis and osteoproliferation, but the correlation of inflammation and osteoproliferation is largely undefined. Here we found uncoordinated endochondral osteogenesis induced by delay fusion of osteoepiphysis resulted in AS-like bone deformation. To clarify the mechanism of inflammation triggering bone formation, we will establish PGIS (Proteoglycan-induced spondylitis) model in HLA-B27;B2M;CD4-Cre;SHP2f/f mice, which carrying pathogenic gene HLA-B27. Furthermore, we will induce arthritis model in HLA-B27;B2M mice through HLA-B27-bound bacteriogenic peptides to explore the mechanism of HLA-B27- restricted T cell activation. We firstly superpose inflammation and bone instability factors to establish comprehensive AS model to expound the regulation of inflammation to new bone formation. We provide appropriate AS model to assess clinical drugs on bone deformation in patients with AS and explore new target to arrest new bone formation in AS.