DKK-1/Wnt信号通路对类风湿关节炎髓源性抑制细胞扩增和活化的调控作用及青藤碱干预研究

Rheumatoid arthritis (RA) is an autoimmune disease that often leads to joint destruction. Our previous study shows that myeloid derived suppressor cells (MDSC) are extensively expanded in RA patients and collagen-induced arthritis (CIA) mice, promoting bone destruction by differentiating into osteoclasts (OC), and sinomenine may alleviate CIA arthritis by reducing MDSC. Yet the relevant immune mechanism remains unclear. Studies have shown that Wnt signaling pathway inhibitor DKK-1 plays an important role in the dysregulation of OC activation. Hence, we hypothesize that DKK-1 and simomenine regulates the expansion and activation of MDSC to OC through the Wnt signaling pathway. To test the hypothesis, this project intends to: ① investigate the correlations of levels of MDSC, DKK-1 and joint destruction in RA; ② clarify the impact of DKK-1 intervention on the differentiation process in a cell model of MDSC differentiating into OC; ③remove DKK-1 or/and MDSC in CIA mice to explore the impact of DKK-1 on MDSC expansion and joint destruction; ④ intervene CIA mouse model and MDSC cell model with sinomenine to explore its treatment mechanism. The project aims to elucidate the regulation mechanism of DKK-1/Wnt pathway in MDSC expansion and activation, and intervention mechanism of sinomenine, so as to seek a new target for RA prevention and treatment.

类风湿关节炎（RA）是一种常导致关节破坏的自身免疫疾病。申请者前期研究发现髓源性抑制细胞（MDSC）在RA患者及动物模型CIA中大量扩增，并分化为破骨细胞（OC）促进骨破坏；中药青藤碱可以减少MDSC的扩增，缓解关节炎症，但相关免疫机制尚不清楚。已有研究表明Wnt信号通路抑制因子DKK-１在OC的异常活化中起重要调节作用，因此我们假说DKK-1及青藤碱通过Wnt信号通路调控MDSC的扩增和活化。为验证该假说，本项目拟①在RA患者中，分析MDSC、DKK-1和骨破坏之间的关系；②在MDSC分化为OC细胞模型中，观察DKK-1干预对其OC分化的影响；③在CIA模型中，剔除DKK-1或/和MDSC，探讨DKK-1对MDSC扩增及骨破坏的影响；④青藤碱干预上述细胞及动物模型，明确其疗效机制。目标是阐明DKK-1/Wnt通路对MDSC扩增和活化的调控作用及青藤碱的疗效机制，为RA的防治提供新的靶标。

类风湿关节炎（RA）致残率高，发病机制尚不完全清楚。申请者前期研究发现髓源性抑制细胞（MDSC）在RA患者及动物模型CIA中大量扩增，并分化为破骨细胞（OC）促进骨破坏；临床及基础研究提示中药青藤碱可以缓解关节炎症，但相关免疫机制尚不完全清楚。已有研究表明Wnt信号通路抑制因子DKK-１在OC的异常活化中起重要调节作用，因此我们假说DKK-1通过抑制Wnt/β-catenin 信号通路，促进RA-MDSC 扩增和活化为OC；中药单体青藤碱通过“DKK-1/Wnt---MDSC---RA骨破坏”轴线发挥治疗作用。基于此假说，本项目开展了以下研究：① MDSC的活化在RA骨破坏中的作用。② DKK-1/Wnt通路调控MDSC的活化参与RA骨破坏机制。③ 青藤碱调控MDSC的活化缓解RA疗效机制。研究发现：①RA患者MDSC-Th17交互作用，促进OC的生成，加剧RA骨破坏；②DKK-1与RA骨破坏正相关，DKK-1通过Wnt/β-catenin途径促进MDSC分化为OC；③青藤碱通过抑制MDSC的促炎（促进Th17应答）及促骨破坏（分化为OC）功能，缓解RA。研究发现了RA中西医结合防治的新的靶点，为青藤碱抗风湿临床应用提供了理论依据。研究成果发表在Rheumatology，Front. Pharmacol等知名期刊。培养研究生5名，其中海外联合培养博士生2名。