从OPN介导的巨噬细胞与滑膜细胞相互作用探讨骨关节炎发病的分子机制

骨关节炎（Osteoarthritis, OA）是一种严重危害人类健康的慢性、退行性关节病变。其核心病理改变包括巨噬细胞分泌炎症因子，滑膜细胞异常增生，软骨细胞凋亡等，是一个多组织受累，多细胞互相作用的过程。骨桥蛋白（Osteopontin,OPN）是OA病程中的重要因子。课题组前期研究发现：滑液中OPN升高且与OA严重程度相关；低氧激活巨噬细胞，使其分泌OPN；OPN能靶向结合滑膜细胞膜受体CD147，致滑膜细胞增生和细胞外基质沉积，可加重关节腔低氧。结合文献，我们推测：OPN介导的巨噬细胞激活和滑膜细胞增生形成的恶性环路将促进OA发生发展。本研究拟通过巨噬细胞-滑膜细胞共培养体系和单核巨噬细胞特异性OPN敲除小鼠，在体外细胞与活体动物两个层面验证此假说，探索两种细胞间的相互联系及作用机制，并阐明这种联系在OA发病中的效应，为OA的治疗提供新的理论依据和防治策略。

Osteoarthritis (OA) is a chronic degenerative joint disease that is critical to human health. The core pathological changes include macrophage secretion of inflammatory factors, hyperplasia of synoviocytes , apoptosis of chondrocytes. So,OA is a multi-tissue involved, multi-cell interacted process. Osteopontin (OPN) is an important factor in the course of OA.We find that OPN is elevated in synovial fluid and correlated with the severity of the disease. Moreover, OA-induced pathogenic hypoxia activates macrophages to secrete OPN. OPN target binds to synoviocyte membrane receptors CD147, causing synovial cell proliferation and extracellular matrix deposition,which further increases hypoxia in the articular cavity. Combined with previous literature, we propose hypotheses: OPN-mediated macrophage activation and synoviocyte proliferation results in a malignant loop which promotes the development of OA. In this study, macrophage-synoviocyte co-culture system and monocyte-macrophage-specific OPN knockout mice were used to validate the hypothesis in vitro and in vivo to explore the intercellular relationship and mechanism, and to clarify the effect of this crosstalk in the pathogenesis of OA.This study will provide the OA treatment with new theoretical basis and treatment strategies.