基于软骨下骨微环境失衡中破骨细胞对软骨细胞的调控探讨PTOA软骨退变机制及修复策略研究

软骨退变是创伤性骨关节炎（PTOA）的主要病理特征，软骨下骨微环境失衡导致软骨细胞（CC）病理性肥大化和功能降低为其关键。新近显示破骨细胞（OC）可促进软骨细胞分化，而其在CC肥大化及软骨退变中的角色尚不清楚。基于前期破骨谱系、外泌体检测及HDACs对软骨稳态的枢纽作用，结合OA中细胞定位关系，我们认为存在OC-CC耦合，即CC可促进局部微环境中随血管长入的OC前体分化，OC亦可促进CC肥大化。推测OC通过外泌体调控HDACs导致软骨细胞衰老，进而软骨代谢失衡及退变。拟采用共培养体系阐明OC与CC的互作细节，尤其关注融合期OC外泌体通过ceRNA对CC肥大化、衰老及凋亡的影响；利用Cre等模式鼠OA模型，采用病理分析、体内成像等技术，探寻不同软骨区域内OC对软骨细胞代谢行为的效应；并从调控破骨角度，探索组织工程技术对OA软骨退变的修复方法和机理，为寻求防治OA新靶点提供实验依据和理论基础。

Cartilage degeneration is the main pathological feature of post-traumatic osteoarthritis (PTOA). The pathological hypertrophy and functional decline of chondrocyte (CC) caused by the imbalance of subchondral bone microenvironment are critical in the pathogenesis. Recently, osteoclasts (OC) have been shown to promote the differentiation of chondrocytes, but their roles in CC hypertrophy and cartilage degeneration of PTOA are still unclear. Based on the previous osteoclast lineage establishment, exosomal detection, and the pivotal role of HDACs in cartilage homeostasis, combined with the osteoclasts-chondrocytes location relationship in human osteoarthritis samples, we believe that there is osteoclasts-chondrocytes (OC-CC) coupling, ie, chondrocytes can promote the differentiation of osteoclast precursors in local microenvironment, and osteoclasts can also promote chondrocyte hypertrophy and senescence. It is speculated that osteoclast regulates the key molecules HDACs through exosomes, leading to chondrocytes senescence, and then the imbalance of cartilage metabolism and degradation. A co-culture system is planned to clarify the interactions between osteoclasts and chondrocytes, with particular attention to the effect of osteoclast exosomes during the fusion phase on the pathological hypertrophy, aging, and apoptosis of chondrocytes through ceRNA mechanism. In our project, we adopted wild type, Cre mice and techniques of pathological analysis for in vivo imaging. In addition, the osteoarthritis model was established to explore the effect of osteoclasts on chondrocytes metabolism in different cartilage regions, and to explore the effect of tissue engineering technology on OA cartilage degradation from the viewpoint of osteoclasts. This project will provide a novel therapeutic strategy for the prevention and treatment of post-traumatic osteoarthritis.