膝关节骨关节炎（OA）是一种常见于中老年人的关节退行性疾病，关节软骨细胞机械微环境的改变在OA发病机制中起关键作用，但关节软骨细胞机械转导的分子机制尚未完全阐明。我们的前期研究显示，Lgr5特异性表达于关节软骨祖细胞，促进关节软骨形成，其表达随关节成熟逐渐减弱；OA患者软骨中以LGR5为转录本的circRNA异常上调。我们推测Lgr5与其配体Rspo2相互作用，将机械刺激转化为生物信号，激活Wnt/β-catenin信号，并与之形成正反馈调节，促进软骨细胞肥大分化和细胞外基质降解。为证实该假说，本项目拟从临床标本、动物模型及体外细胞机械刺激等多角度，研究Lgr5在OA发展中的表达变化，构建Lgr5相关机械转导调控网络，揭示Lgr5介导Wnt/β-catenin参与关节软骨细胞表型及细胞外基质代谢的调控作用，并验证体内阻断Lgr5蛋白合成对软骨机械损伤的保护作用，为OA防治提供新靶点。

Knee osteoarthritis (OA) is a common degenerative disease of the knee joint among the middle-aged and elderly. The changes of the mechanical microenvironment of articular chondrocytes play a key role in the pathogenesis of OA. However, the mechanical transduction mechanisms in articular chondrocytes have not been fully elucidated. Our previous studies have showed that Lgr5 is specifically expressed in articular cartilage progenitor cells and Lgr5+ interzone cells contribute to articular cartilage formation. The expression of Lgr5 is decreased gradually with joint maturation. CircRNA derived from LGR5 transcripts in the cartilage of OA patients was abnormally up-regulated. Thus, we hypothesize that Lgr5 interacts with its ligand Rspo2 to convert mechanical stimulations into biological signals, which activates Wnt/β-catenin signaling pathway, and maintains high activities of Wnt signals by forming a positive feedback loop. Consequently, chondrocyte hypertrophy and extracellular matrix degradation are promoted. In order to identify this hypothesis, studies will be conducted through clinical specimens, rat OA models and in vitro cell mechanical stimulation experiments to explore the role of Lgr5 during OA development. A Lgr5-related mechanical transduction regulatory network will be constructed, and the molecular mechanism of Lgr5-mediated Wnt/β-catenin signaling in mechanical transduction of articular chondrocytes will be revealed. Furthermore, this project will verify that whether blocking Lgr5 in vivo in articular cartilage of OA rat model has a protective effect on cartilage, thus providing a new target for the prevention and treatment of OA.