RANKL-NF-κB-ADAMTS5信号轴调控颞下颌关节软骨退变的机制研究

软骨退变是颞下颌关节髁突吸收的重要病理特征。目前研究发现成骨细胞与骨细胞分泌的RANKL通过激活破骨细胞骨吸收功能，致软骨下骨塌陷，间接造成软骨退变。但我们前期研究发现，RANKL可直接作用于软骨细胞并导致其退变：①髁突吸收患者及动物模型中软骨层RANKL高表达；②RANKL可直接诱导软骨组织退变；③RANKL激活软骨细胞内NF-κB信号轴，降解软骨基质。为此我们提出假说：RANKL 可直接结合到软骨细胞表面RANK受体，激活NF-κB通路，直接上调ADAMTS5，降解细胞外基质，导致软骨退变。为验证该假说，本项目将在前期研究基础上，进一步通过分析已构建的软骨特异性RANK基因敲除小鼠（Col2CreERT,RANKf/f）模型，从分子、细胞、组织水平探讨RANKL-NF-κB-ADAMTS5轴在颞下颌关节软骨退变中的作用机制，并以其为干预靶点，为临床诊治颞下颌关节软骨退变提供新思路。

Cartilage degeneration is one of the most important pathological characteristics of the temporomandibular joint condylar resorption. The current studies have found that RANKL, secreted by osteoblasts and osteoclasts, can cause the subchondral bone collapse by activating osteoclasts, which results in cartilage degeneration indirectly. Our previous studies have demonstrated that RANKL can play a direct role on chondrocytes and lead to cartilage degeneration. Firstly, higher expression of RANKL was found both in specimens of condylar resorption patients and animal models. Secondly, RANKL can directly induce cartilage tissue and chondrocytes degeneration. Last but not least, RANKL can activated NF-κB signaling pathways in chondrocytes and lead to up-regulation of ADAMTS5, which is a key protein degrading cartilage extracellular matrix. In the current study, we aim to unveil the molecular mechanisms of RANKL- NF-κB-ADAMTS5 pathway in regulating cartilage degeneration. By using the established cartilage RANK knockout mice, we will study the role of RANKL and its downstream pathways in cartilage degeneration both from in vitro and in vivo. Collectively, this study aims to identify a novel therapeutic way for temporomandibular joint cartilage degeneration.