关节软骨退变是颞下颌关节骨关节炎（TMJOA）形成的重要原因之一，但软骨退变机制尚不明确。前期研究显示，骨关节炎患者关节中TGF-β1、HTRA1增高，HTRA1在细胞周基质降解及软骨退变中具有关键作用。课题组体外研究发现TGF-β1通过/Smad2/3诱导软骨细胞中HTRA1高表达。由此，TGF-β1/Smad2/3介导HTRA1高表达可能是导致成年个体TMJOA软骨退变的重要途径。本课题将1）在TMJOA小鼠模型中验证TGF-β1、HTRA1表达水平及相关性；2）通过Tet-off系统构建转基因小鼠明确体内TGF-β1/Smad2/3对HTRA1的诱导作用及在软骨退变中的作用和机制；3）进一步探究抑制TGF-β1/Smad2/3介导HTRA1在延缓软骨退变中的作用。本课题将为阐明TMJOA软骨退变机制提供直接的体内证据，并为探寻TMJOA治疗靶点和药物研发提供重要科学依据。

Condylar cartilage degeneration is one of the causes in the development of temporomandibular joint osteoarthritis (TMJOA). However, the molecular basis of the cartilage degeneration remains largely unknown. The results from clinic and basic investigations indicate that the expressions of TGF-β1 and HTRA1 are increased in osteoarthritic cartilages. In the previous study, we showed that HTRA1 played a key role in the pericellular matrix degradation of chondrocytes of joints. We also found that HTRA1 was induced in vitro in chondrocytes by TGF-β1/Smad2/3 signaling. On the basis of the findings from our and other independent studies, we hypothesize that increased expression of HTRA1 induced by TGF-β1/ Smad2/3 signaling pathway may be one of the key molecular events, which leads to the cartilage degeneration of TMJ. In this grant proposal, first, we plan to examine the expression profiles of Tgf-β1 and HtrA1 in mouse models of TMJOA. Second, we plan to utilize mouse genetic regulated-system, Tet-off system, to investigate biological effects of the up-regulated expression of Tgf-β1 on the induction of HtrA1 and in condylar cartilage degeneration of TMJs. Third, we plan to explore the effects of inhibition of the Tgf-β1/Smad2/3/HtrA1 pathway in TMJs. Results from this grant proposal will provide invaluable information for the elucidation of the molecular mechanisms responsible for the pathogenesis of TMJOA and for the development of disease-modifying OA drugs.