DLL4-Notch1/NF-κB相互拮抗在异常咬合致TMJ OA髁突软骨退变中的作用

Our recent study found that unilateral anterior crossbite (UAC) prosthesis could induced mouse temporomandibular joint osteoarthritis-like (TMJ OA) degradation and NF-κB signaling was significantly enhanced while reducing the abnormal loading in TMJ by feeding with small-sized diet or removing the crossbite prosthesis or inhibiting NF-κB signaling, the condylar cartilage degradation was significantly attenuated, suggesting that the TMJ condylar cartilage shows a strong reparative ability, however, the reparative response in UAC condylar cartilage is unclear. The overloading in UAC mouse TMJs could be controlled by using different food consistency or removing the UAC, and therefore can be used to discover new molecular mechanism in the condylar cartilage reparative remodeling. The Notch signaling was believed to stimulate chondrocyte proliferation; however, the role and mechanism of Notch signaling in OA condylar cartilage is controversial and unclear. DLL4-Notch1 signaling was depressed in the UAC induced TMJ OA condylar cartilage and excessive shear force stimulated chondrocytes. In the present study, the effects of DLL4-Notch1 signaling on condylar cartilage metabolism in the process of UAC induced TMJ OA and its interaction with NF-κB signaling are to be determined. UAC mice under different abnormal biomechanical TMJ loading through hard or soft diet feeding or the removal of prosthesis were used as in vivo model and excessive shear force stimulated chondrocytes were used as in vitro model. In vivo TMJ intraarticular injection with DLL4-Notch1 agonist or inhibitor and in vitro treatment with DLL4-Notch1 agonist, inhibitor or siRNA will be adopted to determine the reparative roles of DLL4-Notch1 signaling in the TMJ condylar cartilage degradation and to investigate the competitive interaction between the DLL4-Notch1 signaling and NF-κB signaling in condylar chondrocytes in the process of the TMJ osteoarthritic lesions. The present study will provide a novel mechanism for DLL4-Notch1 signaling to competitively inhibit NF-κB signaling in the repair process of the TMJ OA-like lesions, and to provide rational for occlusion related therapy and a target for TMJ OA treatment.

颞下颌关节骨关节炎（TMJ OA）是一类髁突软骨合成降解代谢失衡和细胞凋亡增殖异常的退行性病变。我们发现单侧前牙反牙合可致小鼠TMJ OA样变，软骨细胞NF-κB信号增强，但细食喂养或拆除反牙合或抑制NF-κB，髁突软骨退变明显减轻，但OA髁突软骨的增殖活动尚不清楚，因此有望通过软食或拆除反牙合来调节关节负荷，进而发现髁突软骨退变和修复的分子机制。Notch信号在多种细胞中发挥着促细胞增殖作用，在TMJ OA软骨中DLL4-Notch1信号明显降低。本项目拟以单侧前牙反牙合小鼠软硬食喂养、拆除反牙合为体内模型，不同剪切力刺激为体外模型，结合关节腔注射DLL4-Notch1激动剂、抑制剂和对软骨细胞予以相关药物和基因干预，探讨DLL4-Notch1信号在异常咬合致TMJ OA软骨退变中的作用及其与NF-κB信号的交互作用，论证DLL4-Notch1通过拮抗NF-κB而抑制髁突软骨退变的机理。