Cadherin-11介导的滑膜炎性反应促颞下颌关节紊乱病发展的分子机制研究

In recent years, the clinical and basic research suggested that the inflammatory response plays important role in the progression of temporomandibular joint disorders. Cadherin 11, as a kind of adhesion proteins, contributes to the stabilization of cellular structure as well as the regulation of cell proliferation,differentiation, and invasion role. It has been reported inflammatory cascade reaction mediated by Cadherin11 is closely related to the joint function and morphology changes. However, the molecular mechanisms of Cadherin11 mediated inflammatory reaction in the temporomandibular joint disorder are unclear. In this study, the impacts of cadherin-11 on MAPK and NF-κB, Wnt/β-catenin and other signaling pathways, as well as expression of ICAM-1, MMP-1 will be investigated in inflammatory induced temporomandibular joint synovials and continued inflammatory induced animal models. It may offer useful clues to reveal cadherin11-mediated inflammatory cascade reaction in TMD pathological process. Moreover, specific inhibitor of Cadherin11 will be used to block the progression of TMD. The study will not only benefit to enhance our understanding of TMD pathogenesis, and is also expected to provide new potential way for the clinical treatment of TMD.

近年来，临床与基础研究均表明炎性反应是颞下颌关节紊乱症病程发展的重要环节，Cadherin 11作为一种粘附蛋白，具有稳定细胞结构、调控细胞增殖分化侵袭等作用。以往在大骨关节研究中发现，由Cadherin11介导的炎性级联反应程度与关节功能与形态变化密切相关。但Cadherin11在颞下颌关节紊乱病程发展中介导炎性反应的分子机制尚不清楚。本研究拟在炎性损伤颞下颌关节滑膜细胞模型和持续炎性诱导整体动物模型上，考察cadherin-11介导MAPK、NF-κB、Wnt/β-catenin等信号通路以及对ICAM-1、MMP-1等细胞黏附蛋白的调控，揭示cadherin11介导的炎症级联反应在TMD病理发展过程中的作用，进而探索cadherin11特异性抑制剂对TMD发生发展的阻断作用。该研究不仅对于深入了解TMD发病机制具有一定的科学意义，而且有望为TMD的临床治疗提供新的研究思路。

近年来，临床与基础研究均表明炎性反应是颞下颌关节紊乱症病程发展的重要环节，但Cadherin11在颞下颌关节紊乱病程发展中介导炎性反应的分子机制尚不清楚。本研究在炎性损伤颞下颌关节滑膜细胞模型和持续炎性诱导整体动物模型上，考察cadherin-11介导MAPK、PI3K-Akt信号通路以及对MMP-1等细胞黏附蛋白的调控。结果表明，在炎症状态与静水压力等外界环境刺激下，颞下颌关节滑膜细胞及滑膜组织中cadherin11表达增加，其后续炎症级联反应与MAPK通路活化相关；发现现有小分子Cadherin11抑制剂尚不能很好地阻断滑膜炎症过程；通过miRNA组学分析，发现miRNA-148a-3p、miRNA3594-5p等10余个差异miRNA可能与偏侧咀嚼所致颞下颌关节形态变化相关。项目研究发表SCI收录研究论文5篇、会议论文1篇，获得国家发明专利授权1项，获得2015年国际牙科联合会Joseph Lister Award和浙江省科学技术二等奖。该研究不仅为深入了解TMD发病机制提供了确凿的科学证据，而且有望为TMD的临床治疗提供新的研究思路。