Adrb2-Mir29b-Wnt5a通路在TMJ-OA髁突软骨下骨丢失中的作用研究

骨关节病（OA）是颞颌关节病的重症表现，软骨下骨丢失是其重要致病因素，但骨丢失机制仍不清楚。我们首先提出并证实：去甲肾上腺素（NE）-β2受体 (Adrb2)信号可促进间充质干细胞（MSC）分泌Wnt5a，介导TMJ-OA髁突软骨下骨丢失，但NE上调MSC Adrb2促进Wnt5a表达的机制仍未阐明。Mir29b是我们通过芯片筛选获得的在TMJOA髁突软骨下骨MSC中显著下调的MicroRNA，预实验结果显示：Adrb2信号活化可下调mir29b；Adrb2及wnt5a非编码区均存在mir29b结合位点。提示Adrb2-mir29b-wnt5a通路可能在TMJOA软骨下骨丢失中发挥关键作用。本项目拟以Adrb2敲除鼠、mir29b调控鼠、TMJOA模型鼠及其MSC为模型，探索上述通路在TMJOA软骨下骨丢失中的调控作用及机制，既为TMJOA病变机制提出新认识，又为发现新的药物靶位提供依据。

Osteoarthritis is one of the most severe pathological changes of the patients with temporomandibular disorders (TMD) which is a common disease occurring in the orofacial region. Subchondral bone loss is the important pathogenic factor in the progression of osteoarthritis, but its pathomechanism is still unclear. We for the first time demonstrated that activation of norepinephrine(NE)-β2 adrenergic receptor(Adrb2)signal could promote the secretion of wnt5a by mesenchymal stem cells (MSCs), leading to the subchondral bone loss in the osteoarthritis of temporomandibular joint (TMJ), but the mechanism that NE increased expression of Adrb2 and wnt5a is not clarified. By MicroRNA array, we found that Mir29b is the most down-regulated MicroRNA in the MSCs isolated from the condylar sunchondral bone of TMJ osteoarthritic rats. Our preliminary data showed that activation of Adrb2 signal could suppressed the expression of mir29b, and there are mir29b binding sites in the untranslated regions of Adrb2 and wnt5a. These results indicates that Adrb2-mir29b-wnt5a axis plays an important pathogenetic role in the progression of subchondral bone loss in TMJ osteoarthritis. The present project will use Adrb2 conditional knock-out mice, mir29b manipulating mice and TMJ-OA mice, and their corresponding MSCs to study the effect and mechanisim of Adrb2-mir29b-wnt5a axis in the subchondral bone loss during the early stage of TMJ osteoarthritis. Taken together, this project will on one hand demonstrate the new knowledge on the pathomechanism of early TMJ osteoarthritis, and on the other hand provide novel drug targets for the therapy of TMJ osteoarthritis.