Dlk2/Syap1调控破骨细胞分化促进颞下颌关节骨关节炎的分子机制研究

软骨下骨的异常改建是颞下颌关节骨关节炎发生发展的重要环节。在研究中我们发现：①Dlk2在小鼠颞下颌关节骨关节炎模型早期的髁突软骨下骨中高表达且与骨量丧失程度相关；②Dlk2过表达促进破骨分化，Dlk2沉默抑制破骨分化；③破骨细胞内Dlk2条件性敲除小鼠骨量上升；④Dlk2与Syap1结合，且Dlk2/Syap1沉默均能抑制破骨分化及MAPK、PI3K/Akt信号通路。为此我们提出假说：在早期颞下颌关节骨关节炎中，Dlk2通过Syap1受体调控破骨细胞形成及下游破骨分化相关信号通路（MAPK、PI3K/Akt），促进破骨细胞异常活化，从而促进软骨下骨异常改建。本项目拟结合已构建的破骨细胞内Dlk2/Syap1条件性敲除鼠进行体内、体外研究，从分子，细胞，组织，基因鼠层面上深入探索Dlk2/Syap1在颞下颌关节骨关节炎中软骨下骨异常改建中的作用机制。

The abnormal remodeling of condylar subchondral bone is an important part of the development of temporomandibular joint osteoarthritis (TMJOA). In our study we found that: ①Dlk2 was highly expressed in condylar subchondral bone in early stage of mice TMJOA models and was related to the degree of bone mass loss. ②Dlk2 overexpression promoted osteoclast differentiation whereas inhibition of Dlk2 inhibited osteoclast differentiation; ③The Dlk2 osteoclast-specific conditional knockout mice showed increased bone mass phenotype. ④Dlk2 interacted with Syap1. Silencing of Dlk2/Syap1 inhibited osteoclast differentiation and MAPK and PI3K/Akt pathways. Thus, we propose a hypothesis: in early stage of TMJOA, Dlk2 regulates osteoclast formation and downstream osteoclast-related signaling pathways (MAPK, PI3K/Akt) through Syap1 receptors, and promotes abnormal osteoclast activation, thus promoting abnormal subchondral bone remodeling. Based on this hypothesis, we intend to use the established Dlk2 and Syap1 osteoclast-specific conditional knockout mice for in vivo and in vitro studies, and to explore the mechanism of Dlk2/Syap1 in regulation of abnormal remodeling of subchondral bone in TMJOA from the cell, tissue, and gene mouse levels.