新型跨膜蛋白DLK2调控颞下颌关节骨关节炎的分子机制研究

颞下颌关节骨关节炎是一种以进行性关节软骨退变、软骨下骨硬化和滑膜炎为病理特征的常见关节病。其中软骨细胞代谢异常是颞下颌关节骨关节炎发病的重要环节。在探索调控软骨分解代谢的系列研究中，我们发现（1）新型跨膜蛋白DLK2在胚胎软骨发育进程中表达逐渐下降；但在小鼠颞下颌关节骨关节炎中表达异常升高；（2）DLK2促进软骨细胞增殖，抑制软骨分化；（3）DLK2激活SRC蛋白磷酸化并促进分解代谢因子MMP-13、ADAMTS-5表达。上述研究提示DLK2是颞下颌关节骨关节炎发生发展中的一个重要因子。为此我们提出假说：DLK2通过激活SRC蛋白激酶、上调分解代谢关键蛋白，导致软骨代谢失衡，引起软骨退变。为验证该假说，我们将结合基因敲除等分子生物学手段，从分子、细胞、组织水平深入探讨DLK2对软骨的调控机制，在国际上首次明确DLK2在颞下颌关节骨关节炎中的重要作用，为颞下颌关节骨关节炎的诊治提供新思路。

Temporomandibular joint osteoarthritis is a common temporomandibular disorder(TMD) characterized by progressive cartilage degeneration, subchondral bone sclerosis and synovial inflammation. The imblance between chondrocyte catabolism and anabolism is the key factor that causes TMJOA. Our previous studies have demonstrated (1) Dlk2 gradual declined during embryonic cartilage development while increased in pathological condition such as in TMJOA mouse model; (2) Overexpression of dlk2 promoted chondrocyte proliferation but suppressed chondrogenesis; (3) Dlk2 enhanced Src phosphorylation and promoted the expression of catabolic factors including MMP-13 and ADAMTS-5. These results suggested that Dlk2 is an important factor in TMJOA. Based on these preliminary data, we proposed that Dlk2 activated SRC kinase, resulted in unbalance of catabolism and anabolism in chondrocytes and thus led to cartilage degeneration. To test this hypothesis, we will investigate the role of DLK2 in TMJOA from molecular, cellular, tissue levels by adopting gene silencing, knockout and other biological techniques. This study aims to identify novel therapeutic target for the understanding and treatment of temporomandibular joint osteoarthritis.