以间充质干细胞为靶点的创伤性颞下颌关节强直早期分子干预治疗

Tramatic TMJ ankylosis is a severe disability to affect the mouth opening and oral function. So far, the only method to treat this disease is ankylosed bone resection. However, there are a lot of complication caused by surgery. Recently, all studies found that the development of traumatic TMJ ankylosis is a kind of bone repair such as distraction ostegenesis or hypertrophic bone non-union. Mesenchymal stem cells (MSCs) play a pivotal role in bone repair.Our previous work found that the radiolucent zone of ankylosed bone contains MSCs. And the mineralized degree of the radiolucent zone is related with the residual mouth opening of ankylosis patients. In this project, we plan to inhibit the osteogenesis of MSCs in the radiolucent zone tissue useing the Runx2-siRNA targeting to bone formation surface deliveried by liposome. The mineralization of radiolucent zone could be inhibted by impaired osteogenesis of MSCs. In this case, the development of ankylosis could be interruped and the patients could preserve funcional mouth openning without surgery.

中文摘要：创伤性颞下颌关节强直是一种因关节损伤导致患者张口受限和牙颌功能丧失的严重疾病。手术作为唯一治疗方法存在创伤大、复发率高和影响颌骨发育等问题。强直的发生本质上是"失控性"异常骨修复，而间充质干细胞对骨损伤修复过程起着重要的调控作用。本课题组已成功建立了创伤性关节强直大动物模型，在前期研究中证实强直骨球内透射带的存在，透射带组织的钙化程度与张口度密切相关，同时还发现透射带组织中存在具有多分化潜能的间充质干细胞。鉴于此，本项目拟以强直透射带组织为目标部位，以间充质干细胞为主要靶细胞，以成骨界面靶向特异的多肽修饰阳离子脂质体为载体，运用 siRNA 敲低Runx2 表达，抑制间充质干细胞的成骨分化，从而阻止透射带组织矿化，达到终止强直病程、限制强直进展的目的。这一研究预期将为分子生物学手段干预和治疗早中期关节强直找到新的有效途径。

近年来，关节强直的临床研究、动物模型以及分子生物学初步研究提示，创伤性颞下颌关节强直可能是一种"异常的骨愈合"。因间充质干细胞（MSCs）参与整个骨折愈合过程，且其增殖和成骨能力与骨愈合密切相关。Runt相关转录因子2（Runx2）是参与到间充质干细胞成骨分化的关键因子之一。本课题组研究发现，骨折愈合的过程中，其表达先上调后维持。而在创伤性颞下颌关节强直的动物模型中，骨性关节强直组Runx2表达远高于纤维性强直组。因此本课题希望通过干扰间充质干细胞Runx2 RNA的表达，减弱骨性强制形成过程中的成骨过程。选取腺相关病毒（AAV）在体内减弱RNA表达，观察对关节强直形成的干预结果。