低强度脉冲超声促进骨性关节炎软骨修复的力化学转导作用机制研究

The limited self-repair ability of articular cartilage is the major cause of ineffective osteoarthritis(OA) treatment，and finally leads to motor dysfunction. Low-intensity pulsed ultrasound(LIPUS) is a noninvasive physical factor, which can promote bone fracture healing through its mechanical effect. Our early study indicated that LIPUS might promote chondrocyte proliferation and matrix synthesis in rabbit OA model, which was closely related to activation of integrin β1,PI3K/Akt and inhibition of MAPKs. We hypothesize that LIPUS may promote OA cartilage repair through activating integrin and related proteins in the mechanochemical transduction cascades consisting of cartilage matrix,chondrocyte membrane,intracellular signal transduction pathway, cell and matrix metabolism.In this study, we'll firstly prove the effect of LIPUS on mechanochemical transduction proteins in rabbit knee OA model. Secondly we'll clarify whether the effect of LIPUS on cartilage is depended on the mechanochemical transduction cascades and determine the targets of LIPUS effect through inhibiting main proteins in the cascades. This study will provide a new idea for OA treatment.

关节软骨自身修复能力差是骨性关节炎（OA）治疗效果不佳,导致运动功能障碍的重要原因。低强度脉冲超声（LIPUS）是一种无创的、促进骨折愈合的物理因子，主要通过机械效应发挥作用。我们的前期研究发现，LIPUS可促进OA关节软骨细胞增殖和基质合成，其作用与激活软骨细胞表面应力受体整合素β1、细胞内PI3K/Akt和抑制MAPK信号通路密切相关，由此推测LIPUS可能经软骨基质→软骨细胞膜→细胞内信号转导通路→细胞/基质代谢这一力化学转导级联途径作用于整合素等相关力化学转导蛋白，促进OA关节软骨的修复。本课题将在整体、细胞及分子水平上探讨LIPUS促进OA软骨修复的力化学转导作用机制，通过研究LIPUS对兔膝OA软骨细胞相关力化学转导蛋白的影响，拟证明LIPUS发挥软骨保护作用的力化学转导级联途径，并逐一抑制级联途径中各关键蛋白，以确定LIPUS促进软骨修复的作用靶点，为OA的治疗提供新思路。

骨性关节炎（OA）因软骨修复能力差，其临床治疗效果有限，探索新的治疗手段，具有重要的临床意义。低强度脉冲超声（LIPUS）是一种新兴的物理治疗因子，本研究采用LIPUS干预兔膝OA，在整体、细胞和分子水平上评估LIPUS对OA软骨修复的作用，同时通过阻断软骨细胞表面应力受体整合素介导的PI3K/Akt和MAPK通路的信号靶点，探索LIPUS 对OA的作用机制。研究结果发现，LIPUS干预可提高OA软骨组织和细胞整合素β1蛋白和mRNA表达，提高FAK介导的PI3K/Akt磷酸化，同时抑制MAPK通路的激活，促进软骨细胞外基质产物II型胶原和蛋白多糖的合成，表明LIPUS可通过整合素介导的力化学信号通路促进软骨修复。同时我们针对LIPUS的作用进行了深入研究，结果发现LIPUS可通过上述信号通路抑制OA软骨细胞凋亡和骨软骨连接处血管形成。这些研究成果证明了LIPUS促进软骨修复的力化学传导机制以及作用靶点，为OA的US治疗提供了新的依据。