张力诱导下钙粘附素-连环素复合体对椎体终板软骨细胞退变的影响

Mechanical signal plays an extremely important role in the process of degeneration and proliferation of cartilage. Our previous study found that tension could induce the chondrocytes calcification of cartilaginous endplate, also found that the signaling pathways of Wnt, MAPK family, RhoA were involved in the process of chondrocytes calcification.Cadherin - catenin complex(CCC) is a receptor of mechanical signal pathway,but the CCC crosstalk with signaling pathways and coupling mechanism between mechanical induction and the molecular signals in chondrocytes is still not clear.So we propose the hypothesis that CCC is the critical node of tension signaling pathway of endplate chondrocytes. On the basis of our previous work, we further investigate the chang of related signaling pathway with tension load by the level of chondrocytes in vitro,whole organ and in vivo, and investigate the role of CCC, also investigate the effect of tension on the cartilaginous endplate chondrocytes signaling pathway by means of gene silencing with siRNA or overexpression with gene transfection, which aims to find the key signaling molecules, finally restore the function of cartilaginous endplate and reduce intervertebral disc degeneration by regulating the molecules.Thus,it can provide a new theory for the prevention and treatment of intervertebral disc degeneration.

力学信号在软骨的增殖和退变过程中具有极为重要的作用，我们的前期研究发现持续张力刺激可诱发终板软骨细胞的钙化，Wnt、MAPK家族、RhoA等信号通路参与软骨细胞的钙化过程，钙粘附素-连环素复合体是力学信号通路的感受器,但该复合体与信号通路间如何进行对话及力学和分子信号的偶联机制尚不清楚，据此我们提出钙粘附素-连环素复合体是终板软骨细胞张力信号通路关键节点的假说。本课题拟在前期工作的基础上，以软骨终板细胞、整体及在体椎间盘器官张力诱导模型为对象，研究张力载荷对终板软骨细胞相关信号通路的影响，揭示钙粘附素-连环素复合体的作用；并通过siRNA干扰途径或转染过表达方式，研究张力对终板软骨细胞信号通路的影响，鉴定关键的靶向信号分子；进而通过靶向分子的调控，恢复软骨终板的正常功能，并调控椎间盘退变。本课题研究将为椎间盘退变防治提供新的理论依据。

本课题以终板软骨为研究对象，发现间歇循环张力可通过激活Wnt/β-catenin、RhoA/ROCK-1和NF-κB信号通路引起终板软骨退变，其机制可能与钙粘附素-连环素复合体与多种信号转导通路关键靶向信号分子偶联作用相关。我们研究了终板软骨细胞在异常力学环境中的功能变化，并发现间歇循环机械张力诱导的钙化可被由雷帕霉素所诱导自噬作用抵制，即自噬可能参与阻止终板软骨细胞钙化。此外，我们证实了间歇循环机械压力引起的终板软骨细胞钙化过程中内源性TGF-β1可介导ANK基因表达下调。这些研究结果可为将来研究终板软骨为椎间盘退变治疗靶点提供坚实的理论依据。该课题项目共发表论文34篇，含 SCI 论文11 篇，Medline收录论文5篇，其他核心期刊文章18篇，这些论文也受到其他学者的引用。同时本课题共培养硕士研究生9名，并获国家专利一项。