低强度脉冲超声通过Integrin-FAP- CSK途径影响软骨细胞相关信号转导的机制研究

Temporomandibular joint osteoarthritis (TMJ-OA) is a severe degenerative joint disorder. The pathological process is characterized by the apoptosis of chondrocytes and the destruction of cartilage matrix. Effective treatment is still lacking. Current studies mostly focus upon the relationship between abnormal metabolism of chondrocytes and inflammatory cytokines, whereas ignore the role of physical stimulation. Our previous study has demonstrated that chondrocytes can experience LIPUS stimulation through the cell membrane receptor Integrin in the early stage of injury, and participate in the transduction of intracellular biological signals through CSK, and involves in the metabolism of chondrocytes. Therefore, understanding the effect of LIPUS on CSK-mediated biological signaling in chondrocytes can provide novel ideas for the early prevention and treatment of TMJ-OA. On the basis of our preliminary investigation, immunology, cell biology and other methods were adopted to observe the changes in cell morphology and related signal transduction. Through the establishment and treatment of TMJ-OA animal models, the molecular mechanism of the effect LIPUS upon chondrocyte-associated signal transduction through the Integrin-FAP-CSK pathway was systematically elucidated, aiming to provide direct experimental evidence for the clinical treatment of TMJ-OA.

颞下颌关节骨关节炎（TMJ-OA）是一类严重的退行性关节紊乱病，其病理过程以软骨细胞凋亡及软骨基质破坏为主要特征，尚无行之有效的治疗措施。现有的研究多集中在软骨细胞代谢异常与炎性因子的关系，忽视了物理刺激的作用。我们前期研究发现，软骨细胞在受损早期可通过细胞膜受体Integrin感受LIPUS的刺激，通过CSK参与细胞内生物信号的转导过程，参与软骨细胞的代谢。因此，了解LIPUS对软骨细胞CSK介导的生物信号作用机制，可为TMJ-OA早期防治提供新思路。本项目拟在前期研究的基础上，采用免疫学、细胞生物学等方法观察细胞形态结构及相关信号转导变化；最终通过TMJ-OA动物治疗实验验证，系统地阐释LIPUS通过调控Integrin-FAP-CSK途径对髁突软骨细胞信号通路转导的分子机制，为TMJ-OA的治疗提供最直接的实验依据。

颞下颌关节骨关节炎（temporomandibular joint osteoarthritis, TMJ-OA）是一类严重的退行性颞下颌关节紊乱病（temporomandibular diorders，TMD），临床表现为颞下颌关节疼痛、功能障碍等，严重影响患者的咀嚼、语言等功能，给患者的身心带来极大影响，且缺乏有效的治疗手段。其病理过程以软骨细胞凋亡及软骨基质破坏为主要特征，病因及发病机制至今尚未完全明确。越来越多的研究表明，多条细胞信号转导参与了髁突细胞的迁移、黏附和侵袭功能，参与了软骨的异常代谢过程，但确切其作用靶点尚不明了。同时针对软骨细胞凋亡及软骨基质异常采取的对抗措施非常有限，因此，需要进一步深入探讨 TMJ-OA的致病机制，同时探索其对抗措施。项目组在前期研究的基础上，成功建立大鼠TMJ-OA动物模型，并通过TMJ-OA动物模型验证了CSK参与细胞内的化学信号传递过程；运用LIPUS对骨、软骨的作用机制进行了探索，发现LIPUS能启动细胞内的化学信号转导过程，激活细胞的多条信号通路，筛选了LIPUS作用于髁突软骨的最佳作用模式，采用免疫学、细胞生物学等方法观察了LIPUS作用后细胞形态结构及相关因子的变化，运用生物信息学技术筛选了多个LIPUS作用于髁突软骨作用靶点。最终通过TMJ-OA动物实验进行了验证，为临床上TMJ-OA 的防治提供新思路。