Myo6介导的囊泡转运与封闭区形成在破骨细胞分化与骨质侵蚀中的作用及其机制研究

The bone erosion of Rheumatoid arthritis was mediated by over-activation of osteoclasts. Bone-resorbing osteoclasts are highly dependent on sealing zone formation and matrix enzyme trafficking and secretion. Therefore inhibition of osteoclast activity may be a protective therapeutic regimen for RA bone erosion. We found that the Myo6 gene was highly expressed during osteoclast differentiation in a time-dependent manner and had a positive correlation with the bone erosion of arthritis in our preliminary experiment, indicating Myo6 might participate in osteoclast differentiation and activation. In this project, we will explore the regulatory mechanism of Myo6 in osteoclast sealing zone formation and matrix enzyme trafficking and secretion in vivo cellular experiments and in vitro animal model of RA based on gene knockdown and overexpression technology; elucidate the important functions of Myo6 in the differentiation and activity of osteoclast. Our study will provide a new target of drug screening for RA treatment.

类风湿关节炎（RA）的骨质侵蚀主要是由破骨细胞的过度活化引起的，而破骨细胞的骨吸收活性依赖于封闭吸收区的形成与基质酶的转运分泌，抑制破骨细胞的活性有可能成为 RA 治疗中保护骨质的可行方案。我们前期的研究发现， 肌球蛋白Myo6基因在破骨细胞分化过程中高表达，且随诱导时间而递增，同时与胶原诱导型关节炎小鼠骨质侵蚀呈正相关，提示Myo6可能参与了破骨细胞的分化与骨吸收过程。本项目将在前期研究基础上，利用基因干扰和过表达技术，从体外的细胞实验与体内的RA动物模型入手，系统探讨Myo6对破骨细胞封闭吸收区的形成与基质酶的转运分泌的调控机制，明确其在破骨细胞分化与骨吸收中的作用，以期为RA的治疗提供新的药物筛选靶点。

破骨细胞过度活化是类风湿关节炎骨质破坏的关键因素，探讨其分化与活化的机制将为骨侵蚀相关疾病的治疗提供可能的靶点。本项目专注于破骨细胞分化过程中所依赖的骨架重拍及囊泡转运过程，采用基因敲除小鼠，分别体外和体内水平研究Myo6在破骨细胞发挥骨吸收功能的调控及其在类风湿关节炎模型中的炎症水平及关节保护作用，阐明了相关的分子机制。本项目的结果显示，敲除Myo6可显著抑制破骨细胞的分化与骨吸收功能，下调破骨相关蛋白表达，且细胞的自噬及焦亡水平受到抑制；在动物实验中，敲除Myo6可降低胶原诱导关节炎模型小鼠的炎症水平，且明显保护小鼠关节免收炎症的破坏。通过本项目的实施，提示Myo6在骨侵蚀过程当中发挥着关键的调控作用，可作为治疗骨侵蚀相关疾病药物开发的潜在靶点进行深入研究。