miR-675靶向TBK1介导骨关节炎免疫微环境调控软骨细胞自噬及补肾活血中药干预研究

骨关节炎(OA)的发病与免疫微环境及软骨细胞自噬水平密切相关，机体免疫炎症对关节局部微环境产生的影响可能是导致OA的主要因素之一，而自噬失衡将不能维持软骨表型并导致损伤的关节软骨难以修复，加快OA的进展。miR-675可通过促进2型胶原的产生维持软骨表型，有助于软骨损伤后的修复，TBK1为IRFs活化所必需的磷酸激酶，可调节免疫反应，而自噬可能是正常细胞遭受异常免疫反应引起炎症时的一种保护或平衡机制。因此，课题组猜想在受炎症、力学负荷、增龄、遗传因素影响下，关节软骨中miR-675表达下调，引起TBK1异常表达，继而激活IRFs后诱导异常免疫炎性反应导致自噬被抑制，从而加速软骨损伤。本课题基于这一假说及中药的特性，阐述软骨细胞自噬功能失调机制可能是OA肾虚血瘀的本质；并以miR-675靶向TBK1介导的骨关节炎免疫微环境为视角，阐明OA软骨自噬的机制及中药靶向干预的分子机制。

The incidence of osteoarthritis (OA) is closely related to the immune microenvironment and the level of chondrocyte autophagy. The effect of immune inflammation on the local microenvironment of the joint may be one of the main factors leading to OA. Chondrocyte autophagy is necessary for the maintenance of chondrocyte phenotype and repairing articular cartilage, so it is difficult for amaged articular cartilage to repair due to chondrocyte autophagy dysfunction, and then accelerate the progress of OA. MiR-675 can help repair cartilage injury by maintaining the chondrocyte phenotype via promoting the production of type 2 collagen.TBK1 is a essential phosphokinase for the functional activation of IRFs, which regulates the immune response, and autophagy may be a protective or balanced mechanism for inflammation caused by abnormal immune responses in normal cells. Therefore, we supposed that under the influence of inflammation, mechanical loading, aging and genetic factors, the expression of miR-675 in articular cartilage is down-regulated, which caused aberrant expression of TBK1, and then induced abnormal immune inflammatory reaction after activating IRFs, subsequently leaded to the inhibition of autophagy, thus accelerating articular cartilage injury. Traditional Chinese medicine has many potential and advantages in the prevention and control of OA with multiple targets and dual regulating functions. The subject is based on this hypothesis and the characteristics of traditional Chinese Medicine, explains the mechanism of chondrocyte autophagy dysfunction may be the essence of kidney deficiency and blood stasis of OA, and explores the mechanism of autophagy of OA cartilage and the molecular mechanism of protective effect on cartilage of traditional Chinese medicine, according to the perspective of immune microenvironment mediated by miR-675 targeting TBK1.