补肾活血方通过Hippo-YAP信号通路调控TBK1抑制软骨细胞“炎性衰老”干预骨性关节炎的机制研究

炎性反应诱导软骨细胞衰老可能是导致骨性关节炎（OA）进展的主要因素之一。近来发现Hippo-YAP通路在细胞衰老中发挥了重要的作用。我们通过预实验发现损伤越严重的软骨组织，YAP的表达量越低；在软骨细胞中抑制YAP表达后，细胞活力受到了抑制，而TBK1和P65的磷酸化活性明显增加，表明YAP可能是通过调控TBK1和炎性反应影响软骨细胞衰老。前期研究发现补肾活血中药可抑制软骨细胞中NF-κB信号通路活性，抑制OA炎性反应，而预实验也发现该药具有上调YAP、下调p-TBK1和p-P65表达的作用。因此，我们猜想在退变关节软骨中Hippo-YAP信号通路活性的改变，导致TBK1异常表达，诱导炎性反应，从而促进软骨细胞衰老，加速OA进程，而补肾活血中药可抑制这一过程。本项目拟通过体内外实验验证补肾活血中药通过Hippo-YAP信号通路调控TBK1介导软骨细胞“炎性衰老”干预OA的生物学作用及意义。

The chondrocytes senescence induced by inflammatory response may be one of the main factors leading to the development of osteoarthritis (OA). Recently, it has been found that Hippo-YAP pathway plays an important role in cell senescence. We found that the more severely injured articular cartilage, the lower YAP expression. After inhibiting the expression of YAP in chondrocytes, the cell viability was significantly inhibited, while the phosphorylation activity of TBK1 and P65 increased significantly, indicating that YAP may affect the senescence of chondrocytes by regulating TBK1 and inflammatory response. In the early stage, it was found that kidney-tonifying and blood-activating herbs could inhibit NF-κB signal pathway activity in cartilage, and inhibit OA inflammatory response，it was also found that this herbs could up regulate YAP, down regulate the expression of p-TBK1 and p-P65. Therefore, we speculate that the change of Hippo-YAP signaling pathway activity in degenerative articular cartilage will lead to the abnormal expression of TBK1 and the induction of inflammatory response, thus accelerating the aging of chondrocytes and the process of OA. While, kidney-tonifying and blood-activating herbs can inhibit this process. The purpose of this project is to verify the biological effect and significance of kidney-tonifying and blood-activating herbs on OA mediated “inflamm-aging” of chondrocytes by TBK1 through Hippo-YAP signal pathway in vitro and in vivo.