Mmp13和Adamts5在TGF-β信号转导和骨性关节炎发病中的作用及补肾活血中药的干预机制研究

Osteoarthritis (OA) is the most common joint disease and is a major cause of disability. Our previous study showed that TGF-β signaling is potentially important in the pathogenesis of OA. Deletion of the type II TGF-β receptor gene (Tgfbr2) in chondrocytes at postnatal stage led to severe and progressive development of OA-like phenotype. In preliminary studies, we found that inhibition of TGF-β signaling is associated with increased Mmp13 and Adamts5 expression in chondrocytes. So, Our overall hypothesis is that Mmp13 and Adamts5 serve as a critical downstream target gene of TGF-β signaling in chondrocytes during OA development, and play an very important role of OA development. MMP13 and ADAMTS5 both are major enzymes that target cartilage for degradation. Inhibition of TGF-β signaling in chondrocytes leads to OA development through up-regulation of Mmp13 and Adamts5 expression. That will be a potentially important mechanism during OA development. In the proposed studies, we will use a genetic approach to specifically delete the Mmp13 or Adamts5 gene under Tgfbr2 cKO background and through the methods of radiography, histology, histomorphometry, real-time RT-PCR to indentify the hypothesis. It may decelerate the progression of OA, if we down regulate the expression of Mmp13 and Adamts5 . In TCM, the pathology of OA is deficiency of Ben and repletion of Biao,the principle of treatment is Nourishing Kidney and Activing Blood. And Modern medical shows that the pathology of OA is related to endocrine system and microcirculation. The herbs of Nourishing Kidney and Activing Blood can block the progress of OA. However, the mechanism of the interventions is still not clear. So, we plan to solve those problems. The results of our study may therefore represent a novel treatment option for OA patients to preserve articular cartilage and joint function instead of simply alleviating OA symptoms like existing treatments.

骨性关节炎是最常见的致残性关节炎。项目组前期研究显示TGF-β对骨性关节炎的发病机制存在潜在重要性。软骨细胞特异性Tgfbr2基因敲除小鼠有骨性关节炎表型，同时TGF-β信号转导抑制可致Mmp13和Adamts5表达上调，因此我们提出科学假说：Mmp13和Adamts5是TGF-β信号通路的关键下游基因，并在骨性关节炎发病过程中发挥重要作用。MMP13和Adamts5都会导致关节软骨降解，其表达受TGF-β信号调控，这可能是骨性关节炎发病的重要机制。中医认为OA病机是"本虚标实"，治疗以"补肾活血"，而现代医学也研究显示OA发病与内分泌、微循环紊乱有密切关系。补肾活血中药干预OA发展的疗效在长期临床中得到充分肯定，但其干预机制不明确，极大影响了补肾活血中药防治OA的推广应用。因此，本项目的研究不仅在骨性关节炎发病机制上有新认识和突破，也为探寻补肾活血中药干预OA的机制提供新的契机和思路。

骨性关节炎发病率极高，是最常见的致残性关节炎。项目组前期研究显示TGF-β信号通路对骨性关节炎的发生和发展具有重要的作用。软骨细胞特异性Tgfbr2基因敲除小鼠有类似人类膝关节骨性关节炎表型，同时TGF-β信号转导抑制可致Mmp13和Adamts5表达上调，因此项目组提出科学假说：Mmp13和Adamts5是TGF-β信号通路的关键下游基因，并在骨性关节炎发病过程中发挥重要作用。MMP13和Adamts5都会导致关节软骨降解，其表达受TGF-β信号调控，这可能是骨性关节炎发病的重要机制。中医认为OA病机是“本虚标实”，治疗以“补肾活血”，而现代医学也研究显示OA发病与内分泌、微循环紊乱有密切关系。补肾活血中药干预OA发展的疗效在长期临床中得到充分肯定，但其干预机制不明确，极大影响了补肾活血中药防治OA的推广应用。本项目组通过体内实验研究证实Mmp13和Adamts5都是TGF-β信号通路的关键下游基因，而Mmp13在TGF-β缺失所致的骨性关节炎发生发展中更为重要，因其可以明显逆转TGF-β缺失所致的骨性关节炎表型。同时，本项目发现补肾活血方能逆转半月板损伤所致的骨性关节炎的表型，而且，能逆转TGF-β缺失所致的骨性关节炎表型，这与Mmp13基因缺失后挽救的OA的表型极为相似，极有可能补肾活血方是通过下调软骨细胞Mmp13的表达而延缓，甚至逆转了骨性关节炎的表型。本项目的研究成果是对骨性关节炎发病机制上的新认识和突破，也为补肾活血中药干预OA的机制提供新的实验依据和思路。