Oleanolic acid, a small-molecule natural product, inhibits ECM degeneration in osteoarthritis by regulating the Hippo/YAP and Wnt/β-catenin pathways

Over the past few decades, osteoarthritis (OA) has been a major health problem worldwide. It is urgent to develop new, effective, and safe drugs to treat OA. There are many pentacyclic triterpenoids in nature that are safe and have health benefits. Oleanolic acid (OLA), one of the pentacyclic triterpenoids, is a potential novel compound for treating OA; however, its mechanism of action is still unclear. In this study, the mechanism of resistance to extracellular matrix (ECM) degradation of OLA and its protective role in the amelioration of OA were investigated by in vivo and in vitro experiments. We found that OLA promoted interleukin-1β (IL-1β)-induced production of type II collagen (collagen II) in rat chondrocytes, decreased the expression of matrix metalloproteinase (MMP)-3 and MMP-13, and inhibited inflammatory cytokine (IL-1β and TNF-α) and cartilage marker (CTX-II and COMP) levels, thereby hindering the pathological process of cartilage. Mechanistically, OLA inhibited the Wnt/β-catenin pathway, activated the Hippo/YAP pathway, and hampered the ECM degradation process by inhibiting the nuclear translocation of β-catenin and YAP. When we knocked down β-catenin, OLA lost its stimulatory effect on the Hippo pathway. These findings confirm that OLA plays an anti-ECM degradation role by regulating the Wnt/β-catenin and Hippo/YAP pathways. Overall, this study provides a theoretical basis for developing highly effective and low-toxic natural products for the prevention and treatment of OA.