Prim-O-glucosylcimifugin alleviate osteoarthritis through regulates autophagy via IGF1R/JAK2/STAT3 axis.

BACKGROUND

Osteoarthritis (OA) is a non-reversible degenerative disease characterized by progressive destruction of joint cartilage, formation of bone spurs, remodeling of subchondral bone plates, and inflammation of the synovium. Prim-O-glucosylcimifugin (POG) has been proven to have multiple biological activities such as anti-inflammatory and antioxidant effects. However, the precise mechanisms underlying POG's efficacy in OA remain to be elucidated.

PURPOSE: The study aims to systematically elucidate the molecular mechanism of POG in anti-osteoarthritis and provide a theoretical basis for its clinical application.

METHODS

In vitro experiments used bone marrow mesenchymal stem cells (BMSCs) and primary rat chondrocytes and SW1353 cells induced by IL-1β. The proliferation effect of POG on chondrocytes was evaluated by MTT and EDU assays. The regulatory effect of POG on extracellular matrix (ECM) of chondrocytes and its promoting chondrogenic differentiation were assessed by Western blotting, RT-qPCR and immunofluorescence experiments. Subsequently, network pharmacology analysis, CETSA, DARTS, autophagy flow detection, and molecular docking studies were used to determine the target of POG and clarify its potential mechanism. In vivo experiments constructed a DMM osteoarthritis rat model. The anti-osteoarthritis effect of POG was further verified by Micro-CT, histological staining and immunohistochemical experiments.

RESULTS

In vitro experiments showed that POG significantly promoted chondrocyte proliferation and regulated the degradation and synthesis of ECM in chondrocytes. In addition, POG inhibited the inflammatory response induced by IL-1β and promoted chondrogenic differentiation of bone marrow mesenchymal stem cells, enhancing the repair ability of cartilage tissue. Mechanism studies revealed that POG further inhibited the activation of the JAK2/Stat3 signaling pathway by targeting IGF1R and promoted autophagy in chondrocytes. In vivo experiments showed that intra-articular injection of POG could significantly improve cartilage damage caused by DMM, reduce the degree of cartilage degeneration, decrease bone spur formation, and delay the process of bone plate remodeling.

CONCLUSION

POG regulates cartilage metabolism by targeting IGF1R and further inhibiting the downstream JAK2/Stat3 signaling pathway, thereby enhancing autophagy in chondrocytes. This provides a new theoretical basis and potential drug selection for the treatment of osteoarthritis.