Knee osteoarthritis (KOA) is a prevalent degenerative joint disease that is primarily managed by improving the destroyed cartilage and reversing subchondral bone remodeling. Total glucosides of white paeony (TGP) capsule primarily contains extracts from the white peony root and has been shown to have various pharmacological effects, but its role in KOA still requires comprehensive evaluation. In this study, we aimed to investigate the protective effect of TGP on knee cartilage and subchondral bone, as well as elucidate the underlying molecular mechanisms. The effect of TGP on KOA progression was evaluated in the destabilization of the medial meniscus (DMM)‐induced KOA model of mouse and interleukin (IL)‐1β‐induced KOA model of primary mouse chondrocytes. In vivo and in vitro experiments demonstrated that TGP had a protective effect on the cartilage. Treatment with TGP could induce the synthesis of critical elements in the cartilage extracellular matrix and downregulate the synthesis of degrading enzymes in the extracellular matrix. Regarding the underlying mechanisms, TGP inhibited the phosphorylation and nuclear translocation of p65 by regulating the nuclear factor‐kappa B (NF‐κB) signaling pathway. In addition, TGP could reduce the secretion of IL‐1β, IL‐6, and tumor necrosis factor‐α (TNF‐α). Moreover, it has a sustained effect on coupled subchondral bone remodeling through regulation of the OPG/RANKL/RANK pathway. In conclusion, TGP may protect articular cartilage by downregulating the NF‐κB signaling pathway and may support coupled subchondral bone remodeling by regulating OPG/RANKL/RANK signaling pathway in the DMM‐induced KOA model of mouse, suggesting a new therapeutic potential for KOA treatment.
