Semaglutide ameliorates osteoarthritis progression through a weight loss-independent metabolic restoration mechanism.

Metabolic disorders have been recognized as a major contributor to the occurrence and progression of osteoarthritis (OA). Identifying novel therapeutic agents to ameliorate the progression of OA with metabolic disorder is crucial. In this study, we demonstrate that semaglutide (SG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, exhibits strong chondroprotective effects in an OA mouse model with obesity, as evidenced by reduced pathological changes, including cartilage degeneration, osteophyte formation, synovial lesion, and pain sensitivity. A randomized pilot clinical study (ChiCTR2200066291) further supports these findings. By designing a precise diet-controlled setting to rule out the effect of appetite suppression and weight loss induced by SG, we demonstrate a weight loss-independent mechanism. Through regulating the "GLP-1R-AMPK-PFKFB3" axis, the SG reprograms chondrocyte metabolism profile from glycolysis to oxidative phosphorylation under inflammatory conditions, resulting in cartilage restoration.