Mouse OA model study combined with a pilot randomized clinical study demonstrating semaglutide's chondroprotective effects through weight-loss-independent metabolic restoration mechanisms, including suppression of cartilage-degrading inflammatory pathways and restoration of chondrocyte metabolism. Semaglutide reduced cartilage degeneration, osteophyte formation, synovial lesions, and pain in obese OA mice. Establishes a direct GLP-1R-mediated mechanism for osteoarthritis protection beyond weight loss—providing biological rationale for a new indication for semaglutide in metabolic OA where joint inflammation is driven by systemic metabolic dysregulation.
Abstract
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.