Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization

Chondrocyte apoptosis and synovial macrophage polarization represent two key pathological hallmarks of osteoarthritis (OA), but the interplay between them remains largely unknown. This study aimed to investigate the roles and mechanisms of the chondrocyte apoptotic secretome in mediating macrophage polarization during the pathological process of OA. In vitro cultures of chondrocytes and macrophages, along with an in vivo surgically induced OA mouse model, were used to evaluate the effect of the chondrocyte apoptotic secretome. Untargeted metabolomics, mitochondrial function assessment, and macrophage-specific AMPKα knockout mice were used to identify key metabolites and their regulatory mechanisms. A sustained-release delivery system for spermidine (SPD) was constructed using lipid nanoparticles (LNPs) and sodium hyaluronate. Apoptotic chondrocytes increased the secretion of SPD in the metabolite secretome. SPD acts as a signaling metabolite to increase AMPKα activation in macrophages, which in turn drives increased oxidative phosphorylation (OXPHOS) and improves mitochondrial function, ultimately promoting M2c macrophage polarization during OA. Exogenous supplementation with SPD via a ROS-responsive SH@LNP@SPD hydrogel alleviated OA progression by promoting M2c macrophage polarization in vivo. Furthermore, elevated SPD levels in synovial fluid correlated with milder clinical symptoms and less severe pathological features. Our findings underscore a significant protective role of chondrocyte apoptosis in early OA mediated through the secretion of SPD, which acts on macrophages. Mechanistically, SPD-induced enhancement of AMPKα activation and OXPHOS occurs specifically in macrophages, driving their beneficial M2c polarization. Synovial fluid SPD may hold diagnostic value for early-stage OA and strategies aimed at sustaining SPD levels may represent effective therapeutic approaches for OA.