Targeting pro-senescent PTGS2+ macrophages alleviates chondrocyte senescence and osteoarthritis progression.

Macrophages contribute to osteoarthritis (OA) pathogenesis, but how specific macrophage states influence chondrocyte senescence remains unclear. Using single-cell RNA sequencing of naturally aged mouse joints, we identified a PTGS2-high macrophage subset associated with joint senescence. In a surgically induced OA model, lineage tracing revealed a marked increase of these macrophages, and their selective depletion using a diphtheria toxin receptor-based mouse model attenuated cartilage senescence and disease progression. PTGS2+ macrophage-derived THBS1 promoted chondrocyte senescence through SDC4-associated pericellular interactions and, at least in part, TGF-β-dependent signaling. Macrophage-specific deletion of Thbs1 reduced chondrocyte senescence markers and attenuated OA-like degeneration. Mechanistically, elevated glycolytic lactate enhanced THBS1 lactylation at lysine 262 (K262), which reduces NEDD4-dependent ubiquitination and stabilizes THBS1 protein. Intra-articular targeting of PTGS2-high macrophages attenuated chondrocyte senescence and OA progression. These findings link macrophage metabolic remodeling to a pro-senescent secreted pathway and suggest a locally delivered strategy for OA.