Multiomic identification of senescent stem cell populations critical for osteoarthritis progression and therapy in subchondral bones

Osteoarthritis (OA) is a challenging degenerative joint disease with limited treatment options. Subchondral bone plays a critical role in maintaining joint homeostasis and influencing OA progression. Here, we investigated the role of senescence in mesenchyme-derived stem/progenitor cells (MDSPCs) during OA progression, aiming to identify potential therapeutic targets. Histopathological evaluations and bioinformatic analyses of OA samples from both humans and mice revealed that EGFR⁺ MDSPCs and EREG⁺ macrophages constitute a senescent skeletal unit within the osteoarthritic articular subchondral bone. In vitro and in vivo experiments demonstrated that EREG promotes senescence and excessive osteogenesis in EGFR⁺ MDSPCs. Moreover, interference with Ereg expression, via adeno-associated virus-mediated Ereg knockdown or genetic knockout in mice, significantly suppressed senescence of EGFR⁺ MDSPCs in subchondral bone and alleviated both pathological sclerosis and pain in OA mice. Our findings indicate that MDSPC senescence in the subchondral bone is a key event driving OA progression, offering a valuable reference point to develop innovative therapeutic strategies for OA.