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

Abstract

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 EGFRMDSPCs and EREGmacrophages 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 EGFRMDSPCs. Moreover, interference withexpression, via adeno-associated virus-mediatedknockdown or genetic knockout in mice, significantly suppressed senescence of EGFRMDSPCs 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.