Li Pei Lin, Tang Jie, Li Xiao Tong, Zhao Shi Rong, Xu Run Xiang, Zhao Zhi Dong, Li Zhong Li, Li Zhi Ling, Yin Bo Feng, Yu Fu Hao, Wu Chu Tse, Zhu Heng
Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing 100850, P.R. China.
Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Sci Adv. 2025 Jul 18;11(29):eadu2294. doi: 10.1126/sciadv.adu2294.
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 expression, via adeno-associated virus-mediated 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.
骨关节炎（OA）是一种具有挑战性的退行性关节疾病，治疗选择有限。软骨下骨在维持关节稳态和影响OA进展中起着关键作用。在此，我们研究了衰老在OA进展过程中对间充质来源的干/祖细胞（MDSPCs）的作用，旨在确定潜在的治疗靶点。对人类和小鼠OA样本的组织病理学评估和生物信息学分析表明，表皮生长因子受体（EGFR）阳性的MDSPCs和双调蛋白（EREG）阳性的巨噬细胞在骨关节炎关节软骨下骨中构成一个衰老的骨骼单元。体外和体内实验表明，EREG促进EGFR阳性MDSPCs的衰老和过度成骨。此外，通过腺相关病毒介导的基因敲低或小鼠基因敲除干扰EREG的表达，可显著抑制软骨下骨中EGFR阳性MDSPCs的衰老，并减轻OA小鼠的病理硬化和疼痛。我们的研究结果表明，软骨下骨中的MDSPC衰老在驱动OA进展中是一个关键事件，为开发OA的创新治疗策略提供了有价值的参考点。
