BMSCs-Derived Exosomal XPO7 Attenuates Osteoarthritis Progression by Targeting KDM2B to Ameliorate Chondrocyte Senescence

Abstract

Chondrocyte senescence is a central driver of osteoarthritis (OA) pathogenesis. While bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) exhibit therapeutic potential, their key functional components remain unclear. We therefore investigated whether Exportin-7 (XPO7), a protein enriched in BMSCs-Exos, alleviates OA by ameliorating chondrocyte senescence-associated changes and explores the underlying mechanism. Using an IL-1β-induced in vitro OA model in rat chondrocytes, we treated cells with exosomes from BMSCs with modulated XPO7 overexpression or knockdown; KDM2B was overexpressed in chondrocytes. Senescence, apoptosis, viability, senescence-associated secretory phenotype (SASP) markers, and extracellular matrix (ECM) metabolism were evaluated. We found that BMSCs-Exos significantly mitigated IL-1β-induced chondrocyte senescence-like changes, apoptosis, SASP (p16, p21, p53, IL-1β, IL-6, TNF-α), and ECM degradation, as evidenced by the reversal of IL-1β-induced suppression of anabolic genes SOX9, COL2, ACAN and elevated catabolic gene MMP13. These protective effects were enhanced by XPO7 overexpression and diminished by its knockdown. Co-immunoprecipitation and immunofluorescence further showed that XPO7 physically interacted with and negatively regulated the histone demethylase KDM2B, and overexpressing KDM2B abolished the protective effects of XPO7-enriched exosomes. In an in vivo rat OA model induced by anterior cruciate ligament transection (ACLT), systemic administration of BMSCs-Exos overexpressing XPO7 attenuated cartilage destruction and improved mechanical allodynia (increased paw withdrawal threshold). These therapeutic benefits were significantly reversed by concurrent intra-articular injection with a KDM2B overexpressing plasmid. Collectively, BMSCs-Exos deliver XPO7, which negatively regulates KDM2B to attenuate chondrocyte senescence-associated phenotypes and OA progression. The XPO7-KDM2B axis may represent a promising therapeutic target for OA intervention.