Mesenchymal stem cell-derived miR-125b-1-3p-abundant exosomes alleviate osteoarthritis by modulating the KDM6B-H3K27me3-FOXM1 axis.

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by the gradual deterioration of articular cartilage and the presence of inflammatory responses. In recent years, the use of exosomes (Exos) derived from bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a promising novel therapeutic approach for OA because of the role of these cells in tissue repair and immunomodulation. This study aimed to elucidate the functions and molecular mechanisms of miR-125b-1-3p, which is enriched in BMSC-Exos, in the progression of OA. METHODS: An in vitro OA model was constructed by exposing chondrocytes to IL-1β, followed by treatment with BMSC-Exos, to evaluate their protective effects. miRNA sequencing was performed to analyse the miRNA expression profile in BMSC-Exos, identifying miR-125b-1-3p as a pivotal molecule. Dual-luciferase reporter assays and chromatin immunoprecipitation quantitative PCR (ChIP‒qPCR) were used to further validate the target genes of miR-125b-1-3p and its downstream regulatory network. Additionally, a rat OA model was constructed, and the therapeutic effects of miR-125b-1-3p in BMSC-Exos were verified in vivo through safranin O staining, HE staining, and immunohistochemical analysis. RESULTS: MicroRNA (miRNA) sequencing revealed that compared with its expression in untreated normal chondrocytes, the expression of miR-125b-1-3p was significantly enriched in BMSC-Exos but downregulated in IL-1β-induced OA chondrocytes. Functional experiments demonstrated that BMSC-Exos delivered miR-125b-1-3p, which markedly enhanced chondrocyte anabolism and migration while inhibiting apoptosis, thereby alleviating OA progression. Mechanistic studies revealed that miR-125b-1-3p targeted the histone demethylase KDM6B, resulting in increased H3K27me3 enrichment at the FOXM1 promoter region and epigenetic suppression of FOXM1 expression, ultimately exerting chondroprotective effects. CONCLUSION: This study elucidates a novel molecular mechanism through which BMSC-Exos shuttle miR-125b-1-3p to alleviate OA by modulating the KDM6B/H3K27me3/FOXM1 signalling axis. These findings provide a theoretical rationale and identify promising therapeutic targets for the development of exosome-based therapeutic strategies against OA.