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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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  • Xiaoming Liu,
  • Jun Zhou,
  • Bin Chai,
  • Yongqiang Xiao,
  • Pingping Li,
  • Tingting Shi,
  • Rui Cui,
  • Guoning Zhang,
  • Shuai Jiang

摘要

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.

Graphical abstract