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Background <p>Osteoarthritis (OA), the most common degenerative joint disease worldwide, currently lacks effective disease-modifying therapies that can halt its progression. This therapeutic challenge stems from the complexity of multiple pathological mechanisms, including chondrocyte metabolic imbalance, inflammatory responses, and extracellular matrix (ECM) degradation. In recent years, epigenetics, particularly reversible methylation modifications, has provided a new perspective for understanding OA.</p> Main body <p>This review systematically analyzes the multi-dimensional methylation regulatory network in OA from a “pan-methylation” perspective. DNA methylation regulates the transcriptional activity of key genes (e.g., SOX9, MMP13) through the DNMTs/TETs enzyme system. RNA epitranscriptomic modifications (e.g., m6A, m5C, m7G methylation) precisely controls mRNA stability, translation efficiency, and splicing processes via its “Writers-Readers-Erasers” machinery (METTL3, FTO, YTHDFs, etc.), influencing autophagy, inflammation, and metabolic balance. Histone methylation (e.g., H3K27me3, H3K79me2) directly regulates catabolic gene expression by altering chromatin states. These multi-layered methylation networks collectively form a complex epigenetic regulatory system in OA.</p> Conclusion <p>Based on these findings, targeting specific methyltransferases has shown great therapeutic potential in preclinical studies. This review not only deepens the understanding of OA pathogenesis but also provides a theoretical basis and innovative strategies for developing disease-modifying therapies targeting the methylation network. Future research should focus on joint-specific drug delivery systems and epigenetic precision therapy to promote a fundamental shift in OA treatment paradigms.</p>

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Methylation regulatory networks in osteoarthritis: mechanisms and targeted therapies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Siman Tian,
  • Xiaoqian Men,
  • Yi Zheng,
  • Yu Liu,
  • Zhikuan Li,
  • Chien-Wei Lee,
  • Shangchun Guo,
  • Hongtao Xu,
  • Jiangtao Dong

摘要

Background

Osteoarthritis (OA), the most common degenerative joint disease worldwide, currently lacks effective disease-modifying therapies that can halt its progression. This therapeutic challenge stems from the complexity of multiple pathological mechanisms, including chondrocyte metabolic imbalance, inflammatory responses, and extracellular matrix (ECM) degradation. In recent years, epigenetics, particularly reversible methylation modifications, has provided a new perspective for understanding OA.

Main body

This review systematically analyzes the multi-dimensional methylation regulatory network in OA from a “pan-methylation” perspective. DNA methylation regulates the transcriptional activity of key genes (e.g., SOX9, MMP13) through the DNMTs/TETs enzyme system. RNA epitranscriptomic modifications (e.g., m6A, m5C, m7G methylation) precisely controls mRNA stability, translation efficiency, and splicing processes via its “Writers-Readers-Erasers” machinery (METTL3, FTO, YTHDFs, etc.), influencing autophagy, inflammation, and metabolic balance. Histone methylation (e.g., H3K27me3, H3K79me2) directly regulates catabolic gene expression by altering chromatin states. These multi-layered methylation networks collectively form a complex epigenetic regulatory system in OA.

Conclusion

Based on these findings, targeting specific methyltransferases has shown great therapeutic potential in preclinical studies. This review not only deepens the understanding of OA pathogenesis but also provides a theoretical basis and innovative strategies for developing disease-modifying therapies targeting the methylation network. Future research should focus on joint-specific drug delivery systems and epigenetic precision therapy to promote a fundamental shift in OA treatment paradigms.