Methylation regulatory networks in osteoarthritis: mechanisms and targeted therapies

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. 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. 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. The interplay between different methylation layers (DNA, RNA, histone) in OA remains poorly mapped. How these modifications coordinate to drive disease progression is a key unresolved question. Most epigenetic studies focus on chondrocytes, while the role of methylation in synovium, subchondral bone, and immune cells within the OA joint is largely unexplored, limiting a holistic view of OA as an organ-level disease. Patient stratification based on epigenetic signatures for precision OA therapy is an emerging concept. Whether methylation patterns can predict disease progression or treatment response remains an open and clinically significant question.