Epigenetics of osteoarthritis: Histones and TGF-β1.

Osteoarthritis (OA) is the most common musculoskeletal and joint disorder. However, no disease-modifying therapy for OA is currently available, and the etiology of OA is poorly understood. Epigenetics has emerged as a new and important area of research on OA. Differing from genetics, Epigenetic factors are known to be tissue-specific and highly dynamic, being dependent on environmental stimuli and developmental stages. Therefore, human studies into OA epigenetics are sensitive to confounding and reverse causation. Here, we will review the epigenetic mechanism in OA onset and progression by focusing on the opposing action of two families of enzymes: histone methyltransferases and histone demethylases, such as DOT1L, KDM4B, KDM6A, KDM6B, EZH2, and LSD1. Moreover, the TGF-β1 signaling pathway has proven to be one of the key factors in cartilage and bone formation, and in recent research, was found to initiate and develop OA disease by TGF-β1 overexpression. Besides the introduction of enzymes and TGF-β1 signaling, some special epigenetic regulation mechanisms associated with key transcription factors (e.g. RUNX2, NFAT1, and SOX9) in OA disease are also reviewed here in detail to clarify the OA epigenetic mechanism. The overall understanding of these epigenetic mechanisms underlying the issues will accelerate the development of novel therapeutic strategies for OA.