Histone Deacetylase 4: The Epigenetic Hub in Degenerative Musculoskeletal Diseases

Aging has rendered Degenerative Musculoskeletal Diseases (DMDs) an increasingly significant public health burden. Growing evidence suggests that epigenetic dysregulation plays a crucial mechanistic role in the pathogenesis of DMDs. Histone Deacetylase 4 (HDAC4), known for its regulatory roles in the nervous, cardiovascular, and cancer systems, has also emerged as a central coordinator of musculoskeletal physiology and pathology. It dynamically modulates cellular metabolism in cartilage, bone, and muscle tissues. This review aims to provide a comprehensive overview of current research on HDAC4 in the context of DMDs, highlighting its roles in chondrocyte homeostasis, synovial inflammation, osteoblast-osteoclast balance, and muscle fiber atrophy. Furthermore, we explore the therapeutic potential of targeting HDAC4 for the treatment of musculoskeletal diseases, including osteoarthritis, osteoporosis, and muscle atrophy.