Histone Deacetylase 4: The Epigenetic Hub in Degenerative Musculoskeletal Diseases

Abstract: 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.