Histone modifications: Unveiling the epigenetic enigma of degenerative skeletal diseases

Degenerative skeletal diseases, including osteoporosis, osteoarthritis, and intervertebral disc degeneration, are prevalent age-related conditions characterized by progressive tissue degeneration and functional decline. Histone modifications are covalent modifications of histone residues, catalyzed by specific enzymes, that modulate chromatin architecture and transcriptional activity. Accumulating evidence highlights the critical involvement of histone modifications in orchestrating disease-associated transcriptional programs. In osteoporosis, histone modifications regulate osteoblast and osteoclast differentiation, thereby disrupting bone homeostasis. In osteoarthritis, they drive the expression of matrix-degrading enzymes in chondrocytes, contributing to cartilage degradation. In intervertebral disc degeneration, they are implicated in nucleus pulposus cell senescence, apoptosis, and extracellular matrix degradation. This review summarizes the distinct mechanistic roles of histone modifications across these conditions and explores the therapeutic potential of targeting histone-modifying enzymes, underscoring epigenetic regulation as a promising strategy for precision intervention in degenerative skeletal diseases. The translational potential of this article: This review comprehensively explores the role of histone modifications in degenerative skeletal diseases and evaluates the potential of histone-modifying enzyme inhibitors as therapeutic targets. These insights provide new strategies and directions for the treatment of degenerative skeletal diseases.