Epigenetics of bone formation and diseases: From mechanisms to therapies

Skeletal homeostasis relies on the balance between bone formation and resorption. Genomic epigenetic mechanisms—including DNA methylation, histone modifications, and chromatin remodeling—translate physiological and environmental cues into lineage-specific transcriptional programs that guide osteoblast differentiation and coordinate bone formation with osteoclast activity. Disruption of these processes contributes to hereditary skeletal malformations and metabolic bone diseases. This review integrates evidence from human genetics, mouse models, and cellular studies to illustrate how DNA methylation, histone methylation, histone acetylation, and non-canonical histone modifications shape osteogenesis and drive skeletal pathology. We highlight how intrinsic factors (aging, hormonal signaling, and metabolism) and extrinsic stimuli (mechanical loading and nutritional input) are encoded by epigenetic machinery to modulate osteogenic signaling and bone-forming programs. Building on these insights, we then summarize current preclinical efforts targeting epigenetic regulation in bone, encompassing both pharmacological and non-pharmacological strategies, and critically discuss key challenges for clinical translation, including systemic toxicity, context-dependent effects, and limited tissue specificity, as well as the rationale for bone-targeted delivery approaches. Finally, we outline future directions in skeletal epigenetics, emphasizing integrated and context-aware regulatory frameworks, improved resolution of skeletal cell heterogeneity and epigenomic profiling, consideration of epigenetic timing and persistence, and incorporation of three-dimensional genome organization as a spatial layer of epigenetic regulation. Together, this synthesis positions epigenetic regulation as a unifying framework for skeletal biology and a promising, yet challenging, avenue for therapeutic innovation.