Histone Acetylation in Bone Remodeling: Metabolic Regulation, Lineage-Specific Chromatin Programs, and Therapeutic Implications

Bone remodeling requires coordinated transcriptional regulation across osteoblasts, osteoclasts, and osteocytes. Histone acetylation connects cellular metabolism to these lineage-specific programs, yet its regulatory effects depend not simply on total cellular acetyl-CoA abundance, but also on metabolic carbon routing, subcellular acetyl-CoA availability, and the targeting of chromatin-modifying enzymes to specific genomic regions. This review examines how these processes shape skeletal-cell differentiation, function, and communication within the bone-remodeling unit. We integrate evidence linking acetyl-CoA metabolism to histone acetylation across skeletal lineages, highlighting the distinct contributions of metabolic substrate utilization, acetylation and deacetylation machinery, and locus-specific chromatin regulation. We further discuss how mechanical loading, aging, inflammation, and metabolic disease reshape these regulatory networks and influence the balance between bone formation and resorption. Particular attention is given to the distinction between metabolic changes and their chromatin consequences, as well as to the experimental approaches needed to resolve acetyl-CoA compartmentalization and trace metabolic carbon into histone acetyl groups. Finally, we evaluate therapeutic opportunities and challenges in targeting metabolic–chromatin pathways while preserving physiological bone remodeling. Integrating metabolic routing, chromatin regulation, and intercellular communication provides a framework for understanding skeletal adaptation and identifying new avenues for therapeutic development.