Networked control of bone homeostasis: interfacing post-translational modifications with cellular signaling

Bone homeostasis depends on the coordinated activity of osteoblasts, osteoclasts, osteocytes, and its microenvironment. Transcriptional programs and classical signaling pathways are central to bone regulation, where post-translational modifications (PTMs) provide an additional control over the activity, stability, localization, and interactions of proteins involved. This review summarizes current evidence regarding PTMs in bone homeostasis, focusing on their regulatory roles in osteoblast, osteoclast, and osteocyte function under physiological and pathological conditions. We organize the evidence around three concepts: bidirectional interactions between PTMs and classical signaling pathways; functional regulatory modes including signal gating, amplification, and dampening; and spatiotemporal regulation across cell types, subcellular compartments, developmental and aging stages, and disease states. Dysregulated PTMs are associated with osteoporosis, osteoarthritis, metabolic and inflammatory bone diseases, and impaired bone repair. Evidence remains uneven across PTM types and skeletal cell populations, and the causal roles of many site-specific PTM events remain unclear. Emerging methods including quantitative PTM proteomics, single-cell and spatial analyses, and multi-omics approaches are beginning to address these limitations. We hope that combining PTM evidence with established signaling pathways will deepen the understanding of bone homeostasis and identify which issues require further experimental validation.