The posttranslational modification landscape of transcription factors in osteoblast differentiation and bone formation

Bone homeostasis is maintained through a dynamic balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts originate from mesenchymal/skeletal stem cells through commitment, proliferation, and differentiation, which are controlled by sequential activation of signaling molecules and transcriptional regulators. Among them, runt-related transcription factor 2 (RUNX2) and Osterix serve as master transcription factors driving osteoblast commitment, differentiation, and maturation. Emerging evidence highlights that posttranslational modifications (PTMs), including phosphorylation, ubiquitination, and acetylation, play indispensable roles in regulating activity, stability, and interactions of these transcription factors. Through reversible chemical modifications, PTMs integrate extracellular cues with transcriptional programs, leading to fine-tuning osteoblast lineage specification and bone formation. This review summarizes recent advances in understanding how PTMs modulate RUNX2 and Osterix during osteoblast development. We cover mechanistic insights from both in vitro and in vivo studies and highlight potential therapeutic implications of targeting PTM-mediated regulatory pathways in skeletal disorders.