TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease.

The transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways are pivotal regulators of cellular processes, playing indispensable roles in embryogenesis, postnatal development, and tissue homeostasis. These pathways are particularly critical within the skeletal system, as they coordinate osteogenesis, chondrogenesis, and bone remodeling through intricate molecular mechanisms. TGF-β/BMP signaling is primarily transduced via canonical Smad-dependent pathways (e.g., ligands, receptors, and intracellular Smads) and the non-canonical Smad-independent (e.g., p38 mitogen-activated protein kinase, MAPK) cascade. Both pathways converge on master transcriptional regulators, including Runx2 and Osterix, and their precise coordination is indispensable for skeletal development, maintenance, and repair. The dysregulation of TGF-β/BMP signaling contributes to a spectrum of skeletal dysplasia and bone pathologies. Advances in molecular genetics, particularly gene-targeting strategies and transgenic mouse models, have deepened our understanding of the spatiotemporal control of TGF-β/BMP signaling in bone and cartilage development. Moreover, emerging research underscores extensive crosstalk between TGF-β/BMP and other critical pathways, such as Wnt/β-catenin, mitogen-activated protein kinase (MAPK), parathyroid hormone (PTH)/PTH-related protein (PTHrP), fibroblast growth factors (FGF), Hedgehog, Notch, insulin-like growth factors (IGF)/insulin-like growth factors receptor (IGFR), Mammalian target of rapamycin (mTOR), and autophagy, forming an integrated regulatory network that ensures skeletal integrity. Our review synthesizes the current knowledge on the molecular components, regulatory mechanisms, and functional integration of TGF-β/BMP signaling in skeletal biology, with an emphasis on its roles in development, regeneration, and disease. By elucidating the molecular underpinnings of TGF-β/BMP pathways and their contextual interactions, we aim to highlight translational opportunities and novel therapeutic strategies for treating skeletal disorders.