Hedgehog Signalling in Osteogenesis and Bone Metabolism: Molecular Mechanisms, Regulatory Networks and Implications for Skeletal Disease

The Hedgehog (Hh) signalling pathway serves as a fundamental regulator in bone development and homeostasis, translating extracellular signals into precise transcriptional programmes that govern osteogenic differentiation and bone remodelling. Central to this process, ligand-dependent Hh activation induces the nuclear translocation of GLI transcription factors (GLI1/2/3), which orchestrate the expression of key osteogenic regulators, including RUNX2 and Osterix (OSX), thereby directing mesenchymal stem cell (MSC) fate commitment. Among Hh ligands, the Indian hedgehog (Ihh) plays a dominant role in endochondral ossification, spatiotemporally controlling osteoprogenitor differentiation and chondrocyte maturation. Notably, the Hh pathway engages in extensive, context-dependent crosstalk with Wnt/β-catenin, BMP, TGF-β, FGF and PTHrP signalling cascades, forming a highly interconnected regulatory network essential for skeletal patterning and morphogenesis. Dysregulation of this balanced system contributes to a spectrum of skeletal disorders, ranging from congenital defects to degenerative bone diseases, highlighting its critical role in maintaining bone integrity. This review synthesises recent advances in Hh-mediated osteogenesis, dissecting its multi-layered interactions within the skeletal gene regulatory framework. By unravelling the molecular logic of Hh-dependent signalling networks, we deepen our understanding of bone biology and illuminate novel therapeutic targets for skeletal pathologies through precision modulation of Hh pathway activity.