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.