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The role of hedgehog signalling in skeletal health and disease

Nature Reviews Rheumatology volume 11, pages 552–560 (2015)Cite this article

Subjects

Key Points

  • Hedgehog signalling regulates several cellular processes that are critical in bone development

  • Osteoarthritis and cartilaginous neoplasia are associated with activation of the hedgehog signalling pathway

  • Several agents that inhibit hedgehog signalling could be used therapeutically to target this pathway

  • Inhibition of hedgehog signalling or modulation of the expression of downstream target genes are potential modalities for the treatment of osteoarthritis and cartilaginous tumours

  • These two modalities could also be used to increase the effectiveness of strategies to improve bone and joint regeneration

Abstract

Hedgehog ligands bind to protein patched homologue 1 (PTC), a conserved receptor that activates the GLI family of transcription factors, which are involved in development, disease and skeletal repair processes. During embryonic development, hedgehog signalling helps to pattern the limbs and plays a critical part in regulating chondrocyte differentiation and osteogenesis during the longitudinal growth of long bones. This signalling pathway also regulates mesenchymal cell differentiation during skeletal repair and regeneration. In pathologic and degenerative processes, such as osteoarthritis or cartilaginous tumour formation, hedgehog signalling is dysregulated. Several pharmacologic strategies can modulate hedgehog signalling, and targeting this pathway could lead to the development of novel therapeutic approaches. For example, by precisely regulating the level of activity of the hedgehog signalling pathway, the pace of degeneration in osteoarthritis could be slowed, bone repair could be enhanced, and cartilaginous tumour cell viability could be inhibited. As such, regulation of hedgehog signalling could be manipulated to safeguard skeletal health.

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Figure 1: The role of growth plate chondrocytes in long bone development.
Figure 2: The hedgehog signalling pathway in Drosophila melanogaster and mammals.
Figure 3: The three mammalian GLI transcription factors (GLI1–GLI3) are homologues of Drosophila Cubitus interruptus (Ci).
Figure 4: In vertebrates, primary cilia can act as an organizing centre for processing GLI proteins.
Figure 5: A model of the regulation of growth plate chondrocyte differentiation by PTHrP and hedgehog signalling.

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Acknowledgements

The author's research referenced in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under Award R01AR066765-01 to B.A.A. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH.

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  1. Department of Orthopedic Surgery and Cell Biology, Duke University, Duke University Medical Centre (DUMC) 2888, 200 Trent Drive, Orange Zone 5th Floor, Durham, 27710, NC, USA

    Benjamin A. Alman

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Alman, B. The role of hedgehog signalling in skeletal health and disease. Nat Rev Rheumatol 11, 552–560 (2015). https://doi.org/10.1038/nrrheum.2015.84

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