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Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches

Abstract

Osteoporosis is a skeletal disorder characterized by bone loss, which results in architectural deterioration of the skeleton, compromised bone strength and an increased risk of fragility fractures. Most current therapies for osteoporosis stabilize the skeleton by inhibiting bone resorption (antiresorptive agents), but the development of anabolic therapies that can increase bone formation and bone mass is of great interest. Wnt signalling induces differentiation of bone-forming cells (osteoblasts) and suppresses the development of bone-resorbing cells (osteoclasts). The Wnt pathway is controlled by antagonists that interact either directly with Wnt proteins or with Wnt co-receptors. The importance of Wnt signalling in bone formation is indicated by skeletal disorders such as sclerosteosis and van Buchem syndrome, which are caused by mutations in the gene encoding the Wnt antagonist sclerostin (SOST). Experiments in mice have shown that downregulation or neutralization of Wnt antagonists enhances bone formation. Phase II clinical trials show that 1-year treatment with antisclerostin antibodies increases bone formation, decreases bone resorption and leads to a substantial increase in BMD. Consequently, Wnt signalling can be targeted by the neutralization of its extracellular antagonists to obtain a skeletal anabolic response.

Key Points

  • Wnt signalling has a critical role in skeletal development and adult skeletal homeostasis

  • Wnt signalling is regulated by a family of secreted Wnt antagonists

  • Canonical Wnt signalling enhances osteoblastogenesis and bone formation and decreases osteoclastogenesis and bone resorption

  • Mutations in the genes encoding Wnt co-receptors and Wnt antagonists cause profound changes in bone mass

  • Wnt antagonists can be targeted to enhance Wnt signalling in the skeleton

  • Treatment with humanized antisclerostin antibodies increases BMD in humans; clinical trials to assess the antifracture efficacy of this intervention are underway

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Figure 1: Canonical Wnt signalling and bone remodelling.

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Acknowledgements

The author's research work is supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers AR021707 and AR063049) and from the National Institute of Diabetes & Digestive & Kidney Diseases (grant number DK045227), both part of the NIH. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH.

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The author declares that he has acted as a consultant for Amgen and Eli Lilly and is a member of the speaker's bureau for Eli Lilly.

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Canalis, E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 9, 575–583 (2013). https://doi.org/10.1038/nrendo.2013.154

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