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OSTEOPOROSIS IN 2018

Overcoming natural Wnt inhibition to optimize therapy

Nature Reviews Rheumatology volume 15, pages 67–68 (2019)Cite this article

Subjects

The Wnt signalling pathway is the target of current anabolic therapies for osteoporosis. Studies in 2018 have revealed more about endogenous control of Wnt-related signalling, including mechanisms of natural Wnt inhibition and new anabolic signalling pathways that could be harnessed to overcome the challenges posed by current therapies.

Key advances

  • Upregulation of endogenous Wnt inhibitors in bone might be responsible for the plateau in the anabolic effect of anti-sclerostin therapy and the limited efficacy of anti-Dickkopf-related protein 1 therapy2,3.

  • Wnt1 signalling might be a new anabolic pathway that is low-density lipoprotein receptor-related protein 5 (LRP5)-independent4.

  • Sphingosine-1-phosphate, previously thought to be a coupling factor, might be an anti-resorptive therapeutic target5.

In a 2018 study, Holdsworth et al.2 suggested that the skeleton has in-built mechanisms to limit anabolic Wnt signalling and to thereby keep excessive bone formation in check. In this study2, multiple natural Wnt inhibitors were upregulated in the bones of mice following anti-sclerostin treatment; these included Dickkopf-related protein 1 (DKK1), DKK2, secreted frizzled-related protein 1 (sFRP1), sFRP2, sFRP4 and Wnt inhibitory factor 1. The authors propose that these inhibitors then limit the anabolic action of subsequent doses of anti-sclerostin antibodies2 (Fig. 1). However, upregulation of natural Wnt inhibitors is not a unique result of this therapeutic approach. In another 2018 study, Witcher et al.3 showed that anti-DKK1 treatment upregulated activity of a sclerostin reporter transgene in osteocytes; whether the concentrations of other natural Wnt inhibitors also increase with anti-DKK1 treatment is not yet known. Such an in-built limitation of Wnt signalling by natural Wnt inhibitors in bone might explain the transient nature of the anabolic effect of anti-sclerostin therapy and the limited ability of anti-DKK1 therapy to promote bone formation. These findings also raise the question of whether other anabolic approaches, such as parathyroid hormone receptor agonists, have their own in-built control mechanisms.

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Fig. 1: Challenges posed by therapies that target canonical Wnt signalling.

References

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Acknowledgements

The work of the author is supported by the St Vincent’s Institute Brenda Shanahan Fellowship and by the State Government of Victoria’s Operational Infrastructure Scheme. The author thanks T. J. Martin for helpful discussions during the preparation of this work.

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  1. St Vincent’s Institute of Medical Research and The University of Melbourne Department of Medicine, St Vincent’s Hospital, Fitzroy, Victoria, Australia

    Natalie A. Sims

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Correspondence to Natalie A. Sims.

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Sims, N.A. Overcoming natural Wnt inhibition to optimize therapy. Nat Rev Rheumatol 15, 67–68 (2019). https://doi.org/10.1038/s41584-018-0153-y

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