Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

OSTEOPOROSIS IN 2018

Overcoming natural Wnt inhibition to optimize therapy

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1.

    Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).

    CAS  Article  Google Scholar 

  2. 2.

    Holdsworth, G. et al. Dampening of the bone formation response following repeat dosing with sclerostin antibody in mice is associated with up-regulation of Wnt antagonists. Bone 107, 93–103 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Witcher, P. C. et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight 3, 98673 (2018).

    Article  Google Scholar 

  4. 4.

    Luther, J. et al. Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Sci. Transl Med. 10, eaau7137 (2018).

    Article  Google Scholar 

  5. 5.

    Weske, S. et al. Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nat. Med. 24, 667–678 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Florio, M. et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat. Commun. 7, 11505 (2016).

    CAS  Article  Google Scholar 

  7. 7.

    Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).

    CAS  Article  Google Scholar 

  8. 8.

    Joeng, K. S. et al. Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J. Clin. Invest. 127, 2678–2688 (2017).

    Article  Google Scholar 

  9. 9.

    Pederson, L. et al. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc. Natl Acad. Sci. USA 105, 20764–20769 (2008).

    CAS  Article  Google Scholar 

  10. 10.

    Sims, N. A. & Martin, T. J. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 3, 481 (2014).

    PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Natalie A. Sims.

Ethics declarations

Competing interests

The author declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing