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.
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.
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Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).
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).
Witcher, P. C. et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight 3, 98673 (2018).
Luther, J. et al. Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Sci. Transl Med. 10, eaau7137 (2018).
Weske, S. et al. Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nat. Med. 24, 667–678 (2018).
Florio, M. et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat. Commun. 7, 11505 (2016).
Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).
Joeng, K. S. et al. Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J. Clin. Invest. 127, 2678–2688 (2017).
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).
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).
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.
The author declares no competing interests.
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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