MKC and IK contributed equally to this work.
Reversing LRP5-Dependent Osteoporosis and SOST Deficiency–Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity
Article first published online: 19 DEC 2013
© 2014 American Society for Bone and Mineral Research
Journal of Bone and Mineral Research
Volume 29, Issue 1, pages 29–42, January 2014
How to Cite
Chang, M.-K., Kramer, I., Keller, H., Gooi, J. H., Collett, C., Jenkins, D., Ettenberg, S. A., Cong, F., Halleux, C. and Kneissel, M. (2014), Reversing LRP5-Dependent Osteoporosis and SOST Deficiency–Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity. J Bone Miner Res, 29: 29–42. doi: 10.1002/jbmr.2059
For a Commentary on this article, please see Williams (J Bone Miner Res. 2014;29:24–48. DOI: 10.1002/jbmr/2154).
- Issue published online: 19 DEC 2013
- Article first published online: 19 DEC 2013
- Accepted manuscript online: 31 JUL 2013 01:02AM EST
- Manuscript Accepted: 29 JUL 2013
- Manuscript Revised: 26 JUL 2013
- Manuscript Received: 5 JUL 2013
- Novartis Institutes for BioMedical Research Education Office Postdoctoral Fellowship Program
- SCLEROSING BONE DISORDERS;
- GENETIC ANIMAL MODELS
The bone formation inhibitor sclerostin encoded by SOST binds in vitro to low-density lipoprotein receptor-related protein (LRP) 5/6 Wnt co-receptors, thereby inhibiting Wnt/β-catenin signaling, a central pathway of skeletal homeostasis. Lrp5/LRP5 deficiency results in osteoporosis-pseudoglioma (OPPG), whereas Sost/SOST deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking Sost (Sost−/−), Lrp5 (Lrp5−/−), or both (Sost−/−;Lrp5−/−) to elucidate the mechanism of action of Sost in vivo. Sost deficiency–induced bone gain was significantly blunted in Sost−/−;Lrp5−/− mice. Yet the Lrp5 OPPG phenotype was fully rescued in Sost−/−;Lrp5−/− mice and most bone parameters were elevated relative to wild-type. To test whether the remaining bone increases in Sost−/−;Lrp5−/− animals depend on Lrp6, we treated wild-type, Sost−/−, and Sost−/−;Lrp5−/− mice with distinct Lrp6 function blocking antibodies. Selective blockage of Wnt1 class–mediated Lrp6 signaling reduced cancellous bone mass and density in wild-type mice. Surprisingly, it reversed the abnormal bone gain in Sost−/− and Sost−/−;Lrp5−/− mice to wild-type levels irrespective of enhancement or blockage of Wnt3a class-mediated Lrp6 activity. Thus, whereas Sost deficiency–induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class–induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from LRP5 loss-of-function should benefit from principles antagonizing SOST/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to SOST deficiency, such as sclerosteosis, van Buchem disease, and autosomal dominant craniodiaphyseal dysplasia, which are rare disorders without viable treatment options. © 2014 American Society for Bone and Mineral Research.