Reversing LRP5-Dependent Osteoporosis and SOST Deficiency-Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity
Ming-Kang Chang, Ina Kramer, Hansjoerg Keller, Jonathan H Gooi, Corinne Collett, David Jenkins, Seth A Ettenberg, Feng Cong, Christine Halleux, Michaela Kneissel
JOURNAL OF BONE AND MINERAL RESEARCH | WILEY | Published : 2014
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..View full abstract
This study was supported by the Novartis Institutes for BioMedical Research Education Office Postdoctoral Fellowship Program (MKC, IK). We thank H. Anklin, M. Fluckiger, P. Ingold, H. Jeker, M. Merdes, M. Pegurri, R. Schumpf, A. Studer, and A. Venturiere for excellent technical assistance.