Reversing LRP5‐Dependent Osteoporosis and SOST Deficiency–Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity. (January 2014)

• Record Type: Journal Article
• Authors: Chang, Ming‐Kang; Kramer, Ina; Keller, Hansjoerg; Gooi, Jonathan H; Collett, Corinne; Jenkins, David; Ettenberg, Seth A; Cong, Feng; Halleux, Christine; Kneissel, Michaela
• Is Part Of: Journal of bone and mineral research. Volume 29:Number 1(2014:Jan.)
• Page Start: 29
• Page End: 42
• Publication Date: 2014-01
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2059
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2059-sec-0001" sec-type="section"> <p>The bone formation inhibitor sclerostin encoded by <italic>SOST</italic> 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. <italic>Lrp5/LRP5</italic> deficiency results in osteoporosis‐pseudoglioma (OPPG), whereas <italic>Sost/SOST</italic> deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking <italic>Sost</italic> (<italic>Sost</italic><sup>−/−</sup>), <italic>Lrp5</italic> (<italic>Lrp5</italic><sup>−/−</sup>), or both (<italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup>) to elucidate the mechanism of action of <italic>Sost</italic> in vivo. <italic>Sost</italic> deficiency–induced bone gain was significantly blunted in <italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup> mice. Yet the <italic>Lrp5</italic> OPPG phenotype was fully rescued in <italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup> mice and most bone parameters were elevated relative to wild‐type. To test whether the remaining bone increases in <italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup> animals depend on Lrp6, we treated wild‐type, <italic>Sost</italic><sup>−/−</sup>, and <italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup> 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 <italic>Sost</italic><sup>−/−</sup> and <italic>Sost</italic><sup>−/−</sup><italic>;Lrp5</italic><sup>−/−</sup> mice to wild‐type levels irrespective of enhancement or blockage of Wnt3a class‐mediated Lrp6 activity. Thus, whereas <italic>Sost</italic> deficiency–induced bone anabolism partially requires <italic>Lrp5</italic>, it fully depends on Wnt1 class–induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from <italic>LRP5</italic> loss‐of‐function should benefit from principles antagonizing <italic>SOST</italic>/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to <italic>SOST</italic> 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.</p> </sec> </abstract>