The Anti‐Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5. (8th June 2015)

• Record Type: Journal Article
• Authors: Yorgan, Timur A; Peters, Stephanie; Jeschke, Anke; Benisch, Peggy; Jakob, Franz; Amling, Michael; Schinke, Thorsten
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 7(2015:Jul.)
• Page Start: 1175
• Page End: 1183
• Publication Date: 2015-06-08
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2461
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2461-sec-0001" sec-type="section"> <p>Activating mutations of the putative Wnt co‐receptor Lrp5 or inactivating mutations of the secreted molecule Sclerostin cause excessive bone formation in mice and humans. Previous studies have suggested that Sclerostin functions as an Lrp5 antagonist, yet clear in vivo evidence was still missing, and alternative mechanisms have been discussed. Moreover, because osteoblast‐specific inactivation of β‐catenin, the major intracellular mediator of canonical Wnt signaling, primarily affected bone resorption, it remained questionable, whether Sclerostin truly acts as a Wnt signaling antagonist by interacting with Lrp5. In an attempt to address this relevant question, we generated a mouse model (<italic>Col1a1‐Sost</italic>) with transgenic overexpression of Sclerostin under the control of a 2.3‐kb <italic>Col1a1</italic> promoter fragment. These mice displayed the expected low bone mass phenotype as a consequence of reduced bone formation. The <italic>Col1a1‐Sost</italic> mice were then crossed with two mouse lines carrying different high bone mass mutations of Lrp5 (<italic>Lrp5</italic><sup><italic>A170V</italic></sup> and <italic>Lrp5</italic><sup><italic>G213V</italic></sup>), both of them potentially interfering with Sclerostin binding. Using µCT‐scanning and histomorphometry we found that the anti‐osteoanabolic influence of Sclerostin overexpression was not observed in <italic>Lrp5</italic><sup><italic>A213V/A213V</italic></sup> mice and strongly reduced in <italic>Lrp5</italic><sup><italic>A170V/A170V</italic></sup> mice. As a control we applied the same strategy with mice overexpressing the transmembrane Wnt signaling antagonist Krm2 and found that the anti‐osteoanabolic influence of the <italic>Col1a1‐Krm2</italic> transgene was not affected by either of the Lrp5 mutations. Taken together, our data support the concept that Sclerostin inhibits bone formation through Lrp5 interaction, yet their physiological relevance remains to be established. © 2015 American Society for Bone and Mineral Research.</p> </sec> </abstract>