The Anti‐Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5 |
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| Authors: | Timur A Yorgan Stephanie Peters Anke Jeschke Peggy Benisch Franz Jakob Michael Amling Thorsten Schinke |
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| Affiliation: | 1. Department of Osteology and Biomechanics, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;2. Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany |
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| Abstract: | 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 (Col1a1‐Sost) with transgenic overexpression of Sclerostin under the control of a 2.3‐kb Col1a1 promoter fragment. These mice displayed the expected low bone mass phenotype as a consequence of reduced bone formation. The Col1a1‐Sost mice were then crossed with two mouse lines carrying different high bone mass mutations of Lrp5 (Lrp5A170V and Lrp5G213V), 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 Lrp5A213V/A213V mice and strongly reduced in Lrp5A170V/A170V 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 Col1a1‐Krm2 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. |
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| Keywords: | BONE FORMATION KRM2 LRP5 SCLEROSTIN WNT SIGNALING |
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