title: The Anti-Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5.
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 (Lrp5(A170V) and Lrp5(G213V)), 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 Lrp5(A213V/A213V) mice and strongly reduced in Lrp5(A170V/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.
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Timur A
authors: TA
authors: Yorgan
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Stephanie
authors: S
authors: Peters
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Anke
authors: A
authors: Jeschke
authors: Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany.
authors: Peggy
authors: P
authors: Benisch
authors: Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany.
authors: Franz
authors: F
authors: Jakob
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Michael
authors: M
authors: Amling
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Thorsten
authors: T
authors: Schinke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D045930:Anabolic Agents / Q000378:metabolism*; D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism*; D010641:Phenotype; D019076:Transgenes; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents; D024042:Collagen Type I; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C486030:Sost protein, mouse
keywords: BONE FORMATION; KRM2; LRP5; SCLEROSTIN; WNT SIGNALING