The Anti-Osteoanabolic Function of Sclerostin is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5

TY - JOUR

T1 - The Anti-Osteoanabolic Function of Sclerostin is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5

AU - Yorgan, Timur A

AU - Peters, Stephanie

AU - Jeschke, Anke

AU - Benisch, Peggy

AU - Jakob, Franz

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - This article is protected by copyright. All rights reserved.

PY - 2015/7

Y1 - 2015/7

N2 - 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, since osteoblast-specific inactivation of β-catenin, the major intracellular mediator of canonical Wnt signaling, primarily affected bone resorption, it remained questionable, if 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 over-expression 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 over-expression 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 over-expressing the transmembrane Wnt signaling antagonist Krm2 and found that the anti-osteoanabolic influence of the Col1a1-Krm2 transgene was not affected by both 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. This article is protected by copyright. All rights reserved.

AB - 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, since osteoblast-specific inactivation of β-catenin, the major intracellular mediator of canonical Wnt signaling, primarily affected bone resorption, it remained questionable, if 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 over-expression 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 over-expression 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 over-expressing the transmembrane Wnt signaling antagonist Krm2 and found that the anti-osteoanabolic influence of the Col1a1-Krm2 transgene was not affected by both 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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/jbmr.2461

DO - 10.1002/jbmr.2461

M3 - SCORING: Journal article

C2 - 25640331

VL - 30

SP - 1175

EP - 1183

JO - J BONE MINER RES

JF - J BONE MINER RES

SN - 0884-0431

IS - 7

ER -