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Calcified Tissue International

01-09-2018 | Original Research

Dkk1 KO Mice Treated with Sclerostin Antibody Have Additional Increases in Bone Volume

Authors: Alyson Morse, Tegan L. Cheng, Aaron Schindeler, Michelle M. McDonald, Sindhu T. Mohanty, Michaela Kneissel, Ina Kramer, David G. Little

Published in: Calcified Tissue International | Issue 3/2018

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Abstract

Dickkopf-1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway and decreased expression of either results in increased bone formation and mass. As both affect the same signaling pathway, we aimed to elucidate the redundancy and/or compensation of sclerostin and DKK1. Weekly sclerostin antibody (Scl-Ab) was used to treat 9-week-old female Dkk1 KO (Dkk1−/−:Wnt3+/−) mice and compared to Scl-Ab-treated wild-type mice as well as vehicle-treated Dkk1 KO and wild-type animals. While Wnt3 heterozygote (Wnt3+/−) mice show no bone phenotype, Scl-Ab and vehicle-treated control groups of this genotype were included. Specimens were harvested after 3 weeks for microCT, bone histomorphometry, anti-sclerostin immunohistochemistry, and biomechanical testing. Scl-Ab enhanced bone anabolism in all treatment groups, but with synergistic enhancement seen in the cancellous compartment of Dkk1 KO mice (bone volume + 55% Dkk1 KO p < 0.01; + 22% wild type p < 0.05). Scl-Ab treatment produced less marked increases in cortical bone of the tibiae, with anabolic effects similar across genotypes. Mechanical testing confirmed that Scl-Ab improved strength across all genotypes; however, no enhancement was seen within Dkk1 KO mice. Dynamic bone labeling showed that Scl-Ab treatment was associated with increased bone formation, regardless of genotype. Immunohistochemical staining for sclerostin protein indicated no differences in the Dkk1 KO mice, indicating that the increased Wnt signaling associated with DKK1 deficiency was not compensated by upregulation of sclerostin protein. These data suggest complex interactions between Wnt signaling factors in bone, but critically illustrate synergy between DKK1 deficiency and Scl-Ab treatment. These data support the application of dual-targeted therapeutics in the modulation of bone anabolism.
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Metadata
Title
Dkk1 KO Mice Treated with Sclerostin Antibody Have Additional Increases in Bone Volume
Authors
Alyson Morse
Tegan L. Cheng
Aaron Schindeler
Michelle M. McDonald
Sindhu T. Mohanty
Michaela Kneissel
Ina Kramer
David G. Little
Publication date
01-09-2018
Publisher
Springer US
Published in
Calcified Tissue International / Issue 3/2018
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-018-0420-6

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