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Dkk1 KO Mice Treated with Sclerostin Antibody Have Additional Increases in Bone Volume
Alyson Morse1,2, Tegan L Cheng1,2, Aaron Schindeler1,2
1Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.
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.
Insights
Sclerostin antibody treatment boosts bone formation, especially in mice lacking Dickkopf-1 (DKK1). This suggests DKK1 deficiency and sclerostin antibody therapy work together to enhance bone anabolism, supporting dual-targeted treatments.
Area of Science:
- Bone biology and Wnt/β-catenin signaling pathway.
- Pharmacology of bone anabolism and therapeutic targets.
Background:
- Dickkopf-1 (DKK1) and sclerostin are key Wnt/β-catenin pathway antagonists that regulate bone formation and mass.
- Decreased expression of DKK1 or sclerostin leads to increased bone formation.
- Understanding the interplay between DKK1 and sclerostin is crucial for developing bone anabolic therapies.
Purpose of the Study:
- To investigate the functional redundancy and/or compensation between Dickkopf-1 (DKK1) and sclerostin in regulating bone formation.
- To determine the synergistic effects of DKK1 deficiency and sclerostin antibody (Scl-Ab) treatment on bone anabolism.
Main Methods:
- Treatment of 9-week-old female Dkk1 knockout (KO) mice and wild-type littermates with weekly sclerostin antibody (Scl-Ab) or vehicle for 3 weeks.
- Assessment of bone parameters using microcomputed tomography (microCT) and bone histomorphometry.
- Evaluation of bone strength through biomechanical testing and bone formation rates via dynamic bone labeling.
- Immunohistochemical analysis of sclerostin protein levels.
Main Results:
- Scl-Ab treatment significantly enhanced bone anabolism in all groups, with a synergistic effect observed in the cancellous bone of Dkk1 KO mice (bone volume +55%).
- Cortical bone in the tibiae showed anabolic effects of Scl-Ab, but these were similar across genotypes.
- While Scl-Ab improved bone strength in all genotypes, no additional enhancement was observed in Dkk1 KO mice.
- Dynamic bone labeling confirmed increased bone formation with Scl-Ab treatment irrespective of genotype.
- Immunohistochemistry revealed no compensatory upregulation of sclerostin protein in Dkk1 KO mice.
Conclusions:
- DKK1 deficiency and sclerostin antibody treatment exhibit a synergistic effect on cancellous bone anabolism.
- Complex interactions exist between Wnt signaling factors in bone regulation.
- These findings support the potential of dual-targeted therapeutics for modulating bone anabolism.
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