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Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition
Phillip C. Witcher, … , Gabriela G. Loots, Alexander G. Robling
Phillip C. Witcher, … , Gabriela G. Loots, Alexander G. Robling
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e98673. https://doi.org/10.1172/jci.insight.98673.
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Research Article Bone biology Therapeutics

Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition

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Abstract

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.

Authors

Phillip C. Witcher, Sara E. Miner, Daniel J. Horan, Whitney A. Bullock, Kyung-Eun Lim, Kyung Shin Kang, Alison L. Adaniya, Ryan D. Ross, Gabriela G. Loots, Alexander G. Robling

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Figure 1

Conditional deletion of Dkk1 from bone cells or antibody-induced systemic neutralization of Dkk1 in WT mice has minor effects on the skeleton.

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Conditional deletion of Dkk1 from bone cells or antibody-induced systemi...
(A and B) Longitudinal dual-energy x-ray absorptiometry–derived (DXA–derived) measures of whole-body bone mineral content (BMC) in (A) female and (B) male mice carrying homozygous floxed loss-of-function alleles for Dkk1, with (+Cre) or without (–Cre) the 10kbDmp1-Cre transgene. (C and D) μCT-derived measurements of bone volume fraction in the distal femur secondary spongiosa (C) and representative 3D tomographic reconstructions of the distal and midshaft femur (images shown represent female mice) (D) from Dkk1fl/fl mice with or without the 10kbDmp1-Cre transgene. (E and F) Percent change (from before to after treatment) in DXA-derived whole-body BMC (E) and peripheral quantitative CT-derived total mineral content at the proximal tibia (F) in male and female WT mice treated for 6 weeks with Dkk1 neutralizing antibody (αDkk1-mAb) or vehicle control. *P < 0.05 compared with sex-matched control mice. For all experiments, n = 11–15 mice/group. Data in A and B were analyzed using repeated-measures ANOVA followed by Fisher’s protected LSD post hoc tests. Data in C, E, and F were analyzed using 1-way ANOVA followed by Fisher’s protected LSD post hoc tests.

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