Increased anabolic bone response in Dkk1 KO mice following tibial compressive loading

Abstract A viable Dkk1 knockout (KO) mouse strain in which embryonic lethality is rescued by developmental Wnt3 heterozygosity (Dkk1−/−:Wnt3+/−) exhibits increased bone formation and a high bone mass phenotype. We hypothesized that in vivo mechanical loading would further augment the bone formation response in Dkk1 KO mice, comparable to results from Sost KO mice. A cyclic loading protocol was applied to Dkk1 KO mice, wild type mice (WT; Dkk1+/+:Wnt3+/+), and Wnt3 heterozygote (Wnt3+/−; Dkk1+/+:Wnt3+/−) controls. The left tibiae of 10-week-old female mice were dynamically loaded in vivo with 7 N maximum compressive force 5 days/week for 2 weeks. Dkk1 KO bones were significantly stiffer, and so an additional group of Dkk1 KO received 12 N maximum compressive force to achieve an equivalent +1200μe strain at the mid-diaphysis. MicroCT and bone histomorphometry analyses were subsequently performed. All groups responded to tibial loading with increased mid-diaphyseal bone volume. The largest effect size was in the Dkk1 KO −12 N group. Thus, Dkk1 KO animals had enhanced sensitivity to mechanical loading. Increases in cortical bone volume reflected increased periosteal bone formation. Bone volume and formation were not altered between WT and Wnt3+/− controls. These data support the concept that agonists of Wnt/β-catenin signaling can act synergistically with load-bearing exercise. Notably, Sost expression decreased with loading in Dkk1 KO and WT mice, independent of genotype. These data suggest that a compensatory downregulation of Sost in Dkk1 KO mice is not likely the primary mechanism for the augmented response to mechanical load.