Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia.
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, United States.
Bone. 2020 Feb;131:115054. doi: 10.1016/j.bone.2019.115054. Epub 2019 Sep 12.
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 7N maximum compressive force 5 days/week for 2 weeks. Dkk1 KO bones were significantly stiffer, and so an additional group of Dkk1 KO received 12N maximum compressive force to achieve an equivalent +1200με 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 -12N 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.
一种可行的 Dkk1 敲除（KO）小鼠品系，其胚胎致死性通过发育性 Wnt3 杂合性（Dkk1:Wnt3）得到挽救，表现出增加的骨形成和高骨量表型。我们假设体内机械加载会进一步增强 Dkk1 KO 小鼠的骨形成反应，与 Sost KO 小鼠的结果相当。对 Dkk1 KO 小鼠、野生型（WT；Dkk1:Wnt3）和 Wnt3 杂合子（Wnt3；Dkk1:Wnt3）对照施加周期性加载方案。10 周龄雌性小鼠的左侧胫骨在体内用 7N 最大压缩力进行动态加载，每周 5 天，持续 2 周。Dkk1 KO 骨骼明显更硬，因此另一组 Dkk1 KO 接受 12N 最大压缩力，以在中干骺端达到等效的+1200με 应变。随后进行了 Dkk1 KO 骨骼的微 CT 和骨组织形态计量学分析。所有组均对胫骨加载做出反应，增加了中干骺端骨体积。最大的效应大小出现在 Dkk1 KO-12N 组中。因此，Dkk1 KO 动物对机械加载具有增强的敏感性。皮质骨体积的增加反映了骨膜骨形成的增加。WT 和 Wnt3 对照之间的骨体积和形成没有改变。这些数据支持 Wnt/β-连环蛋白信号激动剂可以与负重运动协同作用的概念。值得注意的是，Sost 表达在 Dkk1 KO 和 WT 小鼠中随加载而减少，与基因型无关。这些数据表明，Dkk1 KO 小鼠中 Sost 的代偿性下调不太可能是对机械负荷增强反应的主要机制。
