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

Area of Science:

• Bone Biology and Biomechanics
• Skeletal Physiology
• Wnt Signaling Pathway

Background:

• Mice with a viable Dkk1 knockout (KO) rescued by Wnt3 heterozygosity display high bone mass.
• The Wnt/β-catenin signaling pathway is crucial for bone formation.
• Dkk1 inhibits Wnt signaling, while Sost (sclerostin) also negatively regulates bone formation.

Purpose of the Study:

• To investigate if in vivo mechanical loading further enhances bone formation in Dkk1 KO mice.
• To compare the response of Dkk1 KO mice to mechanical loading with wild-type (WT) and Wnt3 heterozygote controls.
• To explore the role of Sost in the augmented bone response to mechanical loading in Dkk1 KO mice.

Main Methods:

• Cyclic mechanical loading applied to tibiae of 10-week-old female Dkk1 KO, WT, and Wnt3+/- mice.
• Loading protocols included 7N and 12N maximum compressive force to achieve specific strains.
• Microcomputed tomography (MicroCT) and bone histomorphometry used for analysis.

Main Results:

• All groups showed increased bone volume in response to loading, with the largest effect in Dkk1 KO mice subjected to 12N force.
• Dkk1 KO animals exhibited enhanced sensitivity to mechanical loading, with increased cortical bone volume due to enhanced periosteal bone formation.
• Sclerostin (Sost) expression decreased with loading in both Dkk1 KO and WT mice, independent of genotype.

Conclusions:

• Dkk1 deficiency enhances the bone formation response to mechanical loading, supporting the synergistic effect of Wnt signaling agonists and exercise.
• The augmented response to mechanical loading in Dkk1 KO mice is not primarily mediated by compensatory downregulation of Sost.
• These findings highlight the potential of targeting Wnt signaling to improve bone adaptation to mechanical stimuli.