Decreased BMD and Limb Deformities in Mice Carrying Mutations in Both Lrp5 and Lrp6

Abstract

Humans and mice lacking Lrp5 have low BMD. To evaluate whether Lrp5 and Lrp6 interact genetically to control bone or skeletal development, we created mice carrying mutations in both Lrp5 and the related gene Lrp6. We found that compound mutants had dose-dependent deficits in BMD and limb formation, suggesting functional redundancy between these two genes in bone and limb development. Introduction: Lrp5 and Lrp6 are closely related members of the low density lipoprotein receptor family and are co-receptors for Wnt ligands. While Lrp5 mutations are associated with low BMD in humans and mice, the role of Lrp6 in bone formation has not been analyzed. Materials and Methods: To address whether Lrp5 and Lrp6 play complimentary roles in bone and skeletal development, we created mice with mutations in both genes. We inspected limbs of mice from the different genotypic classes of compound mutants to identify abnormalities. DXA and μCT were used to evaluate the effect of mutations in Lrp5 and Lrp6 on BMD and microarchitecture. Results: Mice heterozygous for mutations in Lrp6 and either heterozygous or homozygous for a mutation in Lrp5 (Lrp6+/−;Lrp5+/− or Lrp6+/−;Lrp5−/−) display limb defects with incomplete penetrance and variable expression. DXA analysis showed that BMD decreased as mice progressively were more deficient in Lrp5 and Lrp6. Lrp6+/−;Lrp5−/− mice were more severely affected than Lrp6+/+;Lrp5−/− mice, whereas Lrp6+/−;Lrp5+/− mice had statistically higher BMD than Lrp6+/+;Lrp5−/− mice and lower BMD compared with wildtype mice and mice heterozygous for either mutation alone. Conclusions: Lrp6 and Lrp5 genetically interact in limb development in mice. Furthermore, heterozygosity for an inactivating mutation in Lrp6 further reduces BMD in both male and female mice lacking Lrp5.