Analysis of multiple bone responses to graded strains above functional levels, and to disuse, in mice in vivo show that the human Lrp5 G171V High Bone Mass mutation increases the osteogenic response to loading but that lack of Lrp5 activity reduces it

Abstract

Male WT(+/+) controls showed significant strain:response curves for cortical area and trabecular thickness, but Lrp5(-/-) mice showed no detectable strain:response in those same outcomes. Female mice of either WT(+/+) or Lrp5(-/-) genotype did not show significant strain:response curves for cortical or trabecular parameters, the one exception being Tb.Th in Lrp5(-/-) mice. Since female WT(+/+) mice did not respond to loading in a significant dose:responsive manner, the similar lack of responsiveness of the Lrp5(-/-) females could not be ascribed to their Lrp5 status. Cortical bone loss associated with disuse showed no differences between Lrp5(-/-) mice and WT(+/+) controls, but in cancellous bone of both male and females of these mice, there was a greater loss than in WT(+/+) controls. In contrast, the tibias of male and female mice heterozygous for the Lrp5 G171V HBM mutation showed greater osteogenic responsiveness to loading and less bone loss associated with disuse than their WT(HBM-) controls. These data indicate that the presence of the Lrp5 G171V HBM mutation is associated with an increased osteogenic response to loading but support only a marginal gender-related role for normal Lrp5 function in this loading-related response.