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

INTRODUCTION: To investigate the role of the low-density lipoprotein receptor-related protein 5 (Lrp5) in bones' responses to loading, we analysed changes in multiple measures of bone architecture in tibias subjected to loading or disuse in male and female mice with the Lrp5 loss of function mutation (Lrp5(−/−)) or heterozygous for the Lrp5 G171V High Bone Mass (HBM) mutation (Lrp5(HBM+)). MATERIALS AND METHODS: The right tibias of these 17 week old male and female mice and their Wild Type (WT) littermates were subjected to short periods of loading three days a week for two weeks. Each tibia was loaded for 40 cycles, to produce peak strains at the midshaft within the low, medium or high physiological range (~ 1500, 2400 and 3000 microstrain, respectively). In similar groups of mice the right sciatic nerve was severed causing disuse of the right tibia for 3 weeks. Data from microCT of loaded, neurectomised and contra-lateral control tibias were analysed to quantify changes in the cortical and cancellous regions of the bone in the absence of functional strains and in response to graded strains in addition to those derived from function. RESULTS AND CONCLUSION: 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.