Analysis of multiple bone responses to graded strains above functional levels, and to disuse, in XXXX in vivo show that the human Lrp5 @entity73038 High Bone Mass mutation increases the osteogenic response to loading but that lack of Lrp5 activity reduces it.

@entity19 @entity604 @entity164 @entity73038 @entity15143
INTRODUCTION: To investigate the role of the @entity15143 ( @entity15143 ) 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 @entity19 with the @entity15143 loss of function mutation ( @entity15143 (-/-)) or heterozygous for the @entity15143 @entity73038 High Bone Mass (HBM) mutation ( @entity15143 (HBM+)). MATERIALS AND METHODS: The right tibias of these 17week old male and female @entity19 and their @entity164 ( @entity164 ) 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 @entity19 the right sciatic nerve was severed causing disuse of the right tibia for 3weeks. 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 @entity164 (+/+) controls showed significant strain:response curves for cortical area and trabecular thickness, but @entity15143 (-/-) @entity19 showed no detectable strain:response in those same outcomes. Female @entity19 of either @entity164 (+/+) or @entity15143 (-/-) genotype did not show significant strain:response curves for cortical or trabecular parameters, the one exception being Tb.Th in @entity15143 (-/-) @entity19 . Since female @entity164 (+/+) @entity19 did not respond to loading in a significant dose:responsive manner, the similar lack of responsiveness of the @entity15143 (-/-) females could not be ascribed to their @entity15143 status. Cortical @entity604 associated with disuse showed no differences between @entity15143 (-/-) @entity19 and @entity164 (+/+) controls, but in cancellous bone of both male and females of these @entity19 , there was a greater loss than in @entity164 (+/+) controls. In contrast, the tibias of male and female @entity19 heterozygous for the @entity15143 @entity73038 HBM mutation showed greater osteogenic responsiveness to loading and less @entity604 associated with disuse than their @entity164 (HBM-) controls. These data indicate that the presence of the @entity15143 @entity73038 HBM mutation is associated with an increased osteogenic response to loading but support only a marginal gender-related role for normal @entity15143 function in this loading-related response.
