High Bone Mass in Mice Expressing a Mutant LRP5 Gene

作者：Philip Babij, Weiguang Zhao, Clayton G. Small, Yogendra P. Kharode, Paul J. Yaworsky, Mary Bouxsein, Padmalatha S. Reddy, Peter V.N. Bodine, John A. Robinson, Bheem M. Bhat, James R. Marzolf, Robert A. Moran, Frederick J. Bex · 发表于：Journal of Bone and Mineral Research · 年份：2003 · DOI：10.1359/jbmr.2003.18.6.960 · 被引用次数：500 · 研究领域：Muscle Physiology and Disorders、Wnt/β-catenin signaling in development and cancer、Cardiomyopathy and Myosin Studies

A unique mutation in LRP5 is associated with high bone mass in man. Transgenic mice expressing this LRP5 mutation have a similar phenotype with high bone mass and enhanced strength. These results underscore the importance of LRP5 in skeletal regulation and suggest targets for therapies for bone disease. A mutation (G171V) in the low-density lipoprotein receptor related protein 5 (LRP5) has been associated with high bone mass (HBM) in two independent human kindreds. To validate the role of the mutation, several lines of transgenic mice were created expressing either the human LRP5 G171V substitution or the wildtype LRP5 gene in bone. Volumetric bone mineral density (vBMD) analysis by pQCT showed dramatic increases in both total vBMD (30-55%) and trabecular vBMD (103-250%) of the distal femoral metaphysis and increased cortical size of the femoral diaphysis in mutant G171V transgenics at 5, 9, 17, 26, and 52 weeks of age (p < 0.01 for all). In addition, high-resolution microcomputed tomography (microCT) analysis of the distal femorae and lumbar vertebrae revealed an increase (110-232%) in trabecular bone volume fraction caused by both increased trabecular number (41-74%) and increased trabecular thickness (34-46%; p < 0.01 for all) in the mutant G171V mice. The increased bone mass was associated with significant increases in vertebral compressive strength (80-140%) and the increased cortical size with significant increases in femoral bending strength (50-130%). There were no di...