High Bone Mass in Mice Expressing a Mutant LRP5 Gene

Abstract

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 differences in osteoclast number at 17 weeks of age. However, compared with littermate controls, the mutant G171V transgenic mice showed an increase in actively mineralizing bone surface, enhanced alkaline phosphatase staining in osteoblasts, and a significant reduction in the number of TUNEL-positive osteoblasts and osteocytes. These results suggest that the increased bone mineral density in mutant G171V mice was caused by increased numbers of active osteoblasts, which could in part be because of their increased functional lifespan. While slight bone anabolic activity was observed from overexpression of the wildtype LRP5 gene, it is clear that the G171V mutation, rather than overexpression of the receptor itself, is primarily responsible for the dramatic HBM bone effects. Together, these findings establish the importance of this novel and unexpected role of a lipoprotein receptor in regulating bone mass and afford a new model to explore LRP5 and its recent association with Wnt signaling in bone biology. (J Bone Miner Res 2003;18:960 -974)

Function and biological roles of the Dickkopf family of Wnt modulators

“…Conversely, mice that overexpress the G171V LRP5 mutant, have a high bone mass phenotype (Babij et al, 2003). Unlike homozygous mutants, heterozygous Dkk1 þ /À mice are viable and they show an increase in bone mineral density (Morvan et al, 2006).…”

Atherosclerotic Calcification: Wnt Is the Hint

“…On the other hand, gain‐of‐function mutations of LRP5 are associated with a high bone mass phenotype 117, 118. Interestingly, no change in osteoblast activity was observed in mice with increased expression of LRP5 119. These mice did, however, have decreased osteoblast apoptosis, suggesting that the high bone mass phenotype is because of increased osteoblast cell count rather than function.…”

Bone mass is inversely proportional to Dkk1 levels in mice

“…The converse is found in patients with dominant "gain-of-function" mutations in LRP5 which exhibit abnormally high bone density [7,8]. A transgenic mouse model carrying a human LRP5 high bone mass mutation exhibited significant increases in bone density and mechanical properties [9,10]. Studies have shown that removing one Lrp6 copy from Lrp5 −/− mice increases the osteoporosis severity, suggesting that both LRP5 and LRP6 are critical determinants of bone mass [11].…”