The role of low density lipoprotein receptor-related protein 5 (LRP5) high bone mass mutations in bone metabolism

Paul J Niziolek, Purdue University

Abstract

The low density lipoprotein receptor-related protein-5 (LRP5) is a Wnt co-receptor that has been shown to be a key component in regulation of bone metabolism in humans. Mechanical loading studies conducted on Lrp5 knockout mouse models indicated that the anabolic response to mechanical stimulation was severely impaired in the absence of Lrp5. Other mutations in LRP5 have been reported to cause a high bone mass (HBM) phenotype in humans. Preliminary reports, based on a transgenic mouse model of one of these mutations, indicated that the mutations might enhance sensitivity to mechanical stimulation in bone. Furthermore, the mechanism by which these HBM mutations achieved increased bone properties and the effects of external anabolic and catabolic stimuli on the HBM phenotype was unknown. We have developed two Lrp5 HBM knock-in mouse models that harbor of one of two Lrp5 HBM mutations, G171V or A214V. After characterization of the phenotype, we determined the effect of catabolic stimuli (mechanical, hormonal, and antagonist overexpression) and an anabolic stimulus (compressive axial tibial loading model). We found that the two mutations conferred a bone protective effect to catabolic challenges and an enhanced response to mechanical stimulation, although differences between the two mutations suggest that they use different mechanisms to generate their effects. The work in this dissertation supports the importance of the Wnt/Lrp5 pathway on regulation of bone metabolism and the possible use of this pathway’s components as pharmaceutical targets to protect bone in bone-wasting environments, notably bed rest, muscle paralysis, and spaceflight.

Degree

Ph.D.

Advisors

Voytik-Harbin, Purdue University.

Subject Area

Biomedical engineering|Biomechanics

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