High Bone Mass–Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo. (October 2015)

• Record Type: Journal Article
• Authors: Niziolek, Paul J; MacDonald, Bryan T; Kedlaya, Rajendra; Zhang, Minjie; Bellido, Teresita; He, Xi; Warman, Matthew L; Robling, Alexander G
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 10(2015:Oct.)
• Page Start: 1822
• Page End: 1830
• Publication Date: 2015-10
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2514
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jbmr2514-sec-0001" sec-type="section"> <p>Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog‐1 (DKK1). We previously reported the creation of two <italic>Lrp5</italic> HBM knock‐in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous <italic>Lrp5</italic> locus. To determine whether HBM knock‐in mice are resistant to SOST‐ or DKK1‐induced osteopenia, we bred <italic>Lrp5</italic> HBM mice with transgenic mice that overexpress human SOST in osteocytes (<sup>8kb</sup><italic>Dmp1</italic>‐<italic>SOST</italic>) or mouse DKK1 in osteoblasts and osteocytes (<sup>2.3kb</sup><italic>Col1a1</italic>‐<italic>Dkk1</italic>). We observed that the <sup>8kb</sup><italic>Dmp1</italic>‐<italic>SOST</italic> transgene significantly lowered whole‐body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone‐formation rate (BFR) in wild‐type mice but not in mice with <italic>Lrp5</italic> p.G171V and p.A214V alleles. The <sup>2.3kb</sup><italic>Col1a1‐Dkk1</italic> transgene significantly lowered whole‐body BMD, BMC, and vertebral BV/TV in wild‐type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM‐causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1. © 2015 American Society for Bone and Mineral Research.</p> </sec> </abstract>