High bone mass-causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo

Paul J. Niziolek, Bryan T. Macdonald, Rajendra Kedlaya, Minjie Zhang, Teresita Bellido, Xi He, Matthew L. Warman, Alexander Robling

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes (<sup>8kb</sup>Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes (<sup>2.3kb</sup>Col1a1-Dkk1). We observed that the <sup>8kb</sup>Dmp1-SOST 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 Lrp5 p.G171V and p.A214V alleles. The <sup>2.3kb</sup>Col1a1-Dkk1 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.

Original languageEnglish
Pages (from-to)1822-1830
Number of pages9
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume30
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Bone and Bones
Bone Density
Osteocytes
Missense Mutation
Transgenes
Metabolic Bone Diseases
Thigh
Osteoblasts
Osteogenesis
Transgenic Mice
Alleles
Mutation

Keywords

  • A214V
  • DKK1
  • G171V
  • high bone mass (HBM)
  • LRP5
  • osteoporosis
  • sclerostin
  • sost
  • WNT

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

High bone mass-causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo. / Niziolek, Paul J.; Macdonald, Bryan T.; Kedlaya, Rajendra; Zhang, Minjie; Bellido, Teresita; He, Xi; Warman, Matthew L.; Robling, Alexander.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 30, No. 10, 01.10.2015, p. 1822-1830.

Research output: Contribution to journalArticle

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