The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

Nele Vollersen,Björn Busse,Michael Amling,Ahmed Sharaf,Doron Shmerling,Meliha Karsak,Ralf Oheim,Stephan Sonntag,Ernesto Bockamp,Michaela Schweizer,Thorsten Schinke,Felix Nikolai Schmidt,Kilian Elia Stockhausen,Timur Alexander Yorgan,Wenbo Zhao,Simon Von Kroge,Oliver Semler,Fabiola Lange,Tim Rolvien

doi:10.1038/s41413-021-00170-0

Abstract

The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

Highlights

Osteoporosis, the most prevalent skeletal remodeling disorder, is primarily treated by antiresorptive drugs inhibiting the differentiation and/or activity of osteoclasts.[1]
Furtherdisplay a brain pathology but had decreased bone mass and more, the layer thickness of cortical Cux1-positive cells and the skeletal fractures. We utilized this model to demon- number of doublecortin (DCX)-positive neuroblasts in the strate that the homozygous presence of the G177C mutation does not diminish the osteoanabolic response toward parathyroid hormone (PTH) injection or LRP5 activation, and we further identified that impaired bone matrix quality in Wnt1G177C/G177C mice contributes to skeletal fragility
Given the key role of the putative Wnt signaling regulators LRP5 and sclerostin in controlling osteoblast-mediated bone formation in mice and humans,[5,6,7,8] it was highly relevant that several studies have identified WNT1 mutations in individuals with either early-onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI-XV).[9,10,11,12]

Summary

Introduction

Osteoporosis, the most prevalent skeletal remodeling disorder, is primarily treated by antiresorptive drugs inhibiting the differentiation and/or activity of osteoclasts.[1]. Combined research efforts in recent decades have revealed that the WNT signaling pathway is a key regulator of bone metabolism.[4] This research area was initially triggered by the genetic analysis of individuals with sclerosing bone disorders, which are characterized by increased osteoblast activity In these patients, either activating mutations of the putative WNT coreceptor LRP5 or inactivating mutations of the secreted protein sclerostin were identified as disease-causing.[5,6] It was subsequently found that sclerostin binds to LRP5 to antagonize WNT signaling and thereby bone formation and that high bone mass mutations of LRP5 abolish the interaction with sclerostin.[7,8]

Objectives

Methods

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Conclusion