An Fgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton.

Martin Biosse Duplan,Jérome Guicheux,Valentin Estibals,Laurence Legeai-Mallet,Emilie Dambroise,Joelle Veziers

doi:10.1242/dmm.048272

Abstract

ABSTRACTAchondroplasia (ACH), the most common form of dwarfism, is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3). The resulting increase in FGFR3 signaling perturbs the proliferation and differentiation of chondrocytes (CCs), alters the process of endochondral ossification and thus reduces bone elongation. Increased FGFR3 signaling in osteoblasts (OBs) might also contribute to bone anomalies in ACH. In the present study of a mouse model of ACH, we sought to determine whether FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3-activating mutation (Fgfr3Y367C/+) that accurately mimics ACH; we targeted the mutation to either immature OBs and hypertrophic CCs or to mature OBs by using the Osx-cre and collagen 1α1 (2.3 kb Col1a1)-cre mouse strains, respectively. We observed that Fgfr3 activation in immature OBs and hypertrophic CCs (Osx-Fgfr3) not only perturbed the hypertrophic cells of the growth plate (thus affecting long bone growth) but also led to osteopenia and low cortical thickness in long bones in adult (3-month-old) mice but not growing (3-week-old) mice. Importantly, craniofacial membranous bone defects were present in the adult mice. In contrast, activation of Fgfr3 in mature OBs (Col1-Fgfr3) had very limited effects on skeletal shape, size and micro-architecture. In vitro, we observed that Fgfr3 activation in immature OBs was associated with low mineralization activity. In conclusion, immature OBs appear to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs.

Highlights

Achondroplasia (ACH; the most common form of dwarfism in humans) is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3); the mutation activates the receptor and its downstream signaling pathways
Fgfr3 activation in immature OBs and hypertrophic CCs leads to dwarfism and growth plate anomalies The groups of Osx-Fgfr3 (Osxcre/+-Fgfr3Y367C/+) and Col1-Fgfr3 (Col1a1cre/+-Fgfr3Y367C/+) mice were born with the expected Mendelian ratio
The mild dwarfism observed in Osx-Fgfr3 mice prompted us to look at the growth plate of long bones in growing and adult animals

Summary

Introduction

Achondroplasia (ACH; the most common form of dwarfism in humans) is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3); the mutation activates the receptor and its downstream signaling pathways The most common form of craniosynostosis, is due to a single FGFR3 gain-offunction mutation (Muenke et al, 1997)

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