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

Abstract : Achondroplasia (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 or not FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3 activating mutation (Fgfr3 Y367C/+) 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 (2.3kb-Col1α1)-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 in 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 appears to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs.
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https://www.hal.inserm.fr/inserm-03176224
Contributor : Valérie Pecqueret <>
Submitted on : Monday, March 22, 2021 - 11:17:13 AM
Last modification on : Wednesday, June 2, 2021 - 4:26:12 PM

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Martin Biosse Duplan, Emilie Dambroise, Valentin Estibals, Joelle Veziers, Jérome Guicheux, et al.. An Fgfr3-activating mutation in immature osteoblasts affects the appendicular and craniofacial skeleton. Disease Models & Mechanisms, Cambridge Company of Biologists, 2021, pp.dmm.048272. ⟨10.1242/dmm.048272⟩. ⟨inserm-03176224⟩

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