title: An activating Fgfr3 mutation affects trabecular bone formation via a paracrine mechanism during growth.
abstract: The fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the regulation of endochondral ossification. Fgfr3 gain-of-function mutations cause achondroplasia, the most common form of dwarfism, and a spectrum of chondrodysplasias. Despite a significant number of studies on the role of FGFR3 in cartilage, to date, none has investigated the influence of Fgfr3-mediated effects of the growth plate on bone formation. We studied three mouse models, each expressing Fgfr3 mutation either ubiquitously (CMV-Fgfr3(Y367C/+)), in chondrocytes (Col II-Fgfr3(Y367C/+)) or in mature osteoblasts (Col I-Fgfr3(Y367C/+)). Interestingly, we demonstrated that dwarfism with a significant defect in bone formation during growth was only observed in mouse models expressing mutant Fgfr3 in the cartilage. We observed a dramatic reduction in cartilage matrix mineralization and a strong defect of primary spongiosa. Anomalies of primary spongiosa were associated with an increase in osteoclast recruitment and a defect of osteoblasts at the mineralization front. A significant decrease in bone volume, trabecular thickness and number was also observed in the trabecular bone. Interestingly, no anomalies in proliferation and differentiation of primary osteoblasts from CMV-Fgfr3(Y367C/+) mice were observed. Based on these data, we excluded a potential function of Fgfr3 directly on osteoblasts at 3 weeks of age and we obtained evidence that the disorganization of the growth plate is responsible for the anomalies of the trabecular bone during bone formation. Herein, we propose that impaired FGFR3 signaling pathways may affect trabecular bone formation via a paracrine mechanism during growth. These results redefine our understanding of endochondral ossification in FGFR3-related chondrodysplasias.
authors.affiliation: INSERM U781, Universite´ Paris Descartes, Hoˆ pital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Mugniery
authors.forename: Romain
authors.initials: R
authors.lastname: Dacquin
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: de Vernejoul
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Geoffroy
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D019899:Paracrine Communication / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051498:Receptor, Fibroblast Growth Factor, Type 3