{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:48:00Z","timestamp":1790837280650,"version":"4.1.0"},"reference-count":45,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Seventh Framework Programme","award":["602300"],"award-info":[{"award-number":["602300"]}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-10-IAHU-01"],"award-info":[{"award-number":["ANR-10-IAHU-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fondation des Gueules Cass\u00e9es"},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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 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 1\u03b11 (2.3\u00a0kb 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.<\/jats:p>","DOI":"10.1242\/dmm.048272","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T10:50:10Z","timestamp":1616064610000},"source":"Crossref","is-referenced-by-count":11,"title":["An<i>Fgfr3<\/i>-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton"],"prefix":"10.1242","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-3970","authenticated-orcid":false,"given":"Martin","family":"Biosse Duplan","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Imagine Institute, Paris 75015, France"},{"name":"Universit\u00e9 de Paris, Paris 75006, France"},{"name":"Service de M\u00e9decine Bucco-Dentaire, H\u00f4pital Bretonneau, AP-HP, Paris 75018, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2794-7344","authenticated-orcid":false,"given":"Emilie","family":"Dambroise","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Imagine Institute, Paris 75015, France"},{"name":"Universit\u00e9 de Paris, Paris 75006, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Estibals","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Imagine Institute, Paris 75015, France"},{"name":"Universit\u00e9 de Paris, Paris 75006, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2182-5103","authenticated-orcid":false,"given":"Joelle","family":"Veziers","sequence":"additional","affiliation":[{"name":"Inserm, UMR 1229, RMeS \u2013 Regenerative Medicine and Skeleton, Universit\u00e9 de Nantes, ONIRIS, Nantes, F-44042, France"},{"name":"SC3M, SFR Sant\u00e9 F. Bonamy, FED 4203, UMS Inserm 016, CNRS 3556, Nantes F-44042, France"},{"name":"CHU Nantes, PHU4 OTONN, Nantes, F-44093, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2754-3024","authenticated-orcid":false,"given":"J\u00e9rome","family":"Guicheux","sequence":"additional","affiliation":[{"name":"Inserm, UMR 1229, RMeS \u2013 Regenerative Medicine and Skeleton, Universit\u00e9 de Nantes, ONIRIS, Nantes, F-44042, France"},{"name":"SC3M, SFR Sant\u00e9 F. Bonamy, FED 4203, UMS Inserm 016, CNRS 3556, Nantes F-44042, France"},{"name":"CHU Nantes, PHU4 OTONN, Nantes, F-44093, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4989-5856","authenticated-orcid":false,"given":"Laurence","family":"Legeai-Mallet","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Imagine Institute, Paris 75015, France"},{"name":"Universit\u00e9 de Paris, Paris 75006, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"2021082314152876700_DMM048272C1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1097\/SCS.0000000000001267","article-title":"Achondroplasia and multiple-suture craniosynostosis","volume":"26","author":"Albino","year":"2015","journal-title":"J. Craniofac. Surg"},{"key":"2021082314152876700_DMM048272C2","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s10067-012-2126-x","article-title":"Assessment of osteoporotic alterations in achondroplastic patients: a case series","volume":"32","author":"Arita","year":"2013","journal-title":"Clin. Rheumatol"},{"key":"2021082314152876700_DMM048272C3","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/ajmg.a.36130","article-title":"Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association","volume":"161A","author":"Bessenyei","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"2021082314152876700_DMM048272C4","first-page":"2997","article-title":"Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible","volume":"25","author":"Biosse Duplan","year":"2016","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C5","doi-asserted-by":"publisher","first-page":"e85161","DOI":"10.1371\/journal.pone.0085161","article-title":"Osx-Cre Targets multiple cell types besides osteoblast lineage in postnatal mice","volume":"9","author":"Chen","year":"2014","journal-title":"PLoS ONE"},{"key":"2021082314152876700_DMM048272C6","first-page":"245","article-title":"Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast","volume":"224","author":"Dacquin","year":"2002","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat"},{"key":"2021082314152876700_DMM048272C7","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1002\/jbmr.4042","article-title":"Fgfr3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development","volume":"35","author":"Dambroise","year":"2020","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"2021082314152876700_DMM048272C8","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S0925-4773(98)00133-6","article-title":"Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification","volume":"77","author":"Delezoide","year":"1998","journal-title":"Mech. Dev."},{"key":"2021082314152876700_DMM048272C9","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.1093\/hmg\/ddu004","article-title":"FGFR3 mutation causes abnormal membranous ossification in achondroplasia","volume":"23","author":"Di Rocco","year":"2014","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C10","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1016\/j.bone.2011.08.021","article-title":"Genetic mouse models for bone studies\u2014Strengths and limitations","volume":"49","author":"Elefteriou","year":"2011","journal-title":"Bone"},{"key":"2021082314152876700_DMM048272C11","doi-asserted-by":"publisher","first-page":"3937","DOI":"10.1073\/pnas.0700012104","article-title":"Skeletal overgrowth is mediated by deficiency in a specific isoform of fibroblast growth factor receptor 3","volume":"104","author":"Eswarakumar","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021082314152876700_DMM048272C12","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.matbio.2008.07.001","article-title":"Specific expression of Cre recombinase in hypertrophic cartilage under the control of a BAC-Col10a1 promoter","volume":"27","author":"Gebhard","year":"2008","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol"},{"key":"2021082314152876700_DMM048272C13","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1002\/ajmg.a.33744","article-title":"Achondroplasia with synostosis of multiple sutures","volume":"155A","author":"Georgoulis","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"2021082314152876700_DMM048272C14","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/S0140-6736(07)61090-3","article-title":"Achondroplasia","volume":"370","author":"Horton","year":"2007","journal-title":"Lancet Lond. Engl"},{"key":"2021082314152876700_DMM048272C15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s11248-014-9828-6","article-title":"Skeletal defects in Osterix-Cre transgenic mice","volume":"24","author":"Huang","year":"2015","journal-title":"Transgenic Res."},{"key":"2021082314152876700_DMM048272C16","doi-asserted-by":"publisher","first-page":"13551","DOI":"10.1038\/s41598-018-31853-0","article-title":"Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3","volume":"8","author":"Kawane","year":"2018","journal-title":"Sci. Rep"},{"key":"2021082314152876700_DMM048272C17","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1172\/JCI83926","article-title":"Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model","volume":"126","author":"Komla-Ebri","year":"2016","journal-title":"J. Clin. Invest"},{"key":"2021082314152876700_DMM048272C18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00774-011-0288-2","article-title":"FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation","volume":"30","author":"Kyono","year":"2012","journal-title":"J. Bone Miner. Metab"},{"key":"2021082314152876700_DMM048272C19","doi-asserted-by":"publisher","first-page":"43220","DOI":"10.1038\/srep43220","article-title":"Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia","volume":"7","author":"Lee","year":"2017","journal-title":"Sci. Rep"},{"key":"2021082314152876700_DMM048272C20","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/hmg\/ddn339","article-title":"FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway","volume":"18","author":"Matsushita","year":"2008","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C21","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1111\/ped.12890","article-title":"Low bone mineral density in achondroplasia and hypochondroplasia","volume":"58","author":"Matsushita","year":"2016","journal-title":"Pediatr. Int. Off. J. Jpn. Pediatr. Soc"},{"key":"2021082314152876700_DMM048272C22","first-page":"555","article-title":"A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome","volume":"60","author":"Muenke","year":"1997","journal-title":"Am. J. Hum. Genet"},{"key":"2021082314152876700_DMM048272C23","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1093\/hmg\/dds065","article-title":"An activating Fgfr3 mutation affects trabecular bone formation via a paracrine mechanism during growth","volume":"21","author":"Mugniery","year":"2012","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C24","doi-asserted-by":"publisher","first-page":"e1002427","DOI":"10.1371\/journal.pbio.1002427","article-title":"Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice","volume":"14","author":"Murali","year":"2016","journal-title":"PLoS Biol."},{"key":"2021082314152876700_DMM048272C25","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genes. N. Y. N 2000"},{"key":"2021082314152876700_DMM048272C26","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1038\/ncb3067","article-title":"A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones","volume":"16","author":"Ono","year":"2014","journal-title":"Nat. Cell Biol"},{"key":"2021082314152876700_DMM048272C27","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/dvdy.24479","article-title":"Achondroplasia: development, pathogenesis, and therapy","volume":"246","author":"Ornitz","year":"2016","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"2021082314152876700_DMM048272C28","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.bone.2009.06.010","article-title":"Identification of differentially expressed genes between osteoblasts and osteocytes","volume":"45","author":"Paic","year":"2009","journal-title":"Bone"},{"key":"2021082314152876700_DMM048272C29","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.bbadis.2008.11.010","article-title":"Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia","volume":"1792","author":"Pannier","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"2021082314152876700_DMM048272C30","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1242\/dev.127.9.1845","article-title":"Integration of FGF and TWIST in calvarial bone and suture development","volume":"127","author":"Rice","year":"2000","journal-title":"Development"},{"key":"2021082314152876700_DMM048272C31","doi-asserted-by":"publisher","first-page":"3231","DOI":"10.1242\/dev.02480","article-title":"Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors","volume":"133","author":"Rodda","year":"2006","journal-title":"Dev. Camb. Engl"},{"key":"2021082314152876700_DMM048272C32","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/371252a0","article-title":"Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia","volume":"371","author":"Rousseau","year":"1994","journal-title":"Nature"},{"key":"2021082314152876700_DMM048272C33","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1093\/hmg\/ddp590","article-title":"Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis","volume":"19","author":"Su","year":"2010","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C34","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ceb.2019.07.011","article-title":"The extended chondrocyte lineage: implications for skeletal homeostasis and disorders","volume":"61","author":"Tsang","year":"2019","journal-title":"Curr. Opin. Cell Biol"},{"key":"2021082314152876700_DMM048272C35","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1002\/dvdy.21790","article-title":"Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome","volume":"238","author":"Twigg","year":"2009","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat"},{"key":"2021082314152876700_DMM048272C36","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/hmg\/ddh034","article-title":"Defective bone mineralization and osteopenia in young adult FGFR3-\/- mice","volume":"13","author":"Valverde-Franco","year":"2004","journal-title":"Hum. Mol. Genet"},{"key":"2021082314152876700_DMM048272C37","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s00223-014-9945-5","article-title":"Osterix-Cre transgene causes craniofacial bone development defect","volume":"96","author":"Wang","year":"2015","journal-title":"Calcif. Tissue Int"},{"key":"2021082314152876700_DMM048272C38","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1177\/0022034516651823","article-title":"Developmental regulation of the growth plate and cranial synchondrosis","volume":"95","author":"Wei","year":"2016","journal-title":"J. Dent. Res"},{"key":"2021082314152876700_DMM048272C39","doi-asserted-by":"publisher","first-page":"24912","DOI":"10.1074\/jbc.M116.730093","article-title":"Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis","volume":"291","author":"Wen","year":"2016","journal-title":"J. Biol. Chem"},{"key":"2021082314152876700_DMM048272C40","doi-asserted-by":"publisher","first-page":"27743","DOI":"10.1074\/jbc.M314323200","article-title":"Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts","volume":"279","author":"Xiao","year":"2004","journal-title":"J. Biol. Chem"},{"key":"2021082314152876700_DMM048272C41","doi-asserted-by":"publisher","first-page":"12097","DOI":"10.1073\/pnas.1302703111","article-title":"Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation","volume":"111","author":"Yang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021082314152876700_DMM048272C42","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1002\/jbmr.3467","article-title":"Conditional deletion of sost in MSC-derived lineages identifies specific cell-type contributions to bone mass and B-cell development","volume":"33","author":"Yee","year":"2018","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res"},{"key":"2021082314152876700_DMM048272C43","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ics.2006.09.021","article-title":"The FGF ligand\u2013receptor signaling system in chondrogenesis, osteogenesis and vascularization of the endochondral skeleton","volume":"1302","author":"Yu","year":"2007","journal-title":"Int. Congr. Ser"},{"key":"2021082314152876700_DMM048272C44","doi-asserted-by":"publisher","first-page":"12919","DOI":"10.1073\/pnas.0912855107","article-title":"Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice","volume":"107","author":"Zhou","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021082314152876700_DMM048272C45","doi-asserted-by":"publisher","first-page":"e1004820","DOI":"10.1371\/journal.pgen.1004820","article-title":"Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice","volume":"10","author":"Zhou","year":"2014","journal-title":"PLoS Genet."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.048272","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.048272\/2025442\/dmm048272.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.048272\/2025442\/dmm048272.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T10:41:47Z","timestamp":1698057707000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/14\/4\/dmm048272\/237741\/An-Fgfr3-activating-mutation-in-immature-murine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.048272","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,1]]},"article-number":"dmm048272"}}