{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T11:15:28Z","timestamp":1761822928177},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2000,1,1]],"date-time":"2000-01-01T00:00:00Z","timestamp":946684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A G380R substitution in the transmembrane-spanning region of FGFR3 (FGFR3Ach) results in constitutive receptor kinase activity and is the most common cause of achondroplastic dwarfism in humans. The epiphyseal growth plates of affected individuals are disorganized and hypocellular and show aberrant chondrocyte maturation. To examine the molecular basis of these abnormalities, we used a chondrocytic cell line, CFK2, to stably express the b variant of wild-type FGFR3 or the the constitutively active FGFR3Ach. Overexpression of FGFR3 had minimal effects on CFK2 proliferation and maturation compared with the severe growth retardation found in cells expressing FGFR3Ach. Cells expressing the mutant receptor also showed an abnormal apoptotic response to serum deprivation and failed to undergo differentiation under appropriate culture conditions. These changes were associated with altered expression of integrin subunits, which effectively led to a switch in substrate preference of the immature cell from fibronectin to type II collagen. These in vitro observations support those from in vivo studies indicating that FGFR3 mediates an inhibitory influence on chondrocyte proliferation. We now suggest that the mechanism is related to altered integrin expression.<\/jats:p>","DOI":"10.1359\/jbmr.2000.15.1.155","type":"journal-article","created":{"date-parts":[[2006,4,27]],"date-time":"2006-04-27T01:45:01Z","timestamp":1146102301000},"page":"155-165","source":"Crossref","is-referenced-by-count":62,"title":["Expression of FGFR3 with the G380R Achondroplasia Mutation Inhibits Proliferation and Maturation of CFK2 Chondrocytic Cells"],"prefix":"10.1093","volume":"15","author":[{"given":"Janet E.","family":"Henderson","sequence":"first","affiliation":[{"name":"Lady Davis Institute for Medical Research, Division of Enodcrinology and Geriatrics, Sir Mortimer B. Davis\u2013Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Naski","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle M.","family":"Aarts","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Division of Enodcrinology and Geriatrics, Sir Mortimer B. Davis\u2013Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dashen","family":"Wang","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Division of Enodcrinology and Geriatrics, Sir Mortimer B. Davis\u2013Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Cheng","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Division of Enodcrinology and Geriatrics, Sir Mortimer B. Davis\u2013Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Goltzman","sequence":"additional","affiliation":[{"name":"Calcium Research Laboratory, Royal Victoria Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Ornitz","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,2]]},"reference":[{"key":"2024020714111968400_bib1","doi-asserted-by":"crossref","first-page":"11620","DOI":"10.1016\/S0021-9258(19)78170-8","article-title":"Fibroblast growth factor receptor (FGFR) 3: Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF\/FGF-1","volume":"269","author":"Chellaiah","year":"1994","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib2","doi-asserted-by":"crossref","first-page":"16305","DOI":"10.1016\/S0021-9258(18)42001-7","article-title":"Ligand specificity and heparin dependence of fibroblast growth factor receptors 1 and 3","volume":"267","author":"Ornitz","year":"1992","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib3","doi-asserted-by":"crossref","first-page":"15292","DOI":"10.1074\/jbc.271.25.15292","article-title":"Receptor specificity of the fibroblast growth factor family","volume":"271","author":"Ornitz","year":"1996","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib4","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1073\/pnas.93.2.845","article-title":"Preferential self-association of basic fibroblast growth factor is stabilized by heparin during receptor dimerization and activation","volume":"93","author":"Venkataraman","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020714111968400_bib5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1126\/science.7716514","article-title":"Integrins and signal transduction pathways: The road taken","volume":"268","author":"Clark","year":"1995","journal-title":"Science"},{"key":"2024020714111968400_bib6","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/jcs.110.4.401","article-title":"Focal adhesion kinase: at the crossroads of signal transduction","volume":"110","author":"Illic","year":"1997","journal-title":"J Cell Sci"},{"key":"2024020714111968400_bib7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1006\/dbio.1993.1040","article-title":"Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis","volume":"155","author":"Peters","year":"1993","journal-title":"Dev Biol"},{"key":"2024020714111968400_bib8","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.2144\/97226bm12","article-title":"Determination of fibroblast growth factor receptor expression in mouse, rat and human samples using a single primer pair","volume":"22","author":"McEwen","year":"1997","journal-title":"BioTechniques"},{"key":"2024020714111968400_bib9","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/ng0496-390","article-title":"Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3","volume":"12","author":"Colvin","year":"1996","journal-title":"Nature Genet"},{"key":"2024020714111968400_bib10","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/S0092-8674(00)81069-7","article-title":"Fibroblast growth factor receptor 3 is a negative regulator of bone growth","volume":"84","author":"Deng","year":"1996","journal-title":"Cell"},{"key":"2024020714111968400_bib11","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1242\/dev.125.24.4977","article-title":"Repression of hedgehog signalling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3","volume":"125","author":"Naski","year":"1998","journal-title":"Development"},{"key":"2024020714111968400_bib12","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0092-8674(94)90302-6","article-title":"Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia","volume":"78","author":"Shiang","year":"1994","journal-title":"Cell"},{"key":"2024020714111968400_bib13","doi-asserted-by":"crossref","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":"2024020714111968400_bib14","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/ng0395-321","article-title":"Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3","volume":"9","author":"Tavormina","year":"1995","journal-title":"Nat Genet"},{"key":"2024020714111968400_bib15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/(SICI)1096-8628(19960503)63:1<148::AID-AJMG26>3.0.CO;2-N","article-title":"Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia and thanatophoric dwarfism","volume":"63","author":"Bonaventure","year":"1996","journal-title":"Am J Med Gen"},{"key":"2024020714111968400_bib16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/ng0696-233","article-title":"Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia","volume":"13","author":"Naski","year":"1996","journal-title":"Nature Gen"},{"key":"2024020714111968400_bib17","first-page":"179","volume-title":"Cartilage: Molecular Aspects","author":"Poole","year":"1991"},{"key":"2024020714111968400_bib18","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1083\/jcb.126.6.1611","article-title":"Parathyroid hormone-related peptide (PTHrP)-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation","volume":"126","author":"Amizuka","year":"1994","journal-title":"J Cell Biol"},{"key":"2024020714111968400_bib19","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1006\/dbio.1996.0104","article-title":"Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal post-natal bone development","volume":"175","author":"Amizuka","year":"1995","journal-title":"Dev Biol"},{"key":"2024020714111968400_bib20","doi-asserted-by":"crossref","first-page":"5055","DOI":"10.1210\/endo.137.11.8895380","article-title":"Programmed cell death of chondrocytes and aberrant chondrogenesis in mice homozygous for parathyroid hormone-related peptide gene deletion","volume":"137","author":"Amizuka","year":"1996","journal-title":"Endocrinology"},{"key":"2024020714111968400_bib21","first-page":"141","volume-title":"Biological Regulation of the Chondrocytes","author":"Kato","year":"1992"},{"key":"2024020714111968400_bib22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1126\/science.273.5275.613","article-title":"Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein","volume":"273","author":"Vortkamp","year":"1996","journal-title":"Science"},{"key":"2024020714111968400_bib23","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1126\/science.273.5275.663","article-title":"PTH\/PTHrP receptor in early development and Indian hedgehog-regulated bone growth","volume":"273","author":"Lanske","year":"1996","journal-title":"Science"},{"key":"2024020714111968400_bib24","first-page":"59","article-title":"Mice carrying null mutations of the genes encoding insulin-like growth factor 1 (IGF-1) and type 1 IGF receptor (Igf1r)","volume":"75","author":"Liu","year":"1993","journal-title":"Cell"},{"key":"2024020714111968400_bib25","doi-asserted-by":"crossref","first-page":"4064","DOI":"10.1128\/MCB.15.8.4064","article-title":"Nucleolar targeting of PTHrP enhances survival of chondrocytes under conditions that promote cell death by apoptosis","volume":"15","author":"Henderson","year":"1995","journal-title":"Mol Cell Biol"},{"key":"2024020714111968400_bib26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/(SICI)1097-4652(199610)169:1<33::AID-JCP4>3.0.CO;2-F","article-title":"Constitutive expression of parathyroid hormone-related peptide (PTHrP) stimulates growth and inhibits differentiation of CFK2 chondrocytes","volume":"169","author":"Henderson","year":"1996","journal-title":"J Cell Physiol"},{"key":"2024020714111968400_bib27","doi-asserted-by":"crossref","first-page":"10240","DOI":"10.1073\/pnas.93.19.10240","article-title":"Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation","volume":"93","author":"Weir","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020714111968400_bib28","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1101\/gad.8.3.277","article-title":"Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide (PTHrP) gene","volume":"8","author":"Karaplis","year":"1994","journal-title":"Genes Dev"},{"key":"2024020714111968400_bib29","doi-asserted-by":"crossref","first-page":"9170","DOI":"10.1073\/pnas.91.19.9170","article-title":"Identification of soluble forms of the fibroblast growth factor receptor in blood","volume":"91","author":"Hanneken","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020714111968400_bib30","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/jcp.1041450212","article-title":"Establishment of an osseous cell line from fetal rat calvaria using an immunocytolytic method of cell selection: characterization of the cell line and of derived clones","volume":"145","author":"Bernier","year":"1990","journal-title":"J Cell Physiol"},{"key":"2024020714111968400_bib31","doi-asserted-by":"crossref","first-page":"4832","DOI":"10.1074\/jbc.274.8.4832","article-title":"Parathyroid hormone related protein interacts with RNA","volume":"274","author":"Aarts","year":"1999","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib32","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1359\/jbmr.1997.12.7.1124","article-title":"involvement of a5B1 integrin in matrix interactions and proliferation of chondrocytes","volume":"12","author":"Enomoto-Iwamoto","year":"1997","journal-title":"J Bone Miner Res"},{"key":"2024020714111968400_bib33","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1083\/jcb.138.5.1159","article-title":"Integrin a2b1 is a receptor for the cartilage matrix protein chondroadherin","volume":"138","author":"Camper","year":"1997","journal-title":"J Cell Biol"},{"key":"2024020714111968400_bib34","doi-asserted-by":"crossref","first-page":"20383","DOI":"10.1074\/jbc.273.32.20383","article-title":"Isolation, cloning and sequence analysis of the integrin subunit \u03b110, a \u03b21-associated collagen-binding integrin expressed in chondrocytes","volume":"273","author":"Camper","year":"1998","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib35","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/jbmr.5650080412","article-title":"Regulation of expression of the chondrocytic phenotype in the skeletal cell line (CFK2) in vitro","volume":"8","author":"Bernier","year":"1993","journal-title":"J Bone Miner Res"},{"key":"2024020714111968400_bib36","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/S0168-9525(00)89088-5","article-title":"Fibroblast growth factor receptor mutations in human skeletal disorders","volume":"11","author":"Muenke","year":"1995","journal-title":"Trends Genet"},{"key":"2024020714111968400_bib37","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1128\/MCB.17.7.4169","article-title":"Chimeras of the native form of achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells","volume":"17","author":"Thompson","year":"1997","journal-title":"Mol Cell Biol"},{"key":"2024020714111968400_bib38","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1006\/excr.1993.1087","article-title":"B1 integrins mediate chondrocyte interaction with type I collagen, type II collagen and fibronectin","volume":"205","author":"Enomoto","year":"1993","journal-title":"Exp Cell Res"},{"key":"2024020714111968400_bib39","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/358681a0","article-title":"Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis","volume":"358","author":"Mohammadi","year":"1992","journal-title":"Nature"},{"key":"2024020714111968400_bib40","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/358678a0","article-title":"Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis","volume":"358","author":"Peters","year":"1992","journal-title":"Nature"},{"key":"2024020714111968400_bib41","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1073\/pnas.92.3.870","article-title":"Differential activation of mitogen-activated protein kinase in reponse to basic fibroblast growth factor","volume":"92","author":"Campbell","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020714111968400_bib42","doi-asserted-by":"crossref","first-page":"6621","DOI":"10.1074\/jbc.272.10.6621","article-title":"Signal transduction pathway of human fibroblast growth factor 3","volume":"272","author":"Kanai","year":"1997","journal-title":"J Biol Chem"},{"key":"2024020714111968400_bib43","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0092-8674(00)80252-4","article-title":"A lipid-anchored Grb-2 binding protein that links FGF-receptor activation to the Ras\/MAPK signaling pathway","volume":"89","author":"Kouhara","year":"1997","journal-title":"Cell"},{"key":"2024020714111968400_bib44","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1128\/MCB.17.8.4406","article-title":"Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1\/mitogen-activated protein kinase pathway activation","volume":"17","author":"King","year":"1997","journal-title":"Mol Cell Biol"},{"key":"2024020714111968400_bib45","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0092-8674(00)81392-6","article-title":"The adaptor protein Shc couples a class of integrins to the control of cell cycle progression","volume":"87","author":"Wary","year":"1996","journal-title":"Cell"},{"key":"2024020714111968400_bib46","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0955-0674(96)80107-4","article-title":"Integrin cytoplasmic interactions and bidirectional transmembrane signalling","volume":"8","author":"Dedhar","year":"1996","journal-title":"Curr Opin Cell Biol"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.2000.15.1.155","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/15\/1\/155\/56604788\/5650150119.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/15\/1\/155\/56604788\/5650150119.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:59:04Z","timestamp":1710341944000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/15\/1\/155-165\/7515598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,1,1]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2009,12,2]]},"published-print":{"date-parts":[[2000,1,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.2000.15.1.155","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2000,1,1]]},"published":{"date-parts":[[2000,1,1]]}}}