{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:53:00Z","timestamp":1792029180580,"version":"4.4.0"},"reference-count":58,"publisher":"Cold Spring Harbor Laboratory","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"published-print":{"date-parts":[[2002,4,1]]},"abstract":"<jats:p>Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that<jats:italic>Fgf18<\/jats:italic>is expressed in the perichondrium and that mice homozygous for a targeted disruption of<jats:italic>Fgf18<\/jats:italic>exhibit a growth plate phenotype similar to that observed in mice lacking<jats:italic>Fgfr3<\/jats:italic>and an ossification defect at sites that express<jats:italic>Fgfr2<\/jats:italic>. Mice lacking either<jats:italic>Fgf18<\/jats:italic>or<jats:italic>Fgfr3<\/jats:italic>exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking<jats:italic>Fgf18<\/jats:italic>display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking<jats:italic>Fgfr3<\/jats:italic>. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.<\/jats:p>","DOI":"10.1101\/gad.965602","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T00:00:34Z","timestamp":1027728034000},"page":"859-869","source":"Crossref","is-referenced-by-count":416,"title":["Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18"],"prefix":"10.1101","volume":"16","author":[{"given":"Zhonghao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer S.","family":"Colvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Ornitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2002,4,1]]},"reference":[{"key":"2021111508034561000_16.7.859.1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.1141"},{"key":"2021111508034561000_16.7.859.2","unstructured":"Caplan A.I. Pechak D.G. (1987) The cellular and molecular embryology of bone formation. in Bone and mineral research, ed Peck W.A. (Elsevier Science Publishers, New York, NY), pp 117\u00e2\u0080\u0093183."},{"key":"2021111508034561000_16.7.859.3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.5.457"},{"key":"2021111508034561000_16.7.859.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81374-4"},{"key":"2021111508034561000_16.7.859.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-390"},{"key":"2021111508034561000_16.7.859.6","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199909)216:1<72::AID-DVDY9>3.0.CO;2-9"},{"key":"2021111508034561000_16.7.859.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00284-7"},{"key":"2021111508034561000_16.7.859.8","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1242\/dev.128.11.2095","article-title":"Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme.","volume":"128","author":"Colvin","year":"2001","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81069-7"},{"key":"2021111508034561000_16.7.859.10","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.15.4213"},{"key":"2021111508034561000_16.7.859.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80257-3"},{"key":"2021111508034561000_16.7.859.12","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90487-5"},{"key":"2021111508034561000_16.7.859.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(00)00074-8"},{"key":"2021111508034561000_16.7.859.14","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0029(19981015)43:2<191::AID-JEMT10>3.0.CO;2-T"},{"key":"2021111508034561000_16.7.859.15","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S8756-3282(99)00189-1","article-title":"Inhibition of terminal chondrocyte differentiation by bone morphogenetic protein 7 (OP-1) in vitro depends on the periarticular region but is independent of parathyroid hormone-related peptide.","volume":"25","author":"Haaijman","year":"1999","journal-title":"Bone"},{"key":"2021111508034561000_16.7.859.16","doi-asserted-by":"publisher","DOI":"10.1038\/78099"},{"key":"2021111508034561000_16.7.859.17","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF00174948","article-title":"The membranous skeleton: The role of cell condensations in vertebrate skeletogenesis.","volume":"186","author":"Hall","year":"1992","journal-title":"Anat. Embryol. (Berl.)"},{"key":"2021111508034561000_16.7.859.18","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(200002)22:2<138::AID-BIES5>3.0.CO;2-4"},{"key":"2021111508034561000_16.7.859.19","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2000.15.1.155"},{"key":"2021111508034561000_16.7.859.20","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3109\/08977199209021540","article-title":"Basic fibroblast growth factor is synthesized and released by isolated ovine fetal growth plate chondrocytes: Potential role as an autocrine mitogen.","volume":"6","author":"Hill","year":"1992","journal-title":"Growth Factors"},{"key":"2021111508034561000_16.7.859.21","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.13.3505"},{"key":"2021111508034561000_16.7.859.22","doi-asserted-by":"crossref","first-page":"5611","DOI":"10.1242\/dev.126.24.5611","article-title":"Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault.","volume":"126","author":"Iseki","year":"1999","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.23","first-page":"1","article-title":"Structural and functional diversity in the FGF receptor multigene family.","volume":"60","author":"Johnson","year":"1993","journal-title":"Adv. Cancer Res."},{"key":"2021111508034561000_16.7.859.24","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.3.277"},{"key":"2021111508034561000_16.7.859.25","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1242\/dev.127.3.543","article-title":"Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways.","volume":"127","author":"Karp","year":"2000","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.26","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/0470846658.ch2","article-title":"Genetic control of skeletal development.","volume":"232","author":"Karsenty","year":"2001","journal-title":"Novartis Found. Symp."},{"key":"2021111508034561000_16.7.859.27","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S8756-3282(99)00111-8","article-title":"Cbfa1 as a regulator of osteoblast differentiation and function.","volume":"25","author":"Karsenty","year":"1999","journal-title":"Bone"},{"key":"2021111508034561000_16.7.859.28","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":"2021111508034561000_16.7.859.29","doi-asserted-by":"publisher","DOI":"10.1038\/82609"},{"key":"2021111508034561000_16.7.859.30","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1242\/dev.125.6.1067","article-title":"Regulation of growth region cartilage proliferation and differentiation by perichondrium.","volume":"125","author":"Long","year":"1998","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.31","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4644(199609)62:3<372::AID-JCB7>3.0.CO;2-O"},{"key":"2021111508034561000_16.7.859.32","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1101\/gad.12.11.1571","article-title":"The roles of FGFs in the early development of vertebrate limbs.","volume":"12","author":"Martin","year":"1998","journal-title":"Genes & Dev."},{"key":"2021111508034561000_16.7.859.33","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1101\/gad.12.20.3156","article-title":"Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless.","volume":"12","author":"Min","year":"1998","journal-title":"Genes & Dev."},{"key":"2021111508034561000_16.7.859.34","doi-asserted-by":"publisher","DOI":"10.1038\/82601"},{"key":"2021111508034561000_16.7.859.35","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1242\/dev.127.5.989","article-title":"Normal limb development in conditional mutants of Fgf4.","volume":"127","author":"Moon","year":"2000","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(00)89088-5"},{"key":"2021111508034561000_16.7.859.37","doi-asserted-by":"crossref","first-page":"D781","DOI":"10.2741\/A321","article-title":"FGF signaling in skeletal development.","volume":"3","author":"Naski","year":"1998","journal-title":"Front. Biosci."},{"key":"2021111508034561000_16.7.859.38","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1242\/dev.125.24.4977","article-title":"Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3.","volume":"125","author":"Naski","year":"1998","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.39","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1242\/dev.124.11.2235","article-title":"The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor.","volume":"124","author":"Ohuchi","year":"1997","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.40","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/0470846658.ch6","article-title":"Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3.","volume":"232","author":"Ornitz","year":"2001","journal-title":"Novartis Found. Symp."},{"key":"2021111508034561000_16.7.859.41","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1186\/gb-2001-2-3-reviews3005","article-title":"Fibroblast growth factors.","volume":"2","author":"Ornitz","year":"2001","journal-title":"Genome Biol."},{"key":"2021111508034561000_16.7.859.42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.25.15292"},{"key":"2021111508034561000_16.7.859.43","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1242\/dev.113.4.1419","article-title":"Developmental expression of two murine fibroblast growth factor receptors, flg and bek.","volume":"113","author":"Orr-Urtreger","year":"1991","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5672"},{"key":"2021111508034561000_16.7.859.45","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1101\/gad.12.17.2735","article-title":"Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities.","volume":"12","author":"Peters","year":"1998","journal-title":"Genes & Dev."},{"key":"2021111508034561000_16.7.859.46","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1242\/dev.114.1.233","article-title":"Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse.","volume":"114","author":"Peters","year":"1992","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.47","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1993.1040"},{"key":"2021111508034561000_16.7.859.48","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":"2021111508034561000_16.7.859.49","first-page":"85","article-title":"Gene expression in osteoblastic cells.","volume":"1","author":"Rodan","year":"1991","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"2021111508034561000_16.7.859.50","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1101\/gad.13.11.1361","article-title":"FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway.","volume":"13","author":"Sahni","year":"1999","journal-title":"Genes & Dev."},{"key":"2021111508034561000_16.7.859.51","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation.","volume":"13","author":"St-Jacques","year":"1999","journal-title":"Genes & Dev."},{"key":"2021111508034561000_16.7.859.52","doi-asserted-by":"publisher","DOI":"10.1038\/75644"},{"key":"2021111508034561000_16.7.859.53","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1002\/jbmr.5650091110","article-title":"Isolation and localization of basic fibroblast growth factor-immunoreactive substance in the epiphyseal growth plate.","volume":"9","author":"Twal","year":"1994","journal-title":"J. Bone Miner. Res."},{"key":"2021111508034561000_16.7.859.54","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":"2021111508034561000_16.7.859.55","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1242\/dev.128.19.3867","article-title":"Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains.","volume":"128","author":"Wang","year":"2001","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.56","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(99)00034-9"},{"key":"2021111508034561000_16.7.859.57","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1242\/dev.127.9.1833","article-title":"Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures.","volume":"127","author":"Xu","year":"2000","journal-title":"Development"},{"key":"2021111508034561000_16.7.859.58","doi-asserted-by":"publisher","DOI":"10.1038\/nm0298-201"}],"container-title":["Genes &amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/gad.965602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T04:36:14Z","timestamp":1704429374000},"score":1,"resource":{"primary":{"URL":"http:\/\/genesdev.cshlp.org\/lookup\/doi\/10.1101\/gad.965602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,4,1]]},"references-count":58,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2002,4,1]]}},"alternative-id":["10.1101\/gad.965602"],"URL":"https:\/\/doi.org\/10.1101\/gad.965602","relation":{},"ISSN":["0890-9369","1549-5477"],"issn-type":[{"value":"0890-9369","type":"print"},{"value":"1549-5477","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,4,1]]}}}