{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:10:09Z","timestamp":1789848609712,"version":"4.0.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T00:00:00Z","timestamp":1343260800000},"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":[[2013,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fibroblast growth factor 23 (FGF23) is responsible for phosphate wasting and the phenotypic changes observed in human diseases such as X-linked hypophosphatemia (XLH). Targeted overexpression of nuclear high\u2013molecular weight fibroblast growth factor 2 isoforms (HMW isoforms) in osteoblasts resulted in a transgenic mouse with phenotypic changes similar to XLH, including increased FGF23, hypophosphatemia, and rickets\/osteomalacia. The goal of this study was to assess whether HMW isoforms also reduced mineralized bone formation via phosphate-independent effects in bone marrow stromal cells (BMSCs) by modulating FGF23\/FGF receptor (FGFR)\/extracellular signal-regulated kinase (ERK) signaling. To determine if decreased bone formation in BMSC cultures from HMW transgenic mice could be rescued by blocking this pathway, an FGF23 neutralizing antibody, the FGFR tyrosine kinase inhibitor SU5402 and the mitogen-activated protein kinase (MAPK) inhibitor PD98059 were used. FGF23 levels in the conditioned medium of HMW BMSC cultures were dramatically increased compared to BMSC from control (Vector) mice. Mineralized nodule formation was significantly decreased in HMW BMSC cultures compared with control cultures. The decreased nodule formation in HMW cultures was partially rescued by the FGF23 neutralizing antibody, SU5402 and PD98059. mRNA levels for the osteoblast-related genes, osteocalcin, Runt-related transcription factor 2 (Runx2), and osterix, and the osteocyte-related gene dentin matrix acidic phosphoprotein 1 (Dmp1) were significantly decreased in HMW cultures compared with control cultures, and the decreases were partially rescued by SU5402 or PD98059 treatment. Matrix-gla-protein (Mgp) mRNA was significantly higher in HMW cultures compared with control cultures, reduced by SU5402, but further increased by PD98059. Our results suggest that phosphate-independent effects of HMW isoforms in vitro may be directly mediated in part via FGF23 and that HMW isoforms signal via FGF23\/FGFR\/MAPK to inhibit bone formation in vitro. \u00a9 2013 American Society for Bone and Mineral Research<\/jats:p>","DOI":"10.1002\/jbmr.1721","type":"journal-article","created":{"date-parts":[[2012,7,27]],"date-time":"2012-07-27T05:02:07Z","timestamp":1343365327000},"page":"35-45","source":"Crossref","is-referenced-by-count":54,"title":["Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23\/FGFR\/MAPK in vitro"],"prefix":"10.1093","volume":"28","author":[{"given":"Liping","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alycia","family":"Esliger","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja M","family":"Hurley","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,7,26]]},"reference":[{"issue":"3","key":"2024020318452272700_bib1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1210\/endo-124-3-1539","article-title":"Cultured bovine bone cells synthesize basic fibroblast growth factor and store it in their extracellular matrix","volume":"124","author":"Globus","year":"1989","journal-title":"Endocrinology"},{"issue":"11","key":"2024020318452272700_bib2","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1073\/pnas.86.11.3978","article-title":"Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons","volume":"86","author":"Florkiewicz","year":"1989","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2024020318452272700_bib3","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1091\/mbc.10.5.1429","article-title":"Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals","volume":"10","author":"Arese","year":"1999","journal-title":"Mol Biol Cell"},{"issue":"12","key":"2024020318452272700_bib4","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1091\/mbc.6.12.1861","article-title":"Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice","volume":"6","author":"Coffin","year":"1995","journal-title":"Mol Biol Cell"},{"issue":"1","key":"2024020318452272700_bib5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/jcb.20389","article-title":"Over-expression of fibroblast growth factor-2 causes defective bone mineralization and osteopenia in transgenic mice","volume":"95","author":"Sobue","year":"2005","journal-title":"J Cell Biochem"},{"issue":"5","key":"2024020318452272700_bib6","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1074\/jbc.M804900200","article-title":"Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice","volume":"284","author":"Xiao","year":"2009","journal-title":"J Biol Chem"},{"issue":"4","key":"2024020318452272700_bib7","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1074\/jbc.M109.030577","article-title":"Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO","volume":"285","author":"Xiao","year":"2010","journal-title":"J Biol Chem"},{"issue":"7","key":"2024020318452272700_bib8","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1210\/en.2003-1768","article-title":"Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis","volume":"145","author":"Larsson","year":"2004","journal-title":"Endocrinology"},{"issue":"12","key":"2024020318452272700_bib9","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1073\/pnas.73.12.4667","article-title":"Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets","volume":"73","author":"Eicher","year":"1976","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2024020318452272700_bib10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11914-011-0053-4","article-title":"FGF23 in skeletal modeling and remodeling","volume":"9","author":"Lu","year":"2011","journal-title":"Curr Osteoporos Rep"},{"issue":"2","key":"2024020318452272700_bib11","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.bone.2010.05.021","article-title":"Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells","volume":"47","author":"Xiao","year":"2010","journal-title":"Bone"},{"key":"2024020318452272700_bib12","first-page":"481","volume-title":"Theory and practice of histotechnology","author":"Sheehan","year":"1980","edition":"2nd ed"},{"issue":"3","key":"2024020318452272700_bib13","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/jbmr.5650090306","article-title":"Bone marrow from mechanically unloaded rat bones expresses reduced osteogenic capacity in vitro","volume":"9","author":"Keila","year":"1994","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2024020318452272700_bib14","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ab.2004.02.002","article-title":"An Alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction","volume":"329","author":"Gregory","year":"2004","journal-title":"Anal Biochem"},{"issue":"9","key":"2024020318452272700_bib15","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res"},{"issue":"6","key":"2024020318452272700_bib16","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1359\/jbmr.080220","article-title":"Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro","volume":"23","author":"Wang","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"4","key":"2024020318452272700_bib17","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/jcb.10606","article-title":"Integrative nuclear FGFR1 signaling (INFS) as a part of a universal \u201cfeed-forward-and-gate\u201d signaling module that controls cell growth and differentiation","volume":"90","author":"Stachowiak","year":"2003","journal-title":"J Cell Biochem"},{"issue":"9","key":"2024020318452272700_bib18","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1091\/mbc.e08-06-0600","article-title":"Fibroblast growth factor receptor-1 (FGFR1) nuclear dynamics reveal a novel mechanism in transcription control","volume":"20","author":"Dunham-Ems","year":"2009","journal-title":"Mol Biol Cell"},{"issue":"25","key":"2024020318452272700_bib19","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"},{"issue":"4","key":"2024020318452272700_bib20","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/j.1744-9987.2005.00287.x","article-title":"Fibroblast growth factor 23 and its receptors","volume":"9","author":"Yu","year":"2005","journal-title":"Ther Apher Dial"},{"issue":"6","key":"2024020318452272700_bib21","first-page":"555","article-title":"[Fibroblast growth factor (FGF) 23 works as a phosphate-regulating hormone and is involved in the pathogenesis of several disorders of phosphate metabolism]","volume":"55","author":"Fukumoto","year":"2007","journal-title":"Rinsho Byori"},{"issue":"12","key":"2024020318452272700_bib22","first-page":"4003","article-title":"The parathyroid is a target organ for FGF23 in rats","volume":"117","author":"Ben-Dov","year":"2007","journal-title":"J Clin Invest"},{"issue":"31","key":"2024020318452272700_bib23","doi-asserted-by":"crossref","first-page":"28265","DOI":"10.1074\/jbc.M202527200","article-title":"Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway","volume":"277","author":"Yamashita","year":"2002","journal-title":"J Biol Chem"},{"issue":"10","key":"2024020318452272700_bib24","doi-asserted-by":"crossref","first-page":"6120","DOI":"10.1074\/jbc.C500457200","article-title":"Regulation of fibroblast growth factor-23 signaling by klotho","volume":"281","author":"Kurosu","year":"2006","journal-title":"J Biol Chem"},{"issue":"7120","key":"2024020318452272700_bib25","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/nature05315","article-title":"Klotho converts canonical FGF receptor into a specific receptor for FGF23","volume":"444","author":"Urakawa","year":"2006","journal-title":"Nature"},{"issue":"2","key":"2024020318452272700_bib26","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s00223-011-9501-5","article-title":"Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization","volume":"89","author":"Shalhoub","year":"2011","journal-title":"Calcif Tissue Int"},{"issue":"6655","key":"2024020318452272700_bib27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse klotho gene leads to a syndrome resembling ageing","volume":"390","author":"Kuro-o","year":"1997","journal-title":"Nature"},{"issue":"1","key":"2024020318452272700_bib28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0092-8674(01)00622-5","article-title":"The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation","volume":"108","author":"Nakashima","year":"2002","journal-title":"Cell"},{"key":"2024020318452272700_bib29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.gene.2005.12.022","article-title":"Runx2-mediated regulation of the zinc finger Osterix\/Sp7 gene","volume":"372","author":"Nishio","year":"2006","journal-title":"Gene"},{"issue":"4","key":"2024020318452272700_bib30","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/jcb.21900","article-title":"Progressive recruitment of Runx2 to genomic targets despite decreasing expression during osteoblast differentiation","volume":"105","author":"Pregizer","year":"2008","journal-title":"J Cell Biochem"},{"issue":"3\u20134","key":"2024020318452272700_bib31","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1159\/000091378","article-title":"Role of matrix Gla protein in parathyroid hormone inhibition of osteoblast mineralization","volume":"181","author":"Gopalakrishnan","year":"2005","journal-title":"Cells Tissues Organs"},{"issue":"6","key":"2024020318452272700_bib32","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1002\/jcb.10589","article-title":"Effect of overexpressing fibroblast growth factor 2 protein isoforms in osteoblastic ROS 17\/2.8 cells","volume":"89","author":"Xiao","year":"2003","journal-title":"J Cell Biochem"},{"issue":"9","key":"2024020318452272700_bib33","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1210\/me.2009-0085","article-title":"Novel regulators of Fgf23 expression and mineralization in Hyp bone","volume":"23","author":"Liu","year":"2009","journal-title":"Mol Endocrinol"},{"issue":"1","key":"2024020318452272700_bib34","doi-asserted-by":"crossref","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"},{"issue":"3","key":"2024020318452272700_bib35","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1046\/j.1471-4159.2002.00833.x","article-title":"Integrative nuclear FGFR1 signaling (INFS) pathway mediates activation of the tyrosine hydroxylase gene by angiotensin II, depolarization and protein kinase C","volume":"81","author":"Peng","year":"2002","journal-title":"J Neurochem"},{"issue":"6961","key":"2024020318452272700_bib36","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/nature02079","article-title":"Bone recognition mechanism of porcine osteocalcin from crystal structure","volume":"425","author":"Hoang","year":"2003","journal-title":"Nature"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.1721","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/1\/35\/56564200\/1721_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/1\/35\/56564200\/1721_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:47:35Z","timestamp":1710341255000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/28\/1\/35-45\/7598755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,26]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2012,7,26]]},"published-print":{"date-parts":[[2013,1,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.1721","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,1,1]]},"published":{"date-parts":[[2012,7,26]]}}}