{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:33:36Z","timestamp":1790775216598,"version":"4.1.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,8]],"date-time":"2013-08-08T00:00:00Z","timestamp":1375920000000},"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":[[2014,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage-capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss-of-function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte-specific manner using a tamoxifen-inducible system. We found tumor-like nodules on the hands and feet within a month after the initial induction. The SHP2-deficient mice demonstrated an exostosis-like and enchondroma-like phenotype in multiple bones of the hands, feet, and ribs as assessed by X-ray and micro-computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). At molecular levels, we observed an abundant expression of Indian hedgehog protein (IHH) and fibroblast growth factor 2 (FGF2) and impaired expression of mitogen-activated protein kinases (MAPK) in the affected cartilage nodules in the SHP2-deficient mice. In summary, we have generated a mouse model of metachondromatosis that includes manifestations of exostosis and enchondroma. This study provides a novel model for the investigation of the pathophysiology of the disease and advances the understanding of metachondromatosis. This model will be useful to identify molecular mechanisms for the disease cause and progression as well as to develop new therapeutic strategies in the future. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2062","type":"journal-article","created":{"date-parts":[[2013,8,8]],"date-time":"2013-08-08T13:16:55Z","timestamp":1375967815000},"page":"761-769","source":"Crossref","is-referenced-by-count":47,"title":["Targeted Disruption of <i>Shp2<\/i> in Chondrocytes Leads to Metachondromatosis With Multiple Cartilaginous Protrusions"],"prefix":"10.1093","volume":"29","author":[{"given":"Harry KW","family":"Kim","sequence":"first","affiliation":[{"name":"Orthopaedic SurgeryUniversity of Texas Southwestern Medical CenterDallasTXUSA"},{"name":"Texas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen-Sheng","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pathology and Division of Biological SciencesUniversity of California San DiegoLa JollaCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of BiochemistryRush University Medical CenterChicagoILUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D","family":"King","sequence":"additional","affiliation":[{"name":"Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Kamiya","sequence":"additional","affiliation":[{"name":"Orthopaedic SurgeryUniversity of Texas Southwestern Medical CenterDallasTXUSA"},{"name":"Texas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,8,8]]},"reference":[{"issue":"4","key":"2024020318564349400_jbmr2062-bib-0001","doi-asserted-by":"crossref","first-page":"e1002050","DOI":"10.1371\/journal.pgen.1002050","article-title":"Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome","volume":"7","author":"Bowen","year":"2011","journal-title":"PLoS Genet."},{"issue":"6","key":"2024020318564349400_jbmr2062-bib-0002","doi-asserted-by":"crossref","first-page":"e1000991","DOI":"10.1371\/journal.pgen.1000991","article-title":"Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene","volume":"6","author":"Sobreira","year":"2010","journal-title":"PLoS Genet."},{"issue":"2","key":"2024020318564349400_jbmr2062-bib-0003","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/ng1095-137","article-title":"Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1)","volume":"11","author":"Ahn","year":"1995","journal-title":"Nat Genet."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0004","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1148\/radiology.148.1.6602353","article-title":"Metachondromatosis","volume":"148","author":"Kennedy","year":"1983","journal-title":"Radiology."},{"issue":"5","key":"2024020318564349400_jbmr2062-bib-0005","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/BF00197421","article-title":"Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3","volume":"96","author":"Dechert","year":"1995","journal-title":"Hum Genet."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0006","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","article-title":"The RASopathies: developmental syndromes of Ras\/MAPK pathway dysregulation","volume":"19","author":"Tidyman","year":"2009","journal-title":"Curr Opin Genet Dev."},{"issue":"8","key":"2024020318564349400_jbmr2062-bib-0007","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/humu.20748","article-title":"The RAS\/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders","volume":"29","author":"Aoki","year":"2008","journal-title":"Hum Mutat."},{"issue":"6","key":"2024020318564349400_jbmr2062-bib-0008","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1073\/pnas.90.6.2197","article-title":"A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains","volume":"90","author":"Ahmad","year":"1993","journal-title":"Proc Natl Acad Sci USA."},{"issue":"10","key":"2024020318564349400_jbmr2062-bib-0009","doi-asserted-by":"crossref","first-page":"6075","DOI":"10.1128\/MCB.18.10.6075","article-title":"Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells","volume":"18","author":"Qu","year":"1998","journal-title":"Mol Cell Biol."},{"issue":"9","key":"2024020318564349400_jbmr2062-bib-0010","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1093\/emboj\/16.9.2352","article-title":"Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2","volume":"16","author":"Saxton","year":"1997","journal-title":"EMBO.J."},{"issue":"2","key":"2024020318564349400_jbmr2062-bib-0011","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1242\/dmm.006130","article-title":"Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations","volume":"4","author":"Bauler","year":"2011","journal-title":"Dis Model Mech."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0012","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/dvg.20261","article-title":"Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase","volume":"45","author":"Chen","year":"2007","journal-title":"Genesis."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0013","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/5007","article-title":"Generalized lacZ expression with the ROSA26 Cre reporter strain","volume":"21","author":"Soriano","year":"1999","journal-title":"Nat Genet."},{"issue":"4","key":"2024020318564349400_jbmr2062-bib-0014","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods."},{"issue":"12","key":"2024020318564349400_jbmr2062-bib-0015","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1359\/jbmr.080809","article-title":"Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass","volume":"23","author":"Kamiya","year":"2008","journal-title":"J Bone Miner Res."},{"issue":"2","key":"2024020318564349400_jbmr2062-bib-0016","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1359\/jbmr.090806","article-title":"Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts","volume":"25","author":"Kamiya","year":"2010","journal-title":"J Bone Miner Res."},{"issue":"22","key":"2024020318564349400_jbmr2062-bib-0017","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1242\/dev.025825","article-title":"BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway","volume":"135","author":"Kamiya","year":"2008","journal-title":"Development."},{"issue":"7","key":"2024020318564349400_jbmr2062-bib-0018","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nrc2869","article-title":"Cartilage tumours and bone development: molecular pathology and possible therapeutic targets","volume":"10","author":"Bovee","year":"2010","journal-title":"Nat Rev Cancer."},{"issue":"24","key":"2024020318564349400_jbmr2062-bib-0019","doi-asserted-by":"crossref","first-page":"10932","DOI":"10.1073\/pnas.0914642107","article-title":"A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses","volume":"107","author":"Matsumoto","year":"2010","journal-title":"Proc Natl Acad Sci USA."},{"issue":"6937","key":"2024020318564349400_jbmr2062-bib-0020","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0021","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/1529-0131(200101)44:1<85::AID-ANR12>3.0.CO;2-6","article-title":"Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age","volume":"44","author":"De Bari","year":"2001","journal-title":"Arthritis Rheum."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0022","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1053\/joca.2000.0378","article-title":"Localization of chondrocyte precursors in periosteum","volume":"9","author":"Ito","year":"2001","journal-title":"Osteoarthritis Cartilage."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0023","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ng0996-25","article-title":"The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes","volume":"14","author":"Stickens","year":"1996","journal-title":"Nat Genet."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0024","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1002\/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K","article-title":"Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes","volume":"15","author":"Wuyts","year":"2000","journal-title":"Hum Mutat."},{"issue":"1","key":"2024020318564349400_jbmr2062-bib-0025","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.gde.2006.12.011","article-title":"The role of Shp2 (PTPN11) in cancer","volume":"17","author":"Mohi","year":"2007","journal-title":"Curr Opin Genet Dev."},{"issue":"6","key":"2024020318564349400_jbmr2062-bib-0026","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/humu.9149","article-title":"A novel PTPN11 mutation in LEOPARD syndrome","volume":"21","author":"Conti","year":"2003","journal-title":"Hum Mutat."},{"key":"2024020318564349400_jbmr2062-bib-0027","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.genom.6.080604.162305","article-title":"Noonan syndrome and related disorders: genetics and pathogenesis","volume":"6","author":"Tartaglia","year":"2005","journal-title":"Annu Rev Genomics Hum Genet."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0028","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/ng844","article-title":"A mutant PTH\/PTHrP type I receptor in enchondromatosis","volume":"30","author":"Hopyan","year":"2002","journal-title":"Nat Genet."},{"issue":"24","key":"2024020318564349400_jbmr2062-bib-0029","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1242\/dev.128.24.5099","article-title":"Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation","volume":"128","author":"Long","year":"2001","journal-title":"Development."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0030","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S1534-5807(02)00261-7","article-title":"Interaction of FGF, Ihh\/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation","volume":"3","author":"Minina","year":"2002","journal-title":"Dev Cell."},{"issue":"3","key":"2024020318564349400_jbmr2062-bib-0031","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.cellsig.2007.10.002","article-title":"The molecular functions of Shp2 in the Ras\/Mitogen-activated protein kinase (ERK1\/2) pathway","volume":"20","author":"Dance","year":"2008","journal-title":"Cell Signal."}],"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.2062","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/29\/3\/761\/56567193\/jbmr2062.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/29\/3\/761\/56567193\/jbmr2062.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:50:13Z","timestamp":1710341413000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/29\/3\/761-769\/7599126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,8]]},"references-count":31,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2013,8,8]]},"published-print":{"date-parts":[[2014,3,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2062","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,3,1]]},"published":{"date-parts":[[2013,8,8]]}}}