{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:10:13Z","timestamp":1792606213921,"version":"4.5.0"},"reference-count":40,"publisher":"American Society for Clinical Investigation","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,7]]},"abstract":"<jats:p>\n                    During endochondral bone formation, chondrocyte hypertrophy represents a crucial turning point from chondrocyte differentiation to bone formation. Both parathyroid hormone-related protein (PTHrP) and histone deacetylase 4 (HDAC4) inhibit chondrocyte hypertrophy. Using multiple mouse genetics models, we demonstrate in vivo that HDAC4 is required for the effects of PTHrP on chondrocyte differentiation. We further show in vivo that PTHrP leads to reduced HDAC4 phosphorylation at the 14-3-3\u2013binding sites and subsequent HDAC4 nuclear translocation. The\n                    <jats:italic>Hdac4<\/jats:italic>\n                    -KO mouse shares a similar but milder phenotype with the\n                    <jats:italic>Pthrp<\/jats:italic>\n                    -KO mouse, indicating the possible existence of other mediators of PTHrP action. We identify HDAC5 as an additional mediator of PTHrP signaling. While the\n                    <jats:italic>Hdac5<\/jats:italic>\n                    -KO mouse has no growth plate phenotype at birth, the KO of\n                    <jats:italic>Hdac5<\/jats:italic>\n                    in addition to the KO of\n                    <jats:italic>Hdac4<\/jats:italic>\n                    is required to block fully PTHrP action on chondrocyte differentiation at birth in vivo. Finally, we show that PTHrP suppresses myocyte enhancer factor 2 (Mef2) action that allows runt-related transcription factor 2 (\n                    <jats:italic>Runx2<\/jats:italic>\n                    ) mRNA expression needed for chondrocyte hypertrophy. Our results demonstrate that PTHrP inhibits chondrocyte hypertrophy and subsequent bone formation in vivo by allowing HDAC4 and HDAC5 to block the Mef2\/Runx2 signaling cascade. These results explain the phenotypes of several genetic abnormalities in humans.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.97903","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T11:02:59Z","timestamp":1551870179000},"source":"Crossref","is-referenced-by-count":51,"title":["PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3393-3515","authenticated-orcid":true,"given":"Shigeki","family":"Nishimori","sequence":"first","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0159-7673","authenticated-orcid":true,"given":"Forest","family":"Lai","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieno","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Kozhemyakina","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tso-Pang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Lassar","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry M.","family":"Kronenberg","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,3,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11706"},{"issue":"12","key":"B3","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1242\/dev.129.12.2977","article-title":"PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps","volume":"129","author":"Kobayashi","year":"2002","journal-title":"Development"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3067"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2014.03.014"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2010.07.010"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM194111132252007"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.3616618"},{"issue":"18","key":"B9","doi-asserted-by":"crossref","first-page":"8557","DOI":"10.1016\/S0021-9258(18)68339-5","article-title":"The parathyroid hormone-like peptide associated with humoral hypercalcemia of malignancy and parathyroid hormone bind to the same receptor on the plasma membrane of ROS 17\/2.8 cells","volume":"263","author":"J\u00fcppner","year":"1988","journal-title":"J Biol Chem"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.3.277"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5275.663"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2918"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.19.10240"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2485"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.140199597"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.19.8467-8476.2004"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.05.040"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00861-9"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.10.024"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2007.02.004"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00415-09"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.01.023"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.07.011"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<145::AID-GENE14>3.0.CO;2-C"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31960"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02480"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706268200"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.12.6361"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2240"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80258-5"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80259-7"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1174704"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1242\/dev.072652"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.456996"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.7701349"},{"key":"B36","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-8-141","article-title":"Brachydactyly E: isolated or as a feature of a syndrome","volume":"8","author":"Pereda","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1617"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.2.225"},{"key":"B39","first-page":"10","article-title":"Simplified in situ hybridization protocol using non-radioactively labeled probes to detect abundant and rare mRNAs on tissue sections","volume":"1","author":"Braissant","year":"1998","journal-title":"BIOCHEMICA"},{"key":"B40"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/97903\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:34:14Z","timestamp":1779194054000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/97903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,7]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,3,7]]},"published-print":{"date-parts":[[2019,3,7]]}},"alternative-id":["10.1172\/jci.insight.97903"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.97903","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,7]]},"article-number":"e97903"}}