{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:10:35Z","timestamp":1787008235111,"version":"build-2736575974"},"reference-count":34,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T00:00:00Z","timestamp":1556668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T00:00:00Z","timestamp":1556668800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,5]]},"abstract":"\n Background:<\/jats:title>\n Thyroid hormones act in bone and cartilage via thyroid hormone receptor alpha (TR\u03b1). In the absence of triiodothyronine (T3), TR\u03b1 interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TR\u03b1 cause resistance to thyroid hormone alpha (RTH\u03b1; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation, and bone dysplasia. Treatment with thyroxine has been of limited benefit, even in mildly affected individuals, and there is a need for new therapeutic strategies. It was hypothesized that (i) the skeletal manifestations of RTH\u03b1 are mediated by the persistent TR\u03b1\/NCoR1\/HDAC repressor complex containing mutant TR\u03b1, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n The skeletal phenotypes of (i)\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mice, a well characterized model of RTH\u03b1; (ii)\n \n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n mice, which express an NCoR1 mutant that fails to interact with TR\u03b1; and (iii)\n \n Thra1\n PV\/+<\/jats:sup>\n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n double-mutant adult mice were determined. Wild-type,\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n ,\n \n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n , and\n \n Thra1\n PV\/+<\/jats:sup>\n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n double-mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities.\n <\/jats:p>\n <\/jats:sec>\n \n \n Results:<\/jats:bold>\n Thra1\n PV\/+<\/jats:sup>\n <\/jats:title>\n \n mice had a severe skeletal dysplasia, characterized by short stature, abnormal bone morphology, and increased bone mineral content. Despite normal bone length,\n \n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n mice displayed increased cortical bone mass, mineralization, and strength.\n \n Thra1\n PV\/+<\/jats:sup>\n Ncor1\n \u0394ID\/\u0394ID<\/jats:sup>\n <\/jats:italic>\n double-mutant mice displayed only a small improvement of skeletal abnormalities compared to\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bone structure, mineralization, or strength in wild-type or mutant mice.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n These studies indicate treatment with SAHA is unlikely to improve the skeletal manifestations of RTH\u03b1. Nevertheless, the findings (i) confirm that TR\u03b11 has a critical role in the regulation of skeletal development and adult bone mass, (ii) suggest a physiological role for alternative co-repressors that interact with TR in skeletal cells, and (iii) demonstrate a novel role for NCoR1 in the regulation of adult bone mass and strength.<\/jats:p>\n <\/jats:sec>","DOI":"10.1089\/thy.2018.0399","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T04:38:26Z","timestamp":1550119106000},"page":"726-734","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic and Pharmacological Targeting of Transcriptional Repression in Resistance to Thyroid Hormone Alpha"],"prefix":"10.1177","volume":"29","author":[{"given":"Bernard","family":"Freudenthal","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samiksha","family":"Shetty","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie C.","family":"Butterfield","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Logan","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cho Rong","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuguang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Astapova","sequence":"additional","affiliation":[{"name":"Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony N.","family":"Hollenberg","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine and New York Presbyterian\/Weill Cornell Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheue-Yann","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.H. Duncan","family":"Bassett","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham R.","family":"Williams","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,5,13]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2015-1106"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110296"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1120"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2215"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70111-1"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2017.0157"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102936"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2015.0463"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1404"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2017.02.001"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1113940"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1050"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.07.001"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00129-14"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-2156"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.230285997"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261565798"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804604105"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2009.02.028"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0462"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222334110"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt660"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911346107"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-415-5_29"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1814"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706801115"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2004.04.020"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2317"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107474108"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01208-14"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706917114"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603463"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.734"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0224"}],"container-title":["Thyroid\u00ae"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/thy.2018.0399","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2018.0399","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2018.0399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:05:03Z","timestamp":1777586703000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/thy.2018.0399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1089\/thy.2018.0399"],"URL":"https:\/\/doi.org\/10.1089\/thy.2018.0399","relation":{},"ISSN":["1050-7256","1557-9077"],"issn-type":[{"value":"1050-7256","type":"print"},{"value":"1557-9077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5]]}}}