{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T20:41:59Z","timestamp":1783716119848,"version":"3.55.0"},"reference-count":45,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:p>Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2\u2212\/\u2212 mice and determined its skeletal expression in T3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2\u2212\/\u2212 mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TR\u03b1, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TR\u03b1 and TR\u03b2 knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.<\/jats:p>","DOI":"10.1210\/en.2011-1814","type":"journal-article","created":{"date-parts":[[2012,5,17]],"date-time":"2012-05-17T17:16:03Z","timestamp":1337274963000},"page":"3537-3548","source":"Crossref","is-referenced-by-count":23,"title":["Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function"],"prefix":"10.1210","volume":"153","author":[{"given":"J. H. Duncan","family":"Bassett","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Group (J.H.D.B., J.G.L., M.S.C., G.R.W.), Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Logan","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Group (J.H.D.B., J.G.L., M.S.C., G.R.W.), Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Boyde","sequence":"first","affiliation":[{"name":"Centre for Oral Growth and Development (A.B.), Queen Mary College, University of London, London E1 4NS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moira S.","family":"Cheung","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Group (J.H.D.B., J.G.L., M.S.C., G.R.W.), Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Evans","sequence":"first","affiliation":[{"name":"The Mellanby Centre for Bone Research (H.E., P.C.), Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Croucher","sequence":"first","affiliation":[{"name":"The Mellanby Centre for Bone Research (H.E., P.C.), Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom"},{"name":"Garvan Institute for Medical Research (P.C.), Sydney, New South Wales 2010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-yang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Genetics (X.S., S.X., Y.M.), Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Genetics (X.S., S.X., Y.M.), Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiharu","family":"Murata","sequence":"first","affiliation":[{"name":"Department of Genetics (X.S., S.X., Y.M.), Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham R.","family":"Williams","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Group (J.H.D.B., J.G.L., M.S.C., G.R.W.), Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2012,5,16]]},"reference":[{"key":"2020071612442725100_B1","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1101\/gad.14.13.1595","article-title":"A conserved family of calcineurin regulators.","volume":"14","author":"Kingsbury","year":"2000","journal-title":"Genes Dev"},{"key":"2020071612442725100_B2","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1096\/fj.06-7246com","article-title":"Renaming the DSCR1\/Adapt78 gene family as RCAN: regulators of calcineurin.","volume":"21","author":"Davies","year":"2007","journal-title":"FASEB J"},{"key":"2020071612442725100_B3","doi-asserted-by":"crossref","first-page":"6270","DOI":"10.1073\/pnas.76.12.6270","article-title":"Calcineurin: a calcium- and calmodulin-binding protein of the nervous system.","volume":"76","author":"Klee","year":"1979","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612442725100_B4","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S0092-8674(00)80571-1","article-title":"Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT.","volume":"96","author":"Crabtree","year":"1999","journal-title":"Cell"},{"key":"2020071612442725100_B5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1124\/mi.6.4.4","article-title":"The calcineurin-NFAT pathway and bone: intriguing new findings.","volume":"6","author":"Stern","year":"2006","journal-title":"Mol Interv"},{"key":"2020071612442725100_B6","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1093\/hmg\/9.11.1681","article-title":"DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways.","volume":"9","author":"Fuentes","year":"2000","journal-title":"Hum Mol Genet"},{"key":"2020071612442725100_B7","doi-asserted-by":"crossref","first-page":"8719","DOI":"10.1074\/jbc.275.12.8719","article-title":"A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling.","volume":"275","author":"Rothermel","year":"2000","journal-title":"J Biol Chem"},{"key":"2020071612442725100_B8","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1196\/annals.1402.071","article-title":"The role of NFAT in osteoclast formation.","volume":"1116","author":"Takayanagi","year":"2007","journal-title":"Ann NY Acad Sci"},{"key":"2020071612442725100_B9","doi-asserted-by":"crossref","first-page":"17130","DOI":"10.1073\/pnas.0508480102","article-title":"Calcineurin regulates bone formation by the osteoblast.","volume":"102","author":"Sun","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612442725100_B10","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nm1270","article-title":"NFAT and Osterix cooperatively regulate bone formation.","volume":"11","author":"Koga","year":"2005","journal-title":"Nat Med"},{"key":"2020071612442725100_B11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.devcel.2006.04.006","article-title":"Calcineurin\/NFAT signaling in osteoblasts regulates bone mass.","volume":"10","author":"Winslow","year":"2006","journal-title":"Dev Cell"},{"key":"2020071612442725100_B12","doi-asserted-by":"crossref","first-page":"35318","DOI":"10.1074\/jbc.M702435200","article-title":"Conditional disruption of calcineurin B1 in osteoblasts increases bone formation and reduces bone resorption.","volume":"282","author":"Yeo","year":"2007","journal-title":"J Biol Chem"},{"key":"2020071612442725100_B13","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/j.bone.2007.02.017","article-title":"Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation.","volume":"40","author":"Yeo","year":"2007","journal-title":"Bone"},{"key":"2020071612442725100_B14","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/00002281-199505000-00018","article-title":"Organ transplantation and osteoporosis.","volume":"7","author":"Epstein","year":"1995","journal-title":"Curr Opin Rheumatol"},{"key":"2020071612442725100_B15","doi-asserted-by":"crossref","first-page":"14567","DOI":"10.1074\/jbc.271.24.14567","article-title":"Molecular cloning of a novel thyroid hormone-responsive gene, ZAKI-4, in human skin fibroblasts.","volume":"271","author":"Miyazaki","year":"1996","journal-title":"J Biol Chem"},{"key":"2020071612442725100_B16","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1042\/bj20011797","article-title":"Novel human ZAKI-4 isoforms: hormonal and tissue-specific regulation and function as calcineurin inhibitors.","volume":"367","author":"Cao","year":"2002","journal-title":"Biochem J"},{"key":"2020071612442725100_B17","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1210\/me.2004-0093","article-title":"Thyroid hormone induces rapid activation of Akt\/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts.","volume":"19","author":"Cao","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B18","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1210\/endo.142.5.8156","article-title":"Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism.","volume":"142","author":"Siddiq","year":"2001","journal-title":"Endocrinology"},{"key":"2020071612442725100_B19","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1530\/eje.0.1500371","article-title":"Genomic organization of mouse ZAKI-4 gene that encodes ZAKI-4 \u03b1 and \u03b2 isoforms, endogenous calcineurin inhibitors, and changes in the expression of these isoforms by thyroid hormone in adult mouse brain and heart.","volume":"150","author":"Mizuno","year":"2004","journal-title":"Eur J Endocrinol"},{"key":"2020071612442725100_B20","doi-asserted-by":"crossref","first-page":"E61","DOI":"10.1161\/01.RES.87.12.e61","article-title":"Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles.","volume":"87","author":"Yang","year":"2000","journal-title":"Circ Res"},{"key":"2020071612442725100_B21","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1677\/JME-08-0142","article-title":"The skeletal phenotypes of TR\u03b1 and TR\u03b2 mutant mice.","volume":"42","author":"Bassett","year":"2009","journal-title":"J Mol Endocrinol"},{"key":"2020071612442725100_B22","doi-asserted-by":"crossref","first-page":"e14605","DOI":"10.1371\/journal.pone.0014605","article-title":"Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake.","volume":"6","author":"Sun","year":"2011","journal-title":"PLoS One"},{"key":"2020071612442725100_B23","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1210\/me.2005-0224","article-title":"Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor \u03b11 or \u03b2.","volume":"19","author":"O'Shea","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B24","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1210\/me.2002-0296","article-title":"A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone.","volume":"17","author":"O'Shea","year":"2003","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B25","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1210\/me.2007-0157","article-title":"Thyroid status during skeletal development determines adult bone structure and mineralization.","volume":"21","author":"Bassett","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B26","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1210\/me.2007-0033","article-title":"Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism.","volume":"21","author":"Bassett","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B27","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1210\/me.2007-0221","article-title":"A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism.","volume":"22","author":"Bassett","year":"2008","journal-title":"Mol Endocrinol"},{"key":"2020071612442725100_B28","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1073\/pnas.0911346107","article-title":"Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts.","volume":"107","author":"Bassett","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612442725100_B29","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1359\/JBMR.040514","article-title":"Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone.","volume":"19","author":"Dai","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2020071612442725100_B30","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jbiomech.2004.04.020","article-title":"A comparison of mechanical properties derived from multiple skeletal sites in mice.","volume":"38","author":"Schriefer","year":"2005","journal-title":"J Biomech"},{"key":"2020071612442725100_B31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.bone.2004.03.027","article-title":"Morphological and mechanical properties of caudal vertebrae in the SAMP6 mouse model of senile osteoporosis.","volume":"35","author":"Silva","year":"2004","journal-title":"Bone"},{"key":"2020071612442725100_B32","doi-asserted-by":"crossref","first-page":"6222","DOI":"10.1128\/MCB.22.17.6222-6233.2002","article-title":"High bone resorption in adult aging transgenic mice overexpressing cbfa1\/runx2 in cells of the osteoblastic lineage.","volume":"22","author":"Geoffroy","year":"2002","journal-title":"Mol Cell Biol"},{"key":"2020071612442725100_B33","doi-asserted-by":"crossref","first-page":"13453","DOI":"10.1073\/pnas.95.23.13453","article-title":"Impaired osteoclastic bone resorption leads to osteoporosis in cathepsin-K-deficient mice.","volume":"95","author":"Saftig","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612442725100_B34","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1080\/00480169.2005.36489","article-title":"Musculoskeletal responses of 2-year-old Thoroughbred horses to early training. 8. Quantitative back-scattered electron scanning electron microscopy and confocal fluorescence microscopy of the epiphysis of the third metacarpal bone.","volume":"53","author":"Boyde","year":"2005","journal-title":"N Z Vet J"},{"key":"2020071612442725100_B35","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/8756-3282(95)00119-X","article-title":"Mineral density quantitation of the human cortical iliac crest by backscattered electron image analysis: variations with age, sex, and degree of osteoarthritis.","volume":"16","author":"Boyde","year":"1995","journal-title":"Bone"},{"key":"2020071612442725100_B36","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s002239900600","article-title":"The mineralization density of iliac crest bone from children with osteogenesis imperfecta.","volume":"64","author":"Boyde","year":"1999","journal-title":"Calcif Tissue Int"},{"key":"2020071612442725100_B37","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.joca.2007.04.003","article-title":"Variations in articular calcified cartilage by site and exercise in the 18-month-old equine distal metacarpal condyle.","volume":"15","author":"Doube","year":"2007","journal-title":"Osteoarthritis Cartilage"},{"key":"2020071612442725100_B38","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1210\/en.2005-0485","article-title":"Thyroid hormone regulates heparin sulfate proteoglycan expression in the growth plate.","volume":"147","author":"Bassett","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612442725100_B39","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.1128\/MCB.20.22.8329-8342.2000","article-title":"Cloning and characterization of two novel thyroid hormone receptor \u03b2 isoforms.","volume":"20","author":"Williams","year":"2000","journal-title":"Mol Cell Biol"},{"key":"2020071612442725100_B40","doi-asserted-by":"crossref","unstructured":"O'Shea PJ , BassettJHD , ChengSY , WilliamsGR 2006 Characterization of skeletal phenotypes of TR\u03b11PV and TR\u03b2PV mutant mice: implications for tissue thyroid status and T3 target gene expression. Nuclear Receptor Signaling 4:e011(http:\/\/www.nursa.org\/article.cfm?doi=010.1621\/nrs.04011)","DOI":"10.1621\/nrs.04011"},{"key":"2020071612442725100_B41","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.bone.2009.11.032","article-title":"Time sequence of secondary mineralization and microhardness in cortical and cancellous bone from ewes.","volume":"46","author":"Bala","year":"2010","journal-title":"Bone"},{"key":"2020071612442725100_B42","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1007\/s00198-009-0861-x","article-title":"Influence of remodeling on the mineralization of bone tissue.","volume":"20","author":"Boivin","year":"2009","journal-title":"Osteoporos Int"},{"key":"2020071612442725100_B43","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.bone.2008.05.007","article-title":"Critical role of the hypothalamic-pituitary-thyroid axis in bone.","volume":"43","author":"Bassett","year":"2008","journal-title":"Bone"},{"key":"2020071612442725100_B44","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/j.1365-2265.2004.02053.x","article-title":"The thyroid and the skeleton.","volume":"61","author":"Murphy","year":"2004","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071612442725100_B45","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bone.2008.03.019","article-title":"Iodothyronine deiodinase enzyme activities in bone.","volume":"43","author":"Williams","year":"2008","journal-title":"Bone"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/7\/3537\/8984821\/endo3537.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/7\/3537\/8984821\/endo3537.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T21:00:33Z","timestamp":1642280433000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/153\/7\/3537\/2424150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,16]]},"references-count":45,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2012,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2011-1814","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,16]]}}}