{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:44:56Z","timestamp":1777589096885,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,20]],"date-time":"2019-10-20T00:00:00Z","timestamp":1571529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["332438"],"award-info":[{"award-number":["332438"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Arthritis Society","award":["SOG-15-293"],"award-info":[{"award-number":["SOG-15-293"]}]},{"name":"Natural Sciences and Engineering Research Council of Canada Discovery Grant","award":["RGPIN-04090"],"award-info":[{"award-number":["RGPIN-04090"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models<\/jats:p>","DOI":"10.3390\/ijms20205198","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T03:40:29Z","timestamp":1571629229000},"page":"5198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exposure to the RXR Agonist SR11237 in Early Life Causes Disturbed Skeletal Morphogenesis in a Rat Model"],"prefix":"10.3390","volume":"20","author":[{"given":"Holly","family":"Dupuis","sequence":"first","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"},{"name":"Western Bone and Joint Institute, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-4504","authenticated-orcid":false,"given":"Michael Andrew","family":"Pest","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"},{"name":"Western Bone and Joint Institute, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ermina","family":"Hadzic","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"},{"name":"Western Bone and Joint Institute, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thin Xuan","family":"Vo","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-273X","authenticated-orcid":false,"given":"Daniel B.","family":"Hardy","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"},{"name":"Obstetrics and Gynecology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Beier","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University London, London, ON N6A 5C1, Canada"},{"name":"Western Bone and Joint Institute, Western University London, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1242\/dev.105536","article-title":"A pathway to bone: Signaling molecules and transcription factors involved in chondrocyte development and maturation","volume":"142","author":"Kozhemyakina","year":"2015","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1210\/endo.143.5.8776","article-title":"The role of the resting zone in growth plate chondrogenesis","volume":"143","author":"Abad","year":"2002","journal-title":"Endocrinology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nature11940","article-title":"Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions","volume":"495","author":"Cooper","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1101\/gad.845101","article-title":"Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice","volume":"15","author":"Takeda","year":"2001","journal-title":"Genes Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1083\/jcb.153.1.87","article-title":"Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes","volume":"153","author":"Ueta","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1101\/gad.1174704","article-title":"Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog","volume":"18","author":"Yoshida","year":"2004","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.devcel.2007.02.004","article-title":"MEF2C transcription factor controls chondrocyte hypertrophy and bone development","volume":"12","author":"Arnold","year":"2007","journal-title":"Dev. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/nrrheum.2014.168","article-title":"Developmental biology: Is there such a thing as a cartilage-specific knockout mouse?","volume":"10","author":"Pest","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12097","DOI":"10.1073\/pnas.1302703111","article-title":"Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation","volume":"111","author":"Yang","year":"2014","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/bdrc.21060","article-title":"The chondrocytic journey in endochondral bone growth and skeletal dysplasia","volume":"102","author":"Chan","year":"2014","journal-title":"Birth Defects Res. C"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/bdrc.21062","article-title":"Chondrocyte hypertrophy in skeletal development, growth, and disease","volume":"102","author":"Sun","year":"2014","journal-title":"Birth Defects Res. C"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"T1","DOI":"10.1530\/JME-14-0022","article-title":"Recent research on the growth plate: Recent insights into the regulation of the growth plate","volume":"53","author":"Lui","year":"2014","journal-title":"J. Mol. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbalip.2011.09.014","article-title":"The retinoid X receptors and their ligands","volume":"1821","author":"Dawson","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bbalip.2011.04.003","article-title":"Modulation of RXR function through ligand design","volume":"1821","author":"Bourguet","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1124\/pr.58.4.7","article-title":"International Union of Pharmacology. LXIII. Retinoid X Receptors","volume":"58","author":"Germain","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8013","DOI":"10.1038\/ncomms9013","article-title":"Structural mechanism for signal transduction in RXR nuclear receptor heterodimers","volume":"6","author":"Kojetin","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1242\/dev.121.12.3997","article-title":"Mouse embryos lacking RXR alpha are resistant to retinoic-acid-induced limb defects","volume":"121","author":"Sucov","year":"1995","journal-title":"Development"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/tera.1420070310","article-title":"Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid","volume":"7","author":"Kochhar","year":"1973","journal-title":"Teratology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7011","DOI":"10.1093\/emboj\/18.24.7011","article-title":"RAR-independent RXR signaling induces t(15;17) leukemia cell maturation","volume":"18","author":"Benoit","year":"1999","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.advms.2015.09.001","article-title":"The influence of bexarotene, a selective agonist of the retinoid receptor X (RXR), and tazarotene, a selective agonist of the retinoid acid receptor (RAR), on bone metabolism in rats","volume":"61","author":"Nowak","year":"2015","journal-title":"Adv. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1172\/JCI77186","article-title":"Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling","volume":"125","author":"Fuentes","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref_22","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"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1172\/JCI29463","article-title":"Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts","volume":"116","author":"Masuyama","year":"2006","journal-title":"J. Clin. Invest."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5332","DOI":"10.1210\/endo.142.12.8544","article-title":"Aberrant growth plate development in VDR\/RXR gamma double null mutant mice","volume":"142","author":"Yagishita","year":"2001","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1083\/jcb.200106147","article-title":"A regulatory cascade involving retinoic acid, Cbfa1, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation","volume":"155","author":"Alvarez","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1007\/s00018-017-2458-4","article-title":"The multi-faceted role of retinoid X receptor in bone remodeling","volume":"74","author":"Ricote","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"734","DOI":"10.2337\/diabetes.52.3.734","article-title":"Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat","volume":"52","author":"Stoffers","year":"2003","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0006-2952(97)00209-8","article-title":"Mitogenic effect of retinoid X receptor agonists in rat liver","volume":"54","author":"Standeven","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Agoston, H., Khan, S., James, C.G., Gillespie, J.R., Serra, R., Stanton, L.-A., and Beier, F. (2007). C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways. BMC Dev. Biol., 7.","DOI":"10.1186\/1471-213X-7-18"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1002\/art.38758","article-title":"Disturbed cartilage and joint homeostasis resulting from a loss of mitogen-inducible gene 6 in a mouse model of joint dysfunction","volume":"66","author":"Pest","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1210\/en.2010-1412","article-title":"Deletion of glycogen synthase kinase-3\u03b2 in cartilage results in up-regulation of glycogen synthase kinase-3\u03b1 protein expression","volume":"152","author":"Gillespie","year":"2011","journal-title":"Endocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Solomon, L.A., Li, J.R., B\u00e9rub\u00e9, N.G., and Beier, F. (2009). Loss of ATRX in chondrocytes has minimal effects on skeletal development. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007106"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.bone.2009.08.003","article-title":"The role of Akt1 in terminal stages of endochondral bone formation: Angiogenesis and ossification","volume":"45","author":"Ulici","year":"2009","journal-title":"Bone"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:27:58Z","timestamp":1760189278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,20]]},"references-count":33,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20205198"],"URL":"https:\/\/doi.org\/10.3390\/ijms20205198","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/774851","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,20]]}}}