{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:14:06Z","timestamp":1791818046114,"version":"4.3.4"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Orthod Craniofacial Res"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Cleft lip and\/or palate (CLP) is a common craniofacial birth defect caused by genetic as well as environmental factors. The phenotypic spectrum of CLP also includes submucous clefts with a defect in the palatal bone. To elucidate the contribution of vitamin A, we evaluated the effects of the vitamin A metabolite all\u2010trans retinoic acid (ATRA) on the osteogenic differentiation and mineralization of mouse embryonic palatal mesenchymal cells (MEPM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting and Sample Population<\/jats:title><jats:p>MEPM cells were isolated from the prefusion palates of E13 mouse embryos from three different litters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>MEPM cells were cultured with and without 0.5\u00a0\u03bcM ATRA in osteogenic medium. Differentiation was analysed by the expression of osteogenic marker genes and alkaline phosphatase (ALP) activity after 1, 2, and 7\u2009days. The expression of Wnt marker genes was also analysed. Mineralization was assessed by alizarin red staining after 7, 14, 21, and 28\u2009days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The bone marker genes <jats:italic>Sp7<\/jats:italic>, <jats:italic>Runx2<\/jats:italic>, <jats:italic>Alpl<\/jats:italic>, and <jats:italic>Col1a1<\/jats:italic> were inhibited 10%\u2009\u00b1\u20092%, 59%\u2009\u00b1\u20097%, 79%\u2009\u00b1\u200912% and 57%\u2009\u00b1\u200920% (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05) at day 7. ALP activity was inhibited at days 1 and 7 by 35\u2009\u00b1\u20090% (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05) and 23\u2009\u00b1\u20096% (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001). ATRA also inhibited mineralization at 3 and 4\u2009weeks. Finally, expression of the universal Wnt marker gene <jats:italic>Axin2<\/jats:italic> was strongly reduced, by 31\u2009\u00b1\u200918% (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.001), at day 7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data indicate that ATRA (vitamin A) inhibits bone formation by reducing Wnt signalling. This might contribute to the molecular aetiology of submucous clefting.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ocr.12594","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T15:08:58Z","timestamp":1655564938000},"page":"132-139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Excess vitamin a might contribute to submucous clefting by inhibiting <scp>WNT<\/scp>\u2010mediated bone formation"],"prefix":"10.1111","volume":"26","author":[{"given":"Charlotte Lucienne Jacqueline Maria","family":"Krutzen","sequence":"first","affiliation":[{"name":"Department of Dentistry \u2010 Orthodontics and Craniofacial Biology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laury A.","family":"Roa","sequence":"additional","affiliation":[{"name":"Department of Dentistry \u2010 Orthodontics and Craniofacial Biology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences  Nijmegen The Netherlands"},{"name":"Laury A. Roa, Department of Instructive Biomaterial Engineering (IBE) MERLN Institute for Technology\u2010Inspired Regenerative Medicine, Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon","family":"Bloemen","sequence":"additional","affiliation":[{"name":"Department of Dentistry \u2010 Orthodontics and Craniofacial Biology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1616-1576","authenticated-orcid":false,"given":"Johannes W.","family":"Von den Hoff","sequence":"additional","affiliation":[{"name":"Department of Dentistry \u2010 Orthodontics and Craniofacial Biology Radboud University Medical Center, Radboud Institute for Molecular Life Sciences  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2933"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2002.610402.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0722.2012.00948.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034517703580"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034508327868"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSMBR.901142"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225525"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28551"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2016.05.001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00031"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwn035"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/134.11.3106"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/SCS.0b013e318208ba10"},{"issue":"6","key":"e_1_2_10_15_1","first-page":"567","article-title":"The role of RXR\u2010alpha in retinoic acid\u2010induced cleft palate as assessed with the RXR\u2010alpha knockout mouse","volume":"43","author":"Nugent P","year":"1999","journal-title":"Int J Dev Biol"},{"issue":"3","key":"e_1_2_10_16_1","first-page":"153","article-title":"Effects of retinoic acid on the differentiation of chondrogenic progenitor cells, ATDC5","volume":"52","author":"Kirimoto A","year":"2005","journal-title":"J Med Dent Sci"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.2006.12.2031"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20723"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.12.100"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2016.12.007"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2019.105597"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.424"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4938"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420400602"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.9.081307.164437"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007906"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082388"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.21110"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0b013e3181d62980"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v024a29"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2015.09.036"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20115"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.08.036"},{"issue":"6","key":"e_1_2_10_34_1","first-page":"1389","article-title":"Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment","volume":"7","author":"Santiago L","year":"2017","journal-title":"Am J Cancer Res"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20702"}],"container-title":["Orthodontics &amp; 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