{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T21:26:12Z","timestamp":1781299572908,"version":"3.54.1"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2014,10,26]],"date-time":"2014-10-26T00:00:00Z","timestamp":1414281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Soci\u00e9t\u00e9 Fran\u00e7aise de Rhumatologie"},{"name":"Groupe Fran\u00e7ais de Recherche sur la Scl\u00e9rodermie (AMPLI grant)"},{"name":"Association des Scl\u00e9rodermiques de France"},{"name":"CMH Research Projects","award":["00000023728"],"award-info":[{"award-number":["00000023728"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)\/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site\u2010directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin\u2010induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor \u03b2 (TGF\u03b2) receptor type I (T\u03b2RI\u2010CA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Up\u2010regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGF\u03b2 induced the expression of CAR messenger RNA and protein in a Smad\u2010dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGF\u03b2 on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGF\u03b2 on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGF\u03b2 signaling in murine models of SSc and exacerbated bleomycin\u2010induced and T\u03b2RI\u2010CA\u2013induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that CAR is up\u2010regulated in SSc and regulates TGF\u03b2 signaling. Activation of CAR increases the profibrotic effects of TGF\u03b2 in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGF\u03b2 signaling in SSc and in other fibrotic diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38819","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T11:47:33Z","timestamp":1408708053000},"page":"3140-3150","source":"Crossref","is-referenced-by-count":15,"title":["The Nuclear Receptor Constitutive Androstane Receptor\/NR1I3 Enhances the Profibrotic Effects of Transforming Growth Factor \u03b2 and Contributes to the Development of Experimental Dermal Fibrosis"],"prefix":"10.1002","volume":"66","author":[{"given":"J\u00e9r\u00f4me","family":"Avouac","sequence":"first","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"},{"name":"Paris Descartes University, INSERM U1016, and Cochin Hospital, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Palumbo\u2010Zerr","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadira","family":"Ruzehaji","sequence":"additional","affiliation":[{"name":"Paris Descartes University, INSERM U1016, and Cochin Hospital, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Tomcik","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg, Erlangen, Germany, and Charles University in Prague Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Zerr","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dees","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfiya","family":"Distler","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Beyer","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holm","family":"Schneider","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Zurich Center of Integrative Human Physiology, and University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Schett","sequence":"additional","affiliation":[{"name":"University of Erlangen\u2013Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Allanore","sequence":"additional","affiliation":[{"name":"Paris Descartes University, INSERM U1016, and Cochin Hospital, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg H. 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