{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:43:16Z","timestamp":1791603796168,"version":"4.3.4"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T00:00:00Z","timestamp":1688515200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DI 1537\/9\u20101 and \u20102"],"award-info":[{"award-number":["DI 1537\/9\u20101 and \u20102"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DI 1537\/13\u20101"],"award-info":[{"award-number":["DI 1537\/13\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DI 1537\/14\u20101"],"award-info":[{"award-number":["DI 1537\/14\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DI 1537\/17\u20101"],"award-info":[{"award-number":["DI 1537\/17\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MA 9219\/2\u20101"],"award-info":[{"award-number":["MA 9219\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011111","name":"UCB UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011111","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Fibrotic tissues are characterized by excessive crosslinking between extracellular matrix (ECM) proteins, rendering them more resistant to degradation. Although increased crosslinking of ECM is thought to play an important role for progression of tissue fibrosis, enhanced ECM crosslinking has not yet been targeted therapeutically in systemic sclerosis (SSc). Here, we investigated the role of transglutaminase 2 (TG2), a central crosslinking enzyme, in the activation of SSc fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed TG2 expression and activity using TG2 staining, Western blotting, and TG2 activity assays. We inhibited TG2 in fibroblasts cultured under standard 2\u2010dimensional conditions and in a 3\u2010dimensional full\u2010thickness equivalent skin model using monoclonal inhibitory anti\u2010TG2 antibodies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TG2 expression was increased in the skin of patients with SSc compared with healthy controls, with levels particularly high in patients with SSc\u2010associated interstitial lung disease. TG2 expression and TG2 activity were also increased in SSc dermal fibroblasts. Moreover, the levels of circulating TG2 in the plasma samples from SSc patients were increased versus samples from healthy controls. Anti\u2010TG2 antibodies did not show consistent antifibrotic effects across different fibroblast cell lines under 2\u2010dimensional culture conditions; however, anti\u2010TG2 antibodies effectively reduced transforming growth factor \u03b2\u2013induced dermal thickening, myofibroblast differentiation, and collagen accumulation in the 3\u2010dimensional full\u2010thickness model of human skin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We provide the first evidence, to our knowledge, that inhibition of TG2 might be a potential antifibrotic approach in SSc. Our findings have translational potential as anti\u2010TG2 antibodies are currently evaluated in a phase II clinical trial in chronic allograft injury and would thus be available for clinical studies in SSc (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link> identifier: NCT04335578).<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42518-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42518","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T03:50:36Z","timestamp":1681444236000},"page":"1619-1627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Amelioration of Fibrotic Remodeling of Human 3\u2010Dimensional Full\u2010Thickness Skin by Transglutamase 2 Inhibition"],"prefix":"10.1002","volume":"75","author":[{"given":"Xiang","family":"Zhou","sequence":"first","affiliation":[{"name":"Clinic for Rheumatology University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Trinh\u2010Minh","sequence":"additional","affiliation":[{"name":"Clinic for Rheumatology University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3145","authenticated-orcid":false,"given":"Alexandru\u2010Emil","family":"Matei","sequence":"additional","affiliation":[{"name":"Clinic for Rheumatology University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea\u2010Hermina","family":"Gy\u00f6rfi","sequence":"additional","affiliation":[{"name":"Clinic for Rheumatology University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhi","family":"Hong","sequence":"additional","affiliation":[{"name":"Clinic for Rheumatology University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5257-9171","authenticated-orcid":false,"given":"Christina","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3\u2010Rheumatology and Immunology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg (FAU) and University Hospital Erlangen, and Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen\u2010N\u00fcrnberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8740-9615","authenticated-orcid":false,"given":"Georg","family":"Schett","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3\u2010Rheumatology and Immunology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg (FAU) and University Hospital Erlangen, and Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen\u2010N\u00fcrnberg 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