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S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4<jats:sup>\u2212\/\u2212<\/jats:sup> mice are protected from fibrosis. The aim of this study was to assess the antifibrotic effects of anti\u2010S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of patients with SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of anti\u2010S100A4 mAbs were evaluated in a bleomycin\u2010induced skin fibrosis model and in Tsk\u20101 mice with a therapeutic dosing regimen. In addition, the effects of anti\u2010S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Inhibition of S100A4 was effective in the treatment of pre\u2010established bleomycin\u2010induced skin fibrosis and in regression of pre\u2010established fibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumulation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevant to the pathogenesis of SSc on targeted S100A4 inhibition in a bleomycin\u2010induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation\u2010 and fibrosis\u2010relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP\u2010activated protein kinase, calsequestrin\u20101, and phosphorylated STAT3, were validated on the protein level, and STAT3 inhibition was shown to prevent the profibrotic effects of S100A4 on fibroblasts in human skin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inhibition of S100A4 confers dual targeting of inflammatory and fibrotic pathways in complementary mouse models of fibrosis and in SSc skin. These effects support the further development of anti\u2010S100A4 mAbs as disease\u2010modifying targeted therapies for SSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42781","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T04:39:35Z","timestamp":1702874375000},"page":"783-795","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Effect of <scp>Anti\u2010S100A4<\/scp> Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis\u2013Specific Transcriptional Signatures in Human Skin"],"prefix":"10.1002","volume":"76","author":[{"given":"Thuong","family":"Trinh\u2010Minh","sequence":"first","affiliation":[{"name":"University Hospital D\u00fcsseldorf and Heinrich\u2010Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4960-3369","authenticated-orcid":false,"given":"Andrea\u2010Hermina","family":"Gy\u00f6rfi","sequence":"additional","affiliation":[{"name":"University Hospital D\u00fcsseldorf and Heinrich\u2010Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Tomcik","sequence":"additional","affiliation":[{"name":"Institute of Rheumatology, Charles University  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuong","family":"Tran\u2010Manh","sequence":"additional","affiliation":[{"name":"University Hospital D\u00fcsseldorf and Heinrich\u2010Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"University Hospital D\u00fcsseldorf and Heinrich\u2010Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Dickel","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University of Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilgesu Safak","family":"T\u00fcmerdem","sequence":"additional","affiliation":[{"name":"University Hospital D\u00fcsseldorf and Heinrich\u2010Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kreuter","sequence":"additional","affiliation":[{"name":"Helios St. Elisabeth Klinik Oberhausen, University Witten\u2010Herdecke, Oberhausen, and Helios St. Johannes Klinik Duisburg  Duisburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven\u2010Niklas","family":"Burmann","sequence":"additional","affiliation":[{"name":"Helios St. Elisabeth Klinik Oberhausen, University Witten\u2010Herdecke  Oberhausen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Signe Vedel","family":"Borchert","sequence":"additional","affiliation":[{"name":"Arxx Therapeutics, Oslo, Norway, and Roskilde University  Roskilde Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizwan Iqbal","family":"Hussain","sequence":"additional","affiliation":[{"name":"Agiana Pharmaceuticals  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Hall\u00e9n","sequence":"additional","affiliation":[{"name":"Arxx Therapeutics  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Klingelh\u00f6fer","sequence":"additional","affiliation":[{"name":"Arxx Therapeutics  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meik","family":"Kunz","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University of Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-9333","authenticated-orcid":false,"given":"J\u00f6rg H. 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