학술논문
Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis-Specific Transcriptional Signatures in Human Skin.
Document Type
Academic Journal
Author
Trinh-Minh T; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.; Györfi AH; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.; Tomcik M; Charles University, Prague, Czech Republic.; Tran-Manh C; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.; Zhou X; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.; Dickel N; Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.; Tümerdem BS; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.; Kreuter A; Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, and Helios St. Johannes Klinik Duisburg, Duisburg, Germany.; Burmann SN; Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, Germany.; Borchert SV; Arxx Therapeutics, Oslo, Norway, and Roskilde University, Roskilde, Denmark.; Hussain RI; Agiana Pharmaceuticals, Oslo, Norway.; Hallén J; Arxx Therapeutics, Oslo, Norway.; Klingelhöfer J; Arxx Therapeutics, Oslo, Norway.; Kunz M; Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.; Distler JHW; University Hospital Düsseldorf and Heinrich-Heine University, Düsseldorf, Germany.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 101623795 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2326-5205 (Electronic) Linking ISSN: 23265191 NLM ISO Abbreviation: Arthritis Rheumatol Subsets: MEDLINE
Subject
Language
English
Abstract
Objective: S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4 -/- mice are protected from fibrosis. The aim of this study was to assess the antifibrotic effects of anti-S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of patients with SSc.
Methods: The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skin fibrosis model and in Tsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing.
Results: Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skin fibrosis and in regression of pre-established 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-induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation- and fibrosis-relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase, calsequestrin-1, 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.
Conclusion: 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-S100A4 mAbs as disease-modifying targeted therapies for SSc.
(© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
Methods: The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skin fibrosis model and in Tsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing.
Results: Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skin fibrosis and in regression of pre-established 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-induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation- and fibrosis-relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase, calsequestrin-1, 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.
Conclusion: 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-S100A4 mAbs as disease-modifying targeted therapies for SSc.
(© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)