Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis–Specific Transcriptional Signatures in Human Skin

Trinh-Minh T, Györfi AH, Tomcik M, Tran-Manh C, Zhou X, Dickel N, Tümerdem BS, Kreuter A, Burmann SN, Borchert SV, Hussain RI, Hallén J, Klingelhöfer J, Kunz M, Distler JH (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Arthritis and Rheumatology Wiley

Book Volume: 76

Pages Range: 783-795

Journal Issue: 5

DOI: 10.1002/art.42781

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.

Authors with CRIS profile

Nicholas Dickel Lehrstuhl für Medizinische Informatik Meik Kunz Lehrstuhl für Medizinische Informatik

Involved external institutions

Universitätsklinikum Düsseldorf DE Germany (DE) Calluna Pharma NO Norway (NO) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ) Roskilde University (RUC) DK Denmark (DK) Universität Witten/Herdecke DE Germany (DE)

How to cite

APA:

Trinh-Minh, T., Györfi, A.H., Tomcik, M., Tran-Manh, C., Zhou, X., Dickel, N.,... Distler, J.H. (2024). Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis–Specific Transcriptional Signatures in Human Skin. Arthritis and Rheumatology, 76(5), 783-795. https://doi.org/10.1002/art.42781

MLA:

Trinh-Minh, Thuong, et al. "Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis–Specific Transcriptional Signatures in Human Skin." Arthritis and Rheumatology 76.5 (2024): 783-795.

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