Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis

Chakraborty D, Zhu H, Juengel A, Summa L, Li YN, Matei AE, Zhou X, Huang J, Thuong Trinh-Minh , Chen CW, Lafyatis R, Dees C, Bergmann C, Soare A, Luo H, Ramming A, Schett G, Distler O, Distler J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 12

Journal Issue: 563

DOI: 10.1126/scitranslmed.aaz5506

Abstract

Aberrant activation of fibroblasts with progressive deposition of extracellular matrix is a key feature of systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease. Here, we demonstrate that the profibrotic cytokine transforming growth factor. selectively up-regulates fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 to promote fibroblast activation and tissue fibrosis, leading to a prominent FGFR3 signature in the SSc skin. Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 induces multiple profibrotic pathways including endothelin, interleukin-4, and connective tissue growth factor signaling mediated by transcription factor CREB (cAMP response element-binding protein). Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 blocked fibroblast activation and attenuated experimental skin fibrosis in mice. These findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and as a potential target for the treatment of fibrosis.

Authors with CRIS profile

Debomita Chakraborty Department of Medicine 3 – Rheumatology and Immunology Yi-Nan Li Department of Medicine 3 – Rheumatology and Immunology Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Andreas Ramming Medizinische Fakultät Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A079: The nuclear receptor TR4 regulates TGFbeta-induced fibroblast activation and tissue fibrosis Jan. 1, 2021 - June 30, 2023

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Central South University CN China (CN) University of Pittsburgh US United States (USA) (US)

How to cite

APA:

Chakraborty, D., Zhu, H., Juengel, A., Summa, L., Li, Y.-N., Matei, A.-E.,... Distler, J. (2020). Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis. Science Translational Medicine, 12(563). https://dx.doi.org/10.1126/scitranslmed.aaz5506

MLA:

Chakraborty, Debomita, et al. "Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis." Science Translational Medicine 12.563 (2020).

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