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

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 β 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: Debomita Chakraborty, Honglin Zhu, Astrid Jüngel, Lena Summa, Yi-Nan Li, Alexandru-Emil Matei, Xiang Zhou, Jingang Huang, Thuong Trinh-Minh, Chih-Wei Chen, Robert Lafyatis, Clara Dees, Christina Bergmann, Alina Soare, Hui Luo, Andreas Ramming, Georg Schett, Oliver Distler, Jörg H W Distler
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 563 (09 30 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32998972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Transforming Growth Factor beta
• FGFR3 protein, human
• Receptor, Fibroblast Growth Factor, Type 3

Topics

• Animals
• Cells, Cultured
• Fibroblasts (pathology)
• Fibrosis
• Mice
• Receptor, Fibroblast Growth Factor, Type 3 (genetics, metabolism)
• Scleroderma, Systemic (pathology)
• Signal Transduction
• Skin (pathology)
• Transforming Growth Factor beta