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Fighting fibrosis through FGF signaling
Excess extracellular matrix deposition by myofibroblasts contributes to fibrosis. Chakraborty et al. studied fibroblast growth factor (FGF) signaling in systemic sclerosis, an idiopathic fibrotic disease. They found that FGF9 signaled through FGF receptor 3 to drive fibroblast-to-myofibroblast transition. Genetic or pharmacological inactivation of this signaling pathway in mouse models of fibrosis and human fibroblasts prevented disease progression and reduced myofibroblast activation. This study identifies FGF receptor 3 signaling as a potential therapeutic target for 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.
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