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.

Role of fibroblast growth factor signalling in hepatic fibrosis

“…138 Interestingly, in the skin of patients with systemic sclerosis, only FGFR3B but not FGFR3C was found to be overexpressed. 138 In contrast, in lung fibroblasts exhibiting high expression of FGFR3C, FGF9 revealed antifibrotic effects through downregulation of collagen expression and these effects were partially reversed by FGFR3-knockdown. 86 These findings underscore that differences in isoform expression and the cellular context critically determine FGFR-effects in fibrotic diseases.…”

“…Although FGFR3 plays an important role in HCC development and progression 9,103,137 and FGFR3 expression is elevated in human cirrhotic livers, 132 the functional role of FGFR3 and its isoforms has not yet been investigated in the context of hepatic fibrosis. A recent study revealed that FGF9‐activated FGFR3 promoted fibrosis in systemic sclerosis through activation of profibrotic signalling pathways 138 . Interestingly, in the skin of patients with systemic sclerosis, only FGFR3B but not FGFR3C was found to be overexpressed 138 .…”

“…A recent study revealed that FGF9‐activated FGFR3 promoted fibrosis in systemic sclerosis through activation of profibrotic signalling pathways 138 . Interestingly, in the skin of patients with systemic sclerosis, only FGFR3B but not FGFR3C was found to be overexpressed 138 . In contrast, in lung fibroblasts exhibiting high expression of FGFR3C, FGF9 revealed antifibrotic effects through downregulation of collagen expression and these effects were partially reversed by FGFR3‐knockdown 86 .…”

Inhibition of cAMP/PKA/CREB Signaling Axis Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

“…In this study, inhibition of PKA by a chemical compound (H89) or specific peptide (PKI 14-22 amide) also increased the yield of iCM reprogramming. We next studied one of the well-known downstream targets of PKA signaling, CREB, which regulates fibroblast [44][45][46][47][48][49] and cardiac function and disease [50][51][52]. We found that CREB inhibitor improves iCM reprogramming and inhibition of p38 signaling, which also regulate the phosphorylation of CREB, consistently enhanced reprogramming efficiency.…”

SnapshotDx Quiz: June 2021

“…FGFR is expressed in fibroblasts and is present in various tissue types, such as skin, cornea, lung, heart, placenta, kidney, and ureter (Hughes, 1997;Root and Shipley, 2000). FGFR has been shown to activate profibrotic signaling pathways in systemic sclerosis (Chakraborty et al, 2020). Nintedanib is an FDA-approved drug used for pulmonary fibrosis and ILD associated with systemic sclerosis (Distler et al, 2019).…”