Activation of FGFR3 promotes tissue fibrosis in systemic sclerosis

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Fibrotic diseases impose a major socioeconomic burden on modern societies and account for up to 45% of deaths in the developed world. Systemic sclerosis (SSc) is a prototypical idiopathic systemic fibrosing disease with more than half of cases diagnosed with the condition eventually dying as a direct consequence. The common histopathological feature of SSc and other fibrotic disorders is an excessive accumulation of extracellular matrix, which is released by persistently activated fibroblasts. The molecular mechanisms that lead to the pathologic activation of fibroblasts are incompletely understood and consequently, effective targeted therapies are not available for most fibrotic diseases including SSc. We demonstrated that FGFR3 and FGF9 are overexpressed in SSc patients and in experimental models in a TGF-beta dependent manner. FGF9 activates cultured fibroblasts in a FGFR3-dependent manner and induces the expression of pro-fibrotic genes such as endothelin-1, endothelin receptor B, connective tissue growth factor, monocyte chemoattractant protein-1 und interleukin-4 receptor. Moreover, overexpression of FGF9 induced prominent fibrosis. In contrast, knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 ameliorates bleomycin-induced skin fibrosis. We now aim to further characterize the molecular mechanisms of FGF9 / FGFR3 signaling in fibrosis and to further validate the FGF9 / FGFR3 axis as a therapeutic target in fibrotic diseases. We plan to identify the molecular mechanisms underlying the stimulatory effects of TGF-beta on the expression of FGF9 and FGFR3 and the persistent upregulation in SSc fibroblasts. Moreover, we will characterize the intracellular pathways by which FGF9 and FGFR3 regulate the transcription of pro-fibrotic target genes. We also plan to analyze the anti-fibrotic effects of targeted inactivation of FGF9 and FGFR3 in additional mouse models of fibrosis including systemic- and organ-specific models. Finally, we will evaluate the effects of small molecular inhibitors of FGFRs in preclinical models of SSc. We believe that our study may have direct translational implications, because inhibitors of FGFRs have already been evaluated in clinical trials in cancer patients with promising results.