Activation of FGFR3 promotes tissue fibrosis in systemic sclerosis

纤维性疾病给现代社会造成了重大的社会经济负担，占发达国家死亡人数的45%。系统性硬化症(SSC)是一种典型的特发性系统性纤维化疾病，超过一半的病例被诊断为这种疾病，最终直接导致死亡。SSC和其他纤维化疾病的共同组织病理学特征是细胞外基质过度堆积，这些基质由持续激活的成纤维细胞释放。导致成纤维细胞病理性激活的分子机制尚不完全清楚，因此，包括SSc在内的大多数纤维化疾病都没有有效的靶向治疗方法。我们证明了FGFR3和FGF9在SSC患者和实验模型中以依赖于转化生长因子-β的方式过度表达。FGF9以FGFR3依赖的方式激活培养的成纤维细胞，并诱导促纤维化基因的表达，如内皮素1、内皮素B受体、结缔组织生长因子、单核细胞趋化蛋白1和白细胞介素4受体。此外，FGF9的过度表达还导致了明显的纤维化。相反，敲除FGFR3或FGF9或药物抑制FGFR3可缓解博莱霉素诱导的皮肤纤维化。我们现在的目标是进一步研究FGF9/FGFR3信号在纤维化中的分子机制，并进一步验证FGF9/FGFR3轴作为纤维化疾病的治疗靶点。我们计划确定转化生长因子-β刺激SSC成纤维细胞FGF9和FGFR3表达以及持续上调的分子机制。此外，我们还将描述FGF9和FGFR3调控促纤维化靶基因转录的细胞内途径。我们还计划分析靶向失活FGF9和FGFR3在其他小鼠纤维化模型中的抗纤维化作用，包括全身和器官特异性模型。最后，我们将评估FGFRs小分子抑制剂在SSC临床前模型中的效果。我们认为我们的研究可能具有直接的翻译意义，因为FGFRs的抑制剂已经在癌症患者的临床试验中进行了评估，结果令人振奋。

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.