Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis
Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis
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DOI：
10.1126/scitranslmed.aaz5506
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发表时间：
2020-09-30
影响因子：
17.1
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Chakraborty, Debomita;Zhu, Honglin;Distler, Joerg H. W.
成纤维细胞的异常激活和细胞外基质的进行性沉积是系统性硬化症（SSc）的一个关键特征，SSc是一种典型的特发性纤维化疾病。在这里，我们证明了促纤维化细胞因子转化生长因子。选择性上调成纤维细胞生长因子受体3（FGFR 3）及其配体FGF 9以促进成纤维细胞活化和组织纤维化，导致SSc皮肤中显著的FGFR 3特征。转录组分析、计算机模拟分析和功能实验表明，FGFR 3诱导多种促纤维化途径，包括内皮素、白细胞介素-4和由转录因子CREB（cAMP反应元件结合蛋白）介导的结缔组织生长因子信号传导。通过成纤维细胞特异性敲除FGFR 3或FGF 9抑制FGFR 3信号传导或药理学抑制FGFR 3阻断成纤维细胞活化并减弱小鼠中的实验性皮肤纤维化。这些发现将FGFR 3表征为SSc中促纤维化介质网络的上游调节剂，并作为治疗纤维化的潜在靶点。
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. 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.