Activation of FGFR3 promotes tissue fibrosis in systemic sclerosis

FGFR3 激活促进系统性硬化症组织纤维化

• 批准号: 310880801
• 负责人: Professor Dr. Jörg Hans Wilhelm Distler
• 金额: --
• 依托单位: Klinik für Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/310880801?language=en
• 关键词: Activation; FGFR3; promotes; tissue; fibrosis

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.

纤维化疾病对现代社会施加了重大的社会经济负担，并占发达国家死亡的45％。全身性硬化症（SSC）是一种典型的特发性全身性纤维疾病，其中一半以上被诊断为这种疾病的病例最终死于直接结果。 SSC和其他纤维化疾病的常见组织病理学特征是细胞外基质的过度积累，通过持续活化的成纤维细胞释放。未完全了解导致成纤维细胞病理活化的分子机制，因此，包括SSC在内的大多数纤维化疾病无法使用有效的靶向疗法。我们证明，在SSC患者和实验模型中，FGFR3和FGF9以TGF-β依赖性方式过表达。 FGF9以FGFR3依赖性方式激活培养的成纤维细胞，并诱导促纤维化基因的表达，例如内皮素-1，内皮素受体B，结缔组织生长因子，单核细胞化学吸引剂蛋白-1 und prineutain-1和interleukin-4受体。此外，FGF9的过表达诱导了显着的纤维化。相比之下，FGFR3或FGF9或FGFR3的药理抑制可改善博来霉素诱导的皮肤纤维化。现在，我们的目标是进一步将FGF9 / FGFR3信号传导的分子机制进一步表征，并进一步验证FGF9 / FGFR3轴作为纤维化疾病中的治疗靶标。我们计划确定TGF-β对FGF9和FGFR3表达的刺激作用的基础机制，以及SSC成纤维细胞中持续的上调。此外，我们将表征FGF9和FGFR3调节促纤维化靶基因的转录的细胞内途径。我们还计划在包括全身性和器官特异性模型在内的其他小鼠模型中分析FGF9和FGFR3靶向失活的抗纤维化作用。最后，我们将评估FGFR小分子抑制剂在SSC临床前模型中的影响。我们认为我们的研究可能具有直接的翻译意义，因为在癌症患者的临床试验中已经评估了FGFR的抑制剂，结果有希望的结果。

项目成果

Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis

• DOI: 10.1126/scitranslmed.aaz5506
• 发表时间: 2020-09-30
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Chakraborty, Debomita;Zhu, Honglin;Distler, Joerg H. W.
• 通讯作者: Distler, Joerg H. W.

Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis

重组腺苷脱氨酶可改善系统性硬化症临床前模型中的炎症、血管疾病和纤维化

• DOI: 10.1002/art.41259
• 发表时间: 2020
• 期刊: Arthritis & Rheumatology
• 影响因子: 13.3
• 作者: Zhang Y;Layritz F;Wohlfahrt T;Chen CW;Soare A;Bergmann C;Ramming A;Groeber F;Reuter C;Fornasini G;Soukhareva N;Schreiber B;Ramamurthy S;Amann K;Schett G;Distler JHW
• 通讯作者: Distler JHW