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.

纤维化疾病给现代社会带来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，超过一半的诊断患有该病的病例最终直接死亡。 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的过度积累，该基质由持续激活的成纤维细胞释放。导致成纤维细胞病理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无法获得有效的靶向治疗。我们证明 FGFR3 和 FGF9 在 SSc 患者和实验模型中以 TGF-β 依赖性方式过度表达。 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、单核细胞趋化蛋白 1 和白细胞介素 4 受体。此外，FGF9 的过度表达诱导了显着的纤维化。相反，FGFR3或FGF9的敲除或FGFR3的药理抑制可改善博来霉素诱导的皮肤纤维化。我们现在的目标是进一步表征 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 TGF-β 对 FGF9 和 FGFR3 表达的刺激作用以及 SSc 成纤维细胞持续上调的分子机制。此外，我们将描述 FGF9 和 FGFR3 调节促纤维化靶基因转录的细胞内途径。我们还计划在其他小鼠纤维化模型（包括全身和器官特异性模型）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 临床前模型中的作用。我们相信我们的研究可能具有直接的转化意义，因为 FGFR 抑制剂已经在癌症患者的临床试验中进行了评估，并取得了有希望的结果。

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: Debomita Chakraborty;Honglin Zhu;A. Jüngel;L. Summa;Yi;A. Matei;Xiang Zhou;Jingang Huang;T. Trinh;Chih;R. Lafyatis;C. Dees;C. Bergmann;A. Soare;Hui Luo;A. Ramming;G. Schett;O. Distler;J. Distler
• 通讯作者: J. Distler

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; Zhu H; Layritz F; Luo H; 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

PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis

PGC-1α 调节自噬促进成纤维细胞活化和组织纤维化

• DOI: 10.1136/annrheumdis-2020-216963
• 发表时间: 2020-06-01
• 期刊: Annals of the Rheumatic Diseases
• 影响因子: 27.4
• 作者: Yun Zhang;Lichong Shen;Honglin Zhu;K. Dreissigacker;D. Distler;Xiang Zhou;A. Györfi;C. Bergmann;Xianyi Meng;C. Dees;T. Trinh;I. Ludolph;Raymund E. Horch;A. Ramming;G. Schett;J. Distler
• 通讯作者: J. Distler