Inhibition of sumoylation prevents experimental fibrosis
Inhibition of sumoylation prevents experimental fibrosis
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DOI：
10.1136/annrheumdis-2012-201746
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发表时间：
2012-11-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Khodzhigorova, Aisa;Distler, Alfiya;Distler, Joerg H. W.
目的纤维化是系统性硬化症（SSc）的主要死亡原因。首先，表观遗传修饰最近已被证明有助于SSc成纤维细胞的活化。在这里，我们研究了抑制sumoylation作为一种新的antifibrotic approach.Methods抑制Sumoylation的siRNA介导的敲低的小泛素样调节剂（SUMO）E2-共轭酶Ubc 9，这是必不可少的sumoylation。在博来霉素诱导的真皮纤维化和组成型活性TGF-β受体I型（TBR）过表达诱导的纤维化模型中分析了Ubc 9敲低的作用。结果SUMO-1在SSc患者和实验性纤维化患者中表达明显增强，而在正常对照组中表达明显增强。抑制sumoylation产生有效的抗纤维化作用，并防止真皮增厚，肌成纤维细胞分化和胶原蛋白的积累诱导博莱霉素，或过度表达的组成型活性TBR。此外，敲低Ubc 9减少了磷酸化Smad 3在实验性纤维化的积累，表明抑制类小泛素化可能normalise典型的TGF-β信号invivo.Conclusions，我们表明，抑制类小泛素化减少典型的TGF-β信号，并防止实验性纤维化在不同的临床前模型。这些数据提供了第一个证据，靶向异常小泛素化可能是一种新的治疗方法，用于纤维化疾病。
Objectives Fibrosis is a predominant cause of death in systemic sclerosis (SSc). First epigenetic modifications have recently been shown to contribute to activation of SSc fibroblasts. Here, we investigated inhibition of sumoylation as a novel antifibrotic approach.Methods Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation. The effects of knockdown of Ubc9 were analysed in bleomycin-induced dermal fibrosis, and in the model of fibrosis induced by overexpression of a constitutively active TGF-beta receptor type I (TBR). SUMO-1 and phosphorylated Smad3 were detected by immunohistochemistry.Results Increased staining for SUMO-1 was detected in patients with SSc and in experimental fibrosis. Inhibition of sumoylation exerted potent antifibrotic effects and prevented dermal thickening, myofibroblast differentiation and accumulation of collagen induced by bleomycin, or by overexpression of constitutively active TBR. Moreover, knockdown of Ubc9 reduced the accumulation of phosphorylated Smad3 in experimental fibrosis indicating that inhibition of sumoylation may normalise canonical TGF-beta signalling in vivo.Conclusions We demonstrate that inhibition of sumoylation reduces canonical TGF-beta signalling and prevents experimental fibrosis in different preclinical models. These data provide first evidence that targeting of aberrant sumoylation may be a novel therapeutic approach for fibrotic diseases.