Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin
Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin
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DOI：
10.1016/s0002-9440(10)63685-1
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发表时间：
2003-08-01
影响因子：
6
通讯作者：
Trojanowska, M
中科院分区：
文献类型：
--
作者：
Kubo, M;Czuwara-Ladykowska, J;Trojanowska, M
维持健康人皮肤中适当的胶原稳态并负责硬皮病中胶原合成失调的分子和细胞机制仍然主要未知。这项研究表明，Fli 1是一个生理负调节胶原基因表达的真皮成纤维细胞在体外和人体皮肤在体内。Fli 1（-/-）、Fli 1（+/-）和Fli 1（+/+）小鼠的小鼠胚胎成纤维细胞分析支持该结论。在培养的人和小鼠成纤维细胞中，Fli 1表达水平与I型胶原表达水平呈负相关。这些体外观察结果在体内得到验证。在健康人皮肤中，Fli 1蛋白在成纤维细胞和内皮细胞中表达。值得注意的是，个别成纤维细胞中Fli 1表达的缺失与胶原蛋白合成升高相关。与健康皮肤相反，Fli 1蛋白在成纤维细胞中始终缺失，在临床涉及的硬皮病皮肤中的内皮细胞中显著减少，这与系统性硬化症皮肤中胶原合成的增强相关。这项研究支持Fli 1在人体皮肤中作为胶原蛋白转录抑制因子的作用。Fli 1在硬皮病成纤维细胞中的持续下调可能直接导致硬皮病皮肤中不受控制的基质沉积。
The molecular and cellular mechanisms that maintain proper collagen homeostasis in healthy human skin and are responsible for the dysregulated collagen synthesis in scleroderma remain primarily unknown. This study demonstrates that Fli1 is a physiological negative regulator of collagen gene expression in dermal fibroblasts in vitro and in human skin in vivo. This conclusion is supported by the analyses of mouse embryonic fibroblasts from Fli1(-/-), Fli1(+/-), and Fli1(+/+) mice. in cultured human and mouse fibroblasts Fli1 expression levels are inversely correlated with the collagen type I expression levels. These in vitro observations were validated in vivo. in healthy human skin Fli1 protein is expressed in fibroblasts and endothelial cells. Significantly, absence of Fli1 expression in individual fibroblasts correlates with elevated collagen synthesis. in contrast to healthy skin, Fli1 protein is consistently absent from fibroblasts and significantly reduced in endothelial cells in clinically involved scleroderma skin, which correlates with enhanced collagen synthesis in systemic sclerosis skin. This study supports the role of Fli1 as a suppressor of collagen transcription in human skin in vivo. Persistent-down-regulation of Fli1 in scleroderma fibroblasts in vivo may directly contribute to uncontrolled matrix deposition in scleroderma skin.