Kubo Masahide, Czuwara-Ladykowska Joanna, Moussa Omar, Markiewicz Margaret, Smith Edwin, Silver Richard M, Jablonska Stefania, Blaszczyk Maria, Watson Dennis K, Trojanowska Maria
Division of Rheumatology and Immunology and the Laboratory of Cancer Genomics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Am J Pathol. 2003 Aug;163(2):571-81. doi: 10.1016/S0002-9440(10)63685-1.
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.
在健康人体皮肤中维持适当胶原蛋白稳态以及导致硬皮病中胶原蛋白合成失调的分子和细胞机制，目前仍基本未知。本研究表明，Fli1在体外真皮成纤维细胞和体内人体皮肤中是胶原蛋白基因表达的生理性负调节因子。来自Fli1(-/-)、Fli1(+/-)和Fli1(+/+)小鼠的小鼠胚胎成纤维细胞分析支持了这一结论。在培养的人和小鼠成纤维细胞中，Fli1表达水平与I型胶原蛋白表达水平呈负相关。这些体外观察结果在体内得到了验证。在健康人体皮肤中，Fli1蛋白在成纤维细胞和内皮细胞中表达。值得注意的是，单个成纤维细胞中Fli1表达缺失与胶原蛋白合成增加相关。与健康皮肤相反，在临床受累的硬皮病皮肤中，成纤维细胞持续缺乏Fli1蛋白，内皮细胞中Fli1蛋白显著减少，这与系统性硬化症皮肤中胶原蛋白合成增强相关。本研究支持Fli1在体内人体皮肤中作为胶原蛋白转录抑制因子的作用。硬皮病成纤维细胞中Fli1在体内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。
