Dong Chunming, Zhu Shoukang, Wang Tao, Yoon Woohyun, Li Zhiru, Alvarez Rene J, ten Dijke Peter, White Barbara, Wigley Fredrick M, Goldschmidt-Clermont Pascal J
Division of Cardiology, Duke University Medical Center, 7504 Duke Hospital North, Box 3845, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3908-13. doi: 10.1073/pnas.062010399.
Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) beta has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smads have been identified: (i) receptor-regulated Smad2 and -3 (R-Smads); (ii) common partner Smad4 (Co-Smad); and (iii) inhibitory Smad6 and -7 (I-Smads, part of a negative feedback loop). We have investigated the signaling components for the TGF-beta pathway and TGF-beta activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-beta signaling events, including phosphorylation of Smad2 and -3, and transcription of the PAI-1 gene are increased in scleroderma fibroblasts, relative to normal fibroblasts. In vitro adenoviral gene transfer with Smad7 restores normal TGF-beta signaling in scleroderma fibroblasts. These results suggest that alterations in the Smad pathway, including marked Smad7 deficiency and Smad3 up-regulation, may be responsible for TGF-beta hyperresponsiveness observed in scleroderma.
硬皮病是一种导致受累器官纤维化的慢性全身性疾病。转化生长因子（TGF）β与硬皮病的发病机制有关。Smad蛋白是TGF-β受体下游的信号转导分子。已鉴定出三类Smad蛋白：（i）受体调节型Smad2和Smad3（R-Smads）；（ii）共同伴侣Smad4（Co-Smad）；以及（iii）抑制性Smad6和Smad7（I-Smads，负反馈环的一部分）。我们已经在体内硬皮病病变和体外硬皮病成纤维细胞中研究了TGF-β信号通路的信号成分和TGF-β活性。Smad7的基础水平和TGF-β诱导型表达选择性降低，而在硬皮病皮肤和培养的外植硬皮病成纤维细胞中Smad3表达均增加。相对于正常成纤维细胞，硬皮病成纤维细胞中的TGF-β信号事件，包括Smad2和Smad3的磷酸化以及PAI-1基因的转录均增加。体外使用Smad7进行腺病毒基因转移可恢复硬皮病成纤维细胞中正常的TGF-β信号传导。这些结果表明，Smad通路的改变，包括明显的Smad7缺乏和Smad3上调，可能是硬皮病中观察到的TGF-β高反应性的原因。
