Deficient Smad7 expression: A putative molecular defect in scleroderma (Retracted Article)
Deficient Smad7 expression: A putative molecular defect in scleroderma (Retracted Article)
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DOI：
10.1073/pnas.062010399
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Goldschmidt-Clermont, PJ
中科院分区：
文献类型：
--
作者：
Dong, CM;Zhu, SK;Goldschmidt-Clermont, PJ
硬皮病是一种慢性全身性疾病，导致受影响器官的纤维化。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蛋白。已鉴定出三个Smads家族：（i）受体调节的Smad2和-3（R-Smads）;（ii）共同伴侣Smad4。（iii）抑制性Smad6和-7（I-Smads，负反馈环的一部分）。我们研究了体内硬皮病病变和体外硬皮病成纤维细胞中TGF-β途径和TGF-β活性的信号传导成分。基础水平和TGF-β诱导的Smad7的表达选择性降低，而Smad3的表达在硬皮病皮肤和培养的硬皮病成纤维细胞中均增加。相对于正常成纤维细胞，硬皮病成纤维细胞中的TGF-β信号传导事件，包括Smad2和-3的磷酸化以及PAI-1基因的转录增加。体外腺病毒基因转移与Smad7恢复正常的TGF-β信号在硬皮病成纤维细胞。这些结果表明，Smad通路的改变，包括Smad7明显缺乏和Smad3上调，可能是硬皮病中观察到的TGF-β高反应性的原因。
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.