Targeted disruption of TGF-β/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma
Targeted disruption of TGF-β/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma
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DOI：
10.1016/s0002-9440(10)63289-0
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发表时间：
2004-07-01
影响因子：
6
通讯作者：
Varga, J
中科院分区：
文献类型：
--
作者：
Lakos, G;Takagawa, S;Varga, J
转化生长因子-β（TGF-β）是结缔组织积聚的有效刺激物，并且涉及硬皮病和其他纤维化病症的发病机制。Smad3在正常皮肤成纤维细胞中作为促纤维化TGF-β反应的关键细胞内信号转导子发挥作用。Smad3在硬皮病发病机制中的潜在作用在Smad3-null（Smad3（-/-））小鼠中使用通过皮下注射博来霉素诱导的皮肤纤维化模型研究。在早期时间点，博来霉素诱导的真皮中巨噬细胞浸润和局部TGF-β产生在Smad3（-/-）和野生型小鼠中相似。相比之下，在第28天，与野生型小鼠相比，Smad3（-/-）小鼠的病变皮肤显示出减弱的纤维化、较低的胶原合成和积累以及原位胶原基因转录减少。结缔组织生长因子和α-平滑肌肌动蛋白在病变皮肤中的表达也显著减弱。电子显微镜检查显示博来霉素处理的Smad3（-/-）小鼠真皮中没有小直径胶原纤维。与来自野生型小鼠的成纤维细胞相比，Smad3（-/-）成纤维细胞显示出由TGF-β引起的体外增殖和促纤维化反应降低。总之，这些结果表明，Smad3的消融与体内和体外成纤维细胞调节的显著改变有关，并在小鼠中赋予对博来霉素诱导的硬皮病的部分保护。纤维化减少是由于成纤维细胞功能失调，因为博来霉素诱导的炎症反应在野生型和Smad3（-/-）小鼠中相似。
Transforming growth factor-beta (TGF-beta) is a potent stimulus of connective tissue accumulation, and is implicated in the pathogenesis of scleroderma and other fibrotic disorders. Smad3 functions as a key intracellular signal transducer for profibrotic TGF-beta responses in normal skin fibroblasts. The potential role of Smad3 in the pathogenesis of scleroderma. was investigated in Smad3-null (Smad3(-/-)) mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. At early time points, bleomycin-induced macrophage infiltration in the dermis and local TGF-beta production were similar in Smad3(-/-) and wild-type mice. In contrast, at day 28, lesional skin from Smad3(-/-) mice showed attenuated fibrosis, lower synthesis and accumulation of collagen, and reduced collagen gene transcription in situ, compared to wild-type mice. Connective tissue growth factor and a-smooth muscle actin expression in lesional skin were also significantly attenuated. Electron microscopy revealed an absence of small diameter collagen fibrils in the dermis from bleomycin-treated Smad3(-/-) mice. Compared to fibroblasts derived from wild-type mice, Smad3(-/-) fibroblasts showed reduced in vitro proliferative and profibrotic responses elicited by TGF-beta. Together, these results indicate that ablation of Smad3 is associated with markedly altered fibroblast regulation in vivo and in vitro, and confers partial protection from bleomycin-induced scleroderma in mice. Reduced fibrosis is due to deregulated fibroblast function, as the inflammatory response induced by bleomycin was similar in wild-type and Smad3(-/-) mice.