Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts
Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts
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DOI：
10.1002/art.10896
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发表时间：
2003-04-01
影响因子：
--
通讯作者：
Matsuyama, T
中科院分区：
文献类型：
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作者：
Murota, H;Hamasaki, Y;Matsuyama, T
Objective.确定肿瘤坏死因子受体p55（TNFRp 55）介导的信号传导在硬皮病发病机制中的作用。方法。使用了与人类系统性硬化症非常相似的硬皮病小鼠模型。野生型和TNFRp 55缺陷型（TNFRp 55（-/-））小鼠每天接受博来霉素皮下注射。皮肤纤维化的程度通过测量真皮厚度以及组织学检查来确定。通过逆转录-聚合酶链反应或蛋白质印迹法分析体内和体外纤维化细胞因子、前胶原α 1和基质金属蛋白酶1（MMP-1）、MMP-2和MMP-9信使RNA（mRNA）的表达水平。TNFRp 55（-/-）小鼠在皮下注射博来霉素的第3天开始出现严重的真皮硬化变化，而野生型小鼠则没有。在有或没有博莱霉素治疗的情况下，野生型和TNFRp 55（-/-）小鼠皮肤中的纤维形成细胞因子、前胶原α 1、MMP-2和MMP-9 mRNA的表达水平不受影响。博来霉素处理的TNFRp 55（-/-）小鼠皮肤中MMP-1的诱导表达被显著抑制，并且在体外也观察到这种现象。这些结果表明，由TNFRp 55介导的信号传导在MMP-1表达中起重要作用，并且在该鼠模型中的胶原降解过程中起关键作用。本研究为进一步认识硬皮病的发病机制和制定治疗干预措施提供了依据。
Objective. To determine the role of tumor necrosis factor receptor p55 (TNFRp55)-mediated signaling in the pathogenesis of scleroderma.Methods. A murine model of scleroderma that closely resembles systemic sclerosis in humans was used. Wild-type and TNFRp55-deficient (TNFRp55(-/-)) mice received a subcutaneous injection of bleomycin each day. The extent of skin fibrosis was determined by measurements of the dermal thickness, as well as histologic examinations. Expression levels of fibrogenic cytokines, procollagen alpha1, and matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-9 messenger RNA (mRNA) were analyzed, both in vivo and in vitro, by reverse transcriptase-polymerase chain reaction assay or Western blotting.Results. TNFRp55(-/-) mice began to develop severe sclerotic changes of the dermis on day 3 of the subcutaneous injections of bleomycin, while wild-type mice did not. The expression levels of fibrogenic cytokines, procollagen alpha1, and MMP-2 and MMP-9 mRNA were unaffected in the skin of both wild-type and TNFRp55(-/-) mice, with or without bleomycin treatment. Induction of MMP-1 expression was significantly inhibited in the skin from bleomycin-treated TNFRp55(-/-) mice, and this phenomenon was also observed in vitro.Conclusion. These results indicated that signaling mediated by TNFRp55 plays an essential role in MMP-1 expression and a key role in the collagen degradation process in this murine model. This study might provide a basis for understanding the pathogenesis of scleroderma and formulating therapeutic intervention.