Dysregulation of transforming growth factor β signaling in scleroderma -: Overexpression of endoglin in cutaneous scleroderma fibroblasts
Dysregulation of transforming growth factor β signaling in scleroderma -: Overexpression of endoglin in cutaneous scleroderma fibroblasts
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DOI：
10.1002/art.10333
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发表时间：
2002-07-01
影响因子：
--
通讯作者：
Connolly, MK
中科院分区：
文献类型：
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作者：
Leask, A;Abraham, DJ;Connolly, MK
Objective.作为理解系统性硬化症（SSc;硬皮病）表型的基础的初始方法，我们试图鉴定相对于其正常对应物在病变SSc成纤维细胞中上调的转化生长因子β（TGF β）信号通路中的基因。我们使用基因芯片、差异显示、荧光激活细胞分选仪和过表达分析来评估TGF β信号传导组分在纤维化中的潜在作用。成纤维细胞通过穿刺活检从持续时间为2-14个月（平均8个月）的弥漫性皮肤SSc患者和年龄和性别匹配的健康对照组中获得。出乎意料的是，我们发现SSc患者的成纤维细胞显示内皮细胞富集的TGF β受体内皮糖蛋白的表达升高。内皮糖蛋白是非信号传导高亲和力TGF β受体III型家族的成员。endoglin的表达随着疾病的进展而增加。内皮糖蛋白转染成纤维细胞可抑制TGF β介导的结缔组织生长因子启动子活性的诱导。SSc的特征在于基质的过度产生;即，在正常成纤维细胞中作为TGF β信号传导的靶标的基因。我们的研究结果表明，病变SSc成纤维细胞可能过度表达内皮糖蛋白作为一种负反馈机制，试图阻止进一步诱导促纤维化基因的TGF β。
Objective. As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGFbeta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts.Methods. We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGFbeta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects.Results. Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGFbeta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGFbeta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGFbeta-mediated induction of connective tissue growth factor promoter activity.Conclusion. SSc is characterized by overproduction of matrix; that is, genes that are targets of TGFbeta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGFbeta.