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首页> 外文期刊>Journal of Cellular Physiology >Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts.
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Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts.

机译：Endoglin促进及/ Smad1信号硬皮病成纤维细胞。

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摘要

TGF-beta is the primary inducer of extracellular matrix proteins in scleroderma (systemic sclerosis, SSc). Previous studies indicate that in a subset of SSc fibroblasts TGF-beta signaling is activated via elevated levels of activin receptor-like kinase (ALK) 1 and phosphorylated Smad1 (pSmad1). The goal of this study was to determine the role of endoglin/ALK1 in TGF-beta/Smad1 signaling in SSc fibroblasts. In SSc fibroblasts, increased levels of endoglin correlated with high levels of pSmad1, collagen, and connective tissue growth factor (CCN2). Endoglin depletion via siRNA in SSc fibroblasts inhibited pSmad1 but did not affect pSmad2/3. Following endoglin depletion mRNA and protein levels of collagen and CCN2 were significantly decreased in SSc fibroblasts but remained unchanged in normal fibroblasts. ALK1 was expressed at similar levels in SSc and normal fibroblasts. Depletion of ALK1 resulted in inhibition of pSmad1 and a moderate but significant reduction of mRNA and protein levels of collagen and CCN2 in SSc fibroblasts. Furthermore, constitutively high levels of endoglin were found in complexes with ALK1 in SSc fibroblasts. Overexpression of constitutively active ALK1 (caALK1) in normal and SSc fibroblasts led to a moderate increase of collagen and CCN2. However, caALK1 potently induced endothelin 1 (ET-1) mRNA and protein levels in SSc fibroblasts. Additional experiments demonstrated that endoglin and ALK1 mediate TGF-beta induction of ET-1 in SSc and normal fibroblasts. In conclusion, this study has revealed an important profibrotic role of endoglin in SSc fibroblasts. The endoglin/ALK1/Smad1 pathway could be a therapeutic target in patients with SSc if appropriately blocked.
机译：及细胞外的主要诱导物矩阵在硬皮病(系统性的蛋白质硬化,SSc)。SSc成纤维细胞及信号的一个子集通过高浓度的苯丙酸诺龙被激活吗受体激酶(碱性)1和磷酸化Smad1 (pSmad1)。确定endoglin / ALK1的角色鉴定及/ Smad1 SSc成纤维细胞的信号。SSc成纤维细胞,增加endoglin的水平与高水平的pSmad1,胶原蛋白,和结缔组织生长因子(CCN2)。Endoglin损耗通过siRNA SSc成纤维细胞抑制pSmad1 pSmad2/3但没有影响。后endoglin损耗信使rna和蛋白质胶原蛋白和CCN2明显的水平SSc成纤维细胞,但仍然下降维持在正常成纤维细胞。表达了对SSc和正常的在相似的水平成纤维细胞。抑制pSmad1温和但信使rna和蛋白质水平的显著减少SSc成纤维细胞的胶原蛋白和CCN2。此外,持续高水平的SSc endoglin被发现与ALK1复合物成纤维细胞。活动ALK1 (caALK1)在正常和SSc成纤维细胞导致的适度增长胶原蛋白和CCN2。诱导内皮素1 (ET-1)信使rna和蛋白质SSc成纤维细胞的水平。证明endoglin ALK1调解及诱导ET-1 SSc和正常成纤维细胞。透露一个重要profibrotic作用endoglin SSc成纤维细胞。endoglin / ALK1 / Smad1通路可能是一个SSc如果患者的治疗目标适当的屏蔽。

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