Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes.
Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes.
复制标题
DOI：
10.1002/path.4481
复制
发表时间：
2015-04
影响因子：
7.3
通讯作者：
Atit, Radhika P.
中科院分区：
文献类型：
--
作者：
Hamburg-Shields, Emily;DiNuoscio, Gregg J.;Mullin, Nathaniel K.;Lafayatis, Robert;Atit, Radhika P.
纤维化是对组织损伤的终末期反应，其与由于成纤维细胞产生过量细胞外基质（ECM）而导致的器官功能丧失相关。在皮肤中，病理性纤维化在瘢痕疙瘩形成、系统性硬化症（SSc）和硬斑病期间是明显的。这些纤维化疾病中的真皮成纤维细胞表现出增加的Wnt/β-连环蛋白信号传导，这是一种足以引起小鼠纤维化的途径。然而，在这种复杂病理学的背景下，Wnt/β-连环蛋白信号传导的确切促纤维化后果尚不清楚。我们发现，稳定的β-连环蛋白在小鼠真皮成纤维细胞中的表达导致自发的、进行性的皮肤纤维化，胶原纤维增厚，胶原纤维形态改变。纤维化表型主要由常驻真皮成纤维细胞。纤维化小鼠真皮的全基因组分析显示基质编码基因的表达升高，并且这些基因的启动子区域富含Tcf/Lef家族转录因子结合位点。此外，我们在我们的小鼠模型中鉴定了32个β-连环蛋白应答基因，这些基因也在人类纤维化组织中过表达，并准备通过Tcf/Lef家族转录因子进行调节。因此，我们发现了稳定的β-连环蛋白在体内成纤维细胞中的基质调节作用，并确定了一组与纤维化疾病相关的β-连环蛋白应答基因。
Fibrosis is an end-stage response to tissue injury that is associated with loss of organ function as a result of excess extracellular matrix (ECM) production by fibroblasts. In skin, pathologic fibrosis is evident during keloid scar formation, systemic sclerosis (SSc), and morphea. Dermal fibroblasts in these fibrotic diseases exhibit increased Wnt/β-catenin signaling, a pathway that is sufficient to cause fibrosis in mice. However, in the context of this complex pathology, the precise pro-fibrotic consequences of Wnt/β-catenin signaling are not known. We found that expression of stabilized β-catenin in mouse dermal fibroblasts resulted in spontaneous, progressive skin fibrosis with thickened collagen fibres and altered collagen fibril morphology. The fibrotic phenotype was predominated by resident dermal fibroblasts. Genome-wide profiling of the fibrotic mouse dermis revealed elevated expression of matrix-encoding genes, and the promoter regions of these genes were enriched for Tcf/Lef family transcription factor binding sites. Additionally, we identified 32 β-catenin-responsive genes in our mouse model that are also over-expressed in human fibrotic tissues and poised for regulation by Tcf/Lef family transcription factors. Therefore, we have uncovered a matrix-regulatory role for stabilized β-catenin in fibroblasts in vivo and have defined a set of β-catenin-responsive genes with relevance to fibrotic disease.
登录
查看更多内容
DOI：
10.1073/pnas.102657399
发表时间：
2002-05-14
影响因子：
11.1
作者：
Cheon, SS;Cheah, AYL;Alman, BA
通讯作者：
Alman, BA
影响因子：
3.6
作者：
Dees, Clara;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
27.4
作者：
Distler, Alfiya;Lang, Veronika;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.