Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma
Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma
复制标题
DOI：
10.1002/art.22328
复制
发表时间：
2007-01-01
影响因子：
--
通讯作者：
de Crombrugghe, Benoit
中科院分区：
文献类型：
--
作者：
Sonnylal, Sonali;Denton, Christopher P.;de Crombrugghe, Benoit
目标。转化生长因子β信号增强与系统性硬化症(SSC；硬皮病)有关，硬皮病是一种复杂的结缔组织疾病，其特征是胶原和其他细胞外基质成分在全身器官中过度堆积。为了直接评估持续的转化生长因子β信号通路在硬化性硬化症中的作用，我们建立了一种新的小鼠模型，在该模型中，转化生长因子β信号通路在生后激活成纤维细胞。我们使用的小鼠(称为TBR1(CA)；Cre-ER小鼠)既携带针对ROSA位点的可诱导的结构性活性转化生长因子β受体I(TGFβRI)突变的DNA，也携带由成纤维细胞特异性启动子驱动的Cre-ER转基因。出生后2周给予4-羟基三苯氧胺可激活结构性活性的转化生长因子βRi的表达。这些小鼠概括了人类SSc的临床、组织学和生化特征，表现为真皮明显和广泛的纤维化，表皮变薄，毛囊丢失，肺和肾脏的小血管壁纤维性增厚。来自这些小鼠的原代皮肤成纤维细胞显示出下游转化生长因子β靶标的高表达，复制了移植的SSC真皮成纤维细胞的标志性生化表型。小鼠成纤维细胞还表现出转化生长因子β调节的启动子纤溶酶原激活物抑制物1和3TP的基础表达增加，Smad2/3磷酸化增强，促进成纤维细胞分化。生后小鼠成纤维细胞中转化生长因子β信号的结构性激活导致了SSC明显的纤维化表型。这些小鼠应该是测试旨在纠正人类硬皮病过度转化生长因子β信号的治疗方法的优秀模型。
Objective. Increased signaling by transforming growth factor beta (TGF beta) has been implicated in systemic sclerosis (SSc; scleroderma), a complex disorder of connective tissues characterized by excessive accumulation of collagen and other extracellular matrix components in systemic organs. To directly assess the effect of sustained TGF beta signaling in SSc, we established a novel mouse model in which the TGF beta signaling pathway is activated in fibroblasts postnatally.Methods. The mice we used (termed TBR1(CA); Cre-ER mice) harbor both the DNA for an inducible constitutively active TGF beta receptor I (TGF beta RI) mutation, which has been targeted to the ROSA locus, and a Cre-ER transgene that is driven by a fibroblast-specific promoter. Administration of 4-hydroxytamoxifen 2 weeks after birth activates the expression of constitutively active TGF beta RI.Results. These mice recapitulated clinical, histologic, and biochemical features of human SSc, showing pronounced and generalized fibrosis of the dermis, thinner epidermis, loss of hair follicles, and fibrotic thickening of small blood vessel walls in the lung and kidney. Primary skin fibroblasts from these mice showed elevated expression of downstream TGF beta targets, reproducing the hallmark biochemical phenotype of explanted SSc dermal fibroblasts. The mouse fibroblasts also showed elevated basal expression of the TGF beta-regulated promoters plasminogen activator inhibitor 1 and 3TP, increased Smad2/3 phosphorylation, and enhanced myofibroblast differentiation.Conclusion. Constitutive activation of TGF beta signaling in fibroblastic cells of mice after birth caused a marked fibrotic phenotype characteristic of SSc. These mice should be excellent models with which to test therapies aimed at correcting excessive TGF beta signaling in human scleroderma.