Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma

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.