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Abstract

Objective

Increased signaling by transforming growth factor β (TGFβ) 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 TGFβ signaling in SSc, we established a novel mouse model in which the TGFβ signaling pathway is activated in fibroblasts postnatally.

Methods

The mice we used (termed TBR1CA; Cre-ER mice) harbor both the DNA for an inducible constitutively active TGFβ receptor I (TGFβRI) 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 TGFβRI.

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 TGFβ targets, reproducing the hallmark biochemical phenotype of explanted SSc dermal fibroblasts. The mouse fibroblasts also showed elevated basal expression of the TGFβ-regulated promoters plasminogen activator inhibitor 1 and 3TP, increased Smad2/3 phosphorylation, and enhanced myofibroblast differentiation.

Conclusion

Constitutive activation of TGFβ 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 TGFβ signaling in human scleroderma.