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

Abstract

Objective. Increased signaling by transforming growth factor ␤ (TGF␤) 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␤ signaling in SSc, we established a novel mouse model in which the TGF␤ 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␤ receptor I (TGF␤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␤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␤ targets, reproducing the hallmark biochemical phenotype of explanted SSc dermal fibroblasts. The mouse fibroblasts also showed elevated basal expression of the TGF␤-regulated promoters plasminogen activator inhibitor 1 and 3TP, increased Smad2/3 phosphorylation, and enhanced myofibroblast differentiation.Conclusion. Constitutive activation of TGF␤ 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␤ signaling in human scleroderma.

Antiangiogenic plasma activity in patients with systemic sclerosis

“…However, we detected no differences in the level of either plasminogen or PAI-1 between the groups, suggesting that neither plasminogen nor PAI-1 could account for reduced plasmin activity. It should be noted that some studies have shown elevated PAI-1 levels in fibroblasts from patients with SSc (42)(43)(44)(45), while other studies have not (46)(47)(48). It is not clear why results differ in this regard, other than due to relatively small sample sizes in all studies and the high heterogeneity of the SSc patient population.…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…TGF-b also inhibits ECM degradation by downregulating MMP-1, which mediates collagen degradation, and up-regulating tissue inhibitors of matrix metalloproteinases (TIMPs) (Ihn 2005). Activation of the TGF-b pathway in postnatal fibroblasts is sufficient to induce skin fibrosis in mice, including epidermal thinning, loss of hair follicles and dermal fibrosis (Sonnylal et al 2007). Dermal accumulation of collagen type I and III and up-regulation of other ECM proteins, including fibronectin, osteopontin, and SPARC, are observed.…”

Fibroblast‐specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma‐associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model

“…Our group recently developed 2 complementary transgenic mouse strains with fibroblast-specific activation of TGF␤ signaling that demonstrate hallmark pathologic features of SSc. One strain has inducible ligand-independent activation of TGF␤ signaling and develops skin and vascular fibrosis (11). The other transgenic strain (T␤RII⌬k-fib) demonstrates balanced ligand-dependent activation of TGF␤ signaling (12)(13)(14) and is examined further in this study.…”