To better understand the role of disrupted
transforming growth factor beta (
TGFbeta) signaling in
fibrosis, we have selectively expressed a
kinase-deficient human type II
TGFbeta receptor (TbetaRIIDeltak) in fibroblasts of transgenic mice, using a lineage-specific expression cassette subcloned from the pro-alpha2(I)
collagen gene. Surprisingly, despite previous studies that characterized TbetaRIIDeltak as a dominant negative inhibitor of
TGFbeta signaling, adult mice expressing this construct demonstrated
TGFbeta overactivity and developed dermal and
pulmonary fibrosis. Compared with wild type cells, transgenic fibroblasts proliferated more rapidly, produced more extracellular matrix, and showed increased expression of key markers of
TGFbeta activation, including
plasminogen activator inhibitor-1,
connective tissue growth factor, Smad3, Smad4, and Smad7. Smad2/3 phosphorylation was increased in transgenic fibroblasts. Overall, the gene expression profile of explanted transgenic fibroblasts using
cDNA microarrays was very similar to that of littermate wild type cells treated with recombinant TGFbeta1. Despite basal up-regulation of
TGFbeta signaling pathways, transgenic fibroblasts were relatively refractory to further stimulation with TGFbeta1. Thus, responsiveness of endogenous genes to
TGFbeta was reduced, and
TGFbeta-regulated promoter-reporter constructs transiently transfected into transgenic fibroblasts showed little activation by recombinant TGFbeta1. Responsiveness was partially restored by overexpression of wild type type II
TGFbeta receptors. Activation of MAPK pathways by recombinant TGFbeta1 appeared to be less perturbed than Smad-dependent signaling. Our results show that expression of TbetaRIIDeltak selectively in fibroblasts leads to paradoxical
ligand-dependent activation of downstream signaling pathways and causes skin and lung
fibrosis. As well as confirming the potential for nonsignaling receptors to regulate
TGFbeta activity, these findings support a direct role for perturbed
TGFbeta signaling in
fibrosis and provide a novel genetically determined animal model of fibrotic disease.