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J. Biol. Chem., Vol. 278, Issue 27, 25109-25119, July 4, 2003

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Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor (TGF) Receptor Leads to Paradoxical Activation of TGF Signaling Pathways with Fibrosis in Transgenic Mice^*

Christopher P. Denton  , Bing Zheng ¶, Lowri A. Evans , Xu Shi-wen , Voon H. Ong , Ivan Fisher , Konstantinos Lazaridis ||, David J. Abraham , Carol M. Black  and Benoit de Crombrugghe ¶

From the Centre for Rheumatology, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom, ^¶University of Texas M.D. Anderson Cancer Center, Department of Molecular Genetics, Houston, Texas 77030, and the ^||School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom

To better understand the role of disrupted transforming growth factor (TGF) signaling in fibrosis, we have selectively expressed a kinase-deficient human type II TGF receptor (TRIIk) in fibroblasts of transgenic mice, using a lineage-specific expression cassette subcloned from the pro-2(I) collagen gene. Surprisingly, despite previous studies that characterized TRIIk as a dominant negative inhibitor of TGF signaling, adult mice expressing this construct demonstrated TGF 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 TGF 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 TGF1. Despite basal up-regulation of TGF signaling pathways, transgenic fibroblasts were relatively refractory to further stimulation with TGF1. Thus, responsiveness of endogenous genes to TGF was reduced, and TGF-regulated promoter-reporter constructs transiently transfected into transgenic fibroblasts showed little activation by recombinant TGF1. Responsiveness was partially restored by overexpression of wild type type II TGF receptors. Activation of MAPK pathways by recombinant TGF1 appeared to be less perturbed than Smad-dependent signaling. Our results show that expression of TRIIk 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 TGF activity, these findings support a direct role for perturbed TGF signaling in fibrosis and provide a novel genetically determined animal model of fibrotic disease.

Received for publication, January 21, 2003 , and in revised form, April 16, 2003.

^* This work was supported by grants from the Wellcome Trust (UK), the Arthritis Research Campaign (UK), the Raynaud's and Scleroderma Association and the National Institutes of Health including Specialized Center of Research Grant in Scleroderma P50AR44888 at the University of Texas-Houston Health Science Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Centre for Rheumatology, University College London, Royal Free Campus, Rowland Hill St., London NW3 2PF, UK. Tel.: 44-20-7794-0432; Fax: 44-20-7794-0432; E-mail: c.denton{at}rfc.ucl.ac.uk.

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