The transcription factor JunD mediates transforming growth factor β-induced fibroblast activation and fibrosis in systemic sclerosis. Issue 7 (24th April 2011)

• Record Type: Journal Article
• Authors: Palumbo, Katrin; Zerr, Pawel; Tomcik, Michal; Vollath, Stefan; Dees, Clara; Akhmetshina, Alfiya; Avouac, Jerome; Yaniv, Moshe; Distler, Oliver; Schett, Georg; Distler, Jörg H W
• Is Part Of: Annals of the rheumatic diseases. Volume 70:Issue 7(2011)
• Page Start: 1320
• Page End: 1326
• Publication Date: 2011-04-24
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/ard.2010.148296
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: Transforming growth factor β (TGFβ) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGFβ activates fibroblasts are incompletely understood. Here, the role of JunD, a member of the activator protein 1 (AP-1) family of transcription factors, as a downstream mediator of TGFβ signalling in systemic sclerosis (SSc), was investigated. Methods: The expression of JunD was analysed by real-time PCR, immunofluorescence, western blotting and immunohistochemistry. The canonical Smad pathway was specifically targeted by small interfering (si)RNA. The expression of extracellular matrix proteins in JunD deficient (JunD −/− ) fibroblasts was analysed by real-time PCR and hydroxyproline assays. The mouse model of bleomycin-induced dermal fibrosis was used to assess the role of JunD in experimental fibrosis. Results: JunD was overexpressed in SSc skin and in cultured fibroblasts in a TGFβ dependent manner. The expression of JunD colocalised with pSmad 3 in fibrotic skin and silencing of Smad 3 or Smad 4 by siRNA prevented the induction of JunD by TGFβ. JunD −/− fibroblasts were less responsive to TGFβ and released less collagen upon stimulation with TGFβ. Moreover, JunD −/− mice were protected from bleomycin-induced fibrosis with reduced dermal thickening, decreased myofibroblast counts and lower collagen content of lesional skin. Conclusions: These data demonstrate that JunD is overexpressed in SSc and that JunD is a mediator of the profibrotic effects of TGFβ. Considering that inhibitors of AP-1 signalling have recently been developed and are available for clinical trials in SSc, these findings may have translational implications.