TY - JOUR T1 - The transcription factor JunD mediates transforming growth factor β-induced fibroblast activation and fibrosis in systemic sclerosis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1320 LP - 1326 DO - 10.1136/ard.2010.148296 VL - 70 IS - 7 AU - Katrin Palumbo AU - Pawel Zerr AU - Michal Tomcik AU - Stefan Vollath AU - Clara Dees AU - Alfiya Akhmetshina AU - Jerome Avouac AU - Moshe Yaniv AU - Oliver Distler AU - Georg Schett AU - Jörg H W Distler Y1 - 2011/07/01 UR - http://ard.bmj.com/content/70/7/1320.abstract N2 - 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. ER -