The transcription factor JunD mediates transforming growth factor -induced fibroblast activation and fibrosis in systemic sclerosis

K. Palumbo, P. Zerr, M. Tomcik, S. Vollath, C. Dees, A. Akhmetshina, J. Avouac, M. Yaniv, O. Distler, G. Schett, J. H. W. Distler
2011 Annals of the Rheumatic Diseases  
OBJECTIVES: Transforming growth factor (TGF) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGF 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 TGF signalling in systemic sclerosis (SSc), was investigated. METHODS: The expression of JunD was analysed by real-time PCR, immunofluorescence, western blotting and
more » ... n 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 bleomycininduced 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 TGF 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 TGF. JunD(-/-) fibroblasts were less responsive to TGF and released less collagen upon stimulation with TGF. 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 TGF. 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.
doi:10.1136/ard.2010.148296 pmid:21515915 fatcat:xhxogzkl6vhuthurhnf4lqdsne