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