Journal
ANNALS OF THE RHEUMATIC DISEASES
Volume 70, Issue 7, Pages 1320-1326Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/ard.2010.148296
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Funding
- Interdisciplinary Center of Clinical Research (IZKF) in Erlangen [A40]
- Deutsche Forschungsgesellschaft [00000023728]
- Medicine of the Ernst Jung Foundation
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Objectives Transforming growth factor beta (TGF beta) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGF beta 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 beta 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 TGF beta 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 beta. JunD(-/-) fibroblasts were less responsive to TGF beta and released less collagen upon stimulation with TGF beta. 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 beta. 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.
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