Reich, Nicole; Tomcik, Michal; Zerr, Pawel; Lang, Veronika; Dees, Clara; Avouac, Jérome; Palumbo, Katrin; Horn, Angelika; Akhmetshina, Alfiya; Beyer, Christian; Xie, Weilin; Bennett, Brydon L; Distler, Oliver; Schett, Georg; Distler, Jörg H W (2012). Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis. Annals of the Rheumatic Diseases, 71(5):737-745.
Full text not available from this repository.
View at publisher
The hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach.
Phosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis.
Transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis.
These data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFβ and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
|DDC:||610 Medicine & health|
|Deposited On:||11 Jul 2012 07:41|
|Last Modified:||28 Nov 2013 00:56|
|Publisher:||BMJ Publishing Group|
Users (please log in): suggest update or correction for this item
Repository Staff Only: item control page