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.
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OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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|
|Dewey Decimal Classification:||610 Medicine & health|
|Deposited On:||11 Jul 2012 07:41|
|Last Modified:||28 Nov 2013 00:56|
|Publisher:||BMJ Publishing Group|
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