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Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis


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.

Abstract

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.

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.

Citations

23 citations in Web of Science®
24 citations in Scopus®
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Additional indexing

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
Language:English
Date:2012
Deposited On:11 Jul 2012 07:41
Last Modified:05 Apr 2016 15:52
Publisher:BMJ Publishing Group
ISSN:0003-4967
Publisher DOI:10.1136/annrheumdis-2011-200412
PubMed ID:22258492

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