title: Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Veronika
authors.initials: V
authors.lastname: Lang
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Jérome
authors.initials: J
authors.lastname: Avouac
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Weilin
authors.initials: W
authors.lastname: Xie
authors.forename: Brydon L
authors.initials: BL
authors.lastname: Bennett
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D018390:Gene Targeting; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C570789:4-(9-(tetrahydrofuran-3-yl))-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylaminocyclohexan-1-ol; D003511:Cyclohexanols; D016326:Extracellular Matrix Proteins; D011687:Purines; D001761:Bleomycin; D048031:JNK Mitogen-Activated Protein Kinases