title: JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis.
abstract: OBJECTIVE
  To investigate whether JAK-2 contributes to the pathologic activation of fibroblasts in patients with systemic sclerosis (SSc) and to evaluate the antifibrotic potential of JAK-2 inhibition for the treatment of SSc.
  
  
  METHODS
  Activation of JAK-2 in human skin and in experimental fibrosis was determined by immunohistochemical analysis. JAK-2 signaling was inhibited by the selective JAK-2 inhibitor TG101209 or by small interfering RNA. Bleomycin-induced dermal fibrosis in mice and TSK-1 mice were used to evaluate the antifibrotic potential of specific JAK-2 inhibition in vivo.
  
  
  RESULTS
  Increased activation of JAK-2 was detected in the skin of patients with SSc, particularly in fibroblasts. The activation of JAK-2 was dependent on transforming growth factor β (TGFβ) and persisted in cultured SSc fibroblasts. Inhibition of JAK-2 reduced basal collagen synthesis selectively in SSc fibroblasts but not in resting healthy dermal fibroblasts. Moreover, inhibition of JAK-2 prevented the stimulatory effects of TGFβ on fibroblasts. Treatment with TG101209 not only prevented bleomycin-induced fibrosis but also effectively reduced skin fibrosis in TSK-1 mice.
  
  
  CONCLUSIONS
  We demonstrated that JAK-2 is activated in a TGFβ-dependent manner in SSc. Considering the potent antifibrotic effects of JAK-2 inhibition, our study might have direct translational implications, because inhibitors of JAK-2 are currently being evaluated in clinical trials for myeloproliferative disorders and would also be available for evaluation in patients with SSc.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Veronika
authors.initials: V
authors.lastname: Lang
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Kolja
authors.initials: K
authors.lastname: Gelse
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; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D004791:Enzyme Inhibitors; D053614:Janus Kinase 2; D011743:Pyrimidines; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; C522865:TG101209; D000096926:Benzenesulfonamides