JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis

Arthritis Rheum. 2012 Sep;64(9):3006-15. doi: 10.1002/art.34500.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fibrosis / metabolism
  • Humans
  • Janus Kinase 2 / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Phosphorylation
  • Pyrimidines / pharmacology
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Signal Transduction / drug effects
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology
  • Sulfonamides / pharmacology
  • Transforming Growth Factor beta / metabolism*


  • Enzyme Inhibitors
  • Pyrimidines
  • Sulfonamides
  • TG101209
  • Transforming Growth Factor beta
  • Janus Kinase 2