JAK2 as a novel mediator of the pro-fibrotic effects of TGF(beta) in systemic sclerosis
Arthritis & Rheumatism,

Dees C et al. – The authors demonstrated that JAK2 is activated in a TGF(beta) dependent manner in systemic sclerosis (SSc). Considering the potent anti–fibrotic effects of JAK2 inhibition, the study might have direct translational implications, because inhibitors of JAK2 are currently evaluated in clinical trials for myeloproliferative disorders and would be also available for evaluation in SSc patients.

Methods
  • Activation of JAK2 in human skin and in experimental fibrosis was determined by immunohistochemistry.
  • JAK2 signaling was inhibited with the selective JAK2 inhibitor TG 101209 or by siRNA.
  • Bleomycin–induced dermal fibrosis and tight–skin 1 (Tsk–1) mice were used to evaluate the anti–fibrotic potential of a specific JAK2 inhibition in vivo.

Results
  • Increased activation of JAK2 was detected in the skin of SSc patients, particularly in fibroblasts.
  • The activation of JAK2 was TGFΒ dependent and persisted in cultured SSc fibroblasts. Inhibition of JAK2 reduced the basal collagen synthesis selectively in SSc fibroblasts but not in resting healthy dermal fibroblasts.
  • Moreover, inhibition of JAK2 prevented the stimulatory effects of TGFΒ on fibroblasts.
  • Treatment with TG 101209 did not only prevent bleomycin–induced fibrosis, but also effectively reduced skin fibrosis in Tsk–1 mice.

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