JAK-2 as a Novel Mediator of the Profibrotic Effects of Transforming Growth Factor β in Systemic Sclerosis

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 beta (TGF beta) 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 TGF beta 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 TGF beta-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.