Dr. O. Distler has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, Bristol-Myers Squibb, Sanofi Aventis, United BioSource, Medac, Swedish Orphan Biovitrum, Novartis, 4D Science, and Active Biotec in the area of potential treatments of scleroderma.
JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis
Article first published online: 27 AUG 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 9, pages 3006–3015, September 2012
How to Cite
Dees, C., Tomcik, M., Palumbo-Zerr, K., Distler, A., Beyer, C., Lang, V., Horn, A., Zerr, P., Zwerina, J., Gelse, K., Distler, O., Schett, G. and Distler, J. H. W. (2012), JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis & Rheumatism, 64: 3006–3015. doi: 10.1002/art.34500
- Issue published online: 27 AUG 2012
- Article first published online: 27 AUG 2012
- Accepted manuscript online: 1 MAY 2012 11:48AM EST
- Manuscript Accepted: 5 APR 2012
- Manuscript Received: 6 JUL 2011
- Deutsche Forschungsgesellschaft
- Interdisciplinary Center of Clinical Research in Erlangen (IZKF). Grant Number: A20
- CMH. Grant Number: Research Projects no. 00000023728
- Ernst Jung Foundation Career Support Award of Medicine
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.
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.
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.
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.