Arthritis Rheum. 2012 Sep;64(9):3006-15. doi: 10.1002/art.34500.
JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor ß in systemic sclerosis.
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, Distler JH.
University of Erlangen-Nuremberg, Erlangen, Germany.
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 ß (TGFß) 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 TGFß 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 TGFß-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.
(TG101209 is SAR302503, JAK2 selective with respect to JAK3, don't know what it does at JAK1.... also very active at ret and flt3.... Sanofi) |
