Evaluation of the TGF-ß induced activation of JAK2 / STAT3 signaling as a key-pathway for fibroblast activation in fibrotic diseases

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Fibrotic diseases impose a major socioeconomic burden on modern societies and account for up to 45% of deaths in the developed world. The common histopathological feature of all fibrotic disorders is an excessive accumulation of extracellular matrix, which is released by persistently activated fibroblasts. The molecular mechanisms that lead to the pathologic activation of fibroblasts are incompletely understood and consequently, effective targeted therapies are not yet available for the treatment of fibrotic diseases. We demonstrated for the first time that transforming growth factor-beta (TGF-beta) activates JAK2 / STAT3 signaling in fibroblasts and that activation of JAK2 / STAT3 signaling in fibroblasts is a common feature of fibrotic diseases. We also showed that activation of JAK2 / STAT3 is required for the pro-fibrotic effects of TGF-beta, because pharmacologic or genetic inactivation of JAK2 inhibits TGF-beta induced fibroblasts activation in vitro and prevents fibrosis in murine models of systemic fibrosis in vivo. We now aim to further investigate JAK2 and STAT3 as potential targets for anti-fibrotic therapies. We plan to inhibit STAT3 signaling in experimental models of fibrosis using small molecule inhibitors and mice with fibroblast-specific deletion of STAT3. We also plan to characterize the molecular mechanisms, by which TGF-ß activates JAK2 / STAT3 signaling. Moreover, we will analyze how JAK2 / STAT3 activate myofibroblast differentiation and stimulate the release of collagen. Finally, we will transfer our findings from preclinical models of SSc to other fibrotic diseases with enhanced JAK2 / STAT3 signaling and analyze the anti-fibrotic effects of JAK2- and STAT3 inhibition in murine models of idiopathic pulmonary fibrosis (IPF), sclerodermatous graft-versus-host disease (cGvHD), renal fibrosis and non-alcoholic liver fibrosis. We believe that our study may have direct translational implications, because first JAK inhibitors have already been approved for clinical use in rheumatoid arthritis and myeloproliferative diseases and would thus be available for clinical trials in fibrotic diseases. Moreover, additional JAK2- and STAT3 inhibitors are currently in clinical development.