The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis
Nicole Reich
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorAlfiya Akhmetshina
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorPaulius Venalis
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorKatrin Palumbo
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorJochen Zwerina
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorTatiana Nevskaya
Russian Academy of Medical Sciences, Moscow, Russia
Search for more papers by this authorOliver Distler
University Hospital Zurich, Zurich, Switzerland
Dr. O. Distler has received consulting fees, speaking fees, and/or honoraria from Encysive, Actelion, Array BioPharma, Biovitrum, Ergonex, Fibrogen, Nicox, Pfizer, and Bristol-Myers Squibb (less than $10,000 each).
Search for more papers by this authorGeorg Schett
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Jörg H. W. Distler
University of Erlangen–Nuremberg, Erlangen, Germany
Dr. J. H. W. Distler has received consulting fees, speaking fees, and/or honoraria from Encysive/Pfizer and Actelion (less than $10,000 each).
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen–Nuremberg, Universitätsstrasse 29, 91054 Erlangen, GermanySearch for more papers by this authorNicole Reich
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorAlfiya Akhmetshina
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorPaulius Venalis
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorKatrin Palumbo
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorJochen Zwerina
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorTatiana Nevskaya
Russian Academy of Medical Sciences, Moscow, Russia
Search for more papers by this authorOliver Distler
University Hospital Zurich, Zurich, Switzerland
Dr. O. Distler has received consulting fees, speaking fees, and/or honoraria from Encysive, Actelion, Array BioPharma, Biovitrum, Ergonex, Fibrogen, Nicox, Pfizer, and Bristol-Myers Squibb (less than $10,000 each).
Search for more papers by this authorGeorg Schett
University of Erlangen–Nuremberg, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Jörg H. W. Distler
University of Erlangen–Nuremberg, Erlangen, Germany
Dr. J. H. W. Distler has received consulting fees, speaking fees, and/or honoraria from Encysive/Pfizer and Actelion (less than $10,000 each).
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen–Nuremberg, Universitätsstrasse 29, 91054 Erlangen, GermanySearch for more papers by this authorAbstract
Objective
Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis.
Methods
Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2–transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor β (TGFβ), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors.
Results
Fra-2–transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFβ and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGFβ and PDGF and decreased the release of collagen from SSc fibroblasts.
Conclusion
We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFβ and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc.
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