Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Transforming Growth Factor Beta Mediated Activation of Canonical Wnt Signaling Is Crucial for the Development of Fibrosis In Systemic Sclerosis.

Akhmetshina1,  Alfiya, Palumbo2,  Katrin, Bergmann2,  Christina, Venalis2,  Paulius, Dees2,  Clara, Zerr2,  Pawel, Horn2,  Angelika

Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
University of Erlangen-Nuremberg, Erlangen, Germany
Department of Pediatrics, University of Erlangen-Nuremberg, Erlangen, Germany
University Hospital Zurich, Zurich, Switzerland

Background/Purpose:

Wnt signaling profoundly affects developmental processes and plays an important role for tissue homeostasis. Aberrant activation of the canonical Wnt pathway has been implicated in a variety of different diseases. To avoid uncontrolled activation, Wnt signaling is tightly controlled by negative regulators such as dickkopf-1 (Dkk-1). Here, we investigated the interaction between TGFb dependent pathways and canonical Wnt signaling as a novel molecular mechanism in SSc.

Methods:

Canonical Wnt signaling was modulated in vivo using Wnt10b- and Dickkopf (Dkk)-1 transgenic mice. The role of Wnt signaling was investigated in the mouse model of bleomycin-induced dermal fibrosis, in tight-skin-1 (Tsk-1) mice and in mice overexpressing constitutively active TGFb receptor type I.

Results:

Canonical Wnt signaling is activated in SSc and in experimental fibrosis with nuclear accumulation of b-catenin and increased expression of the target gene axin-2. We demonstrate that the activation of canonical Wnt signaling in SSc is mediated by TGFb. TGFb decreases the mRNA and protein levels of Dkk-1, a potent inhibitor of Wnt signaling, in a p38 dependent, Smad-independent manner by more than 80%. Indeed, the expression of Dkk-1 is almost undetectable in the skin of SSc patients and in different models of experimental models of fibrosis. Stimulation with TGF-b or overexpression of constitutively active TGFb receptor type I potently activated canonical Wnt signaling in vitro and in vivo with nuclear accumulation of b-catenin, increased TOP-reporter activity and induction of axin-2. In contrast, inhibition of TGFb-signaling in experimental models of fibrosis by SD-208, a selective inhibitor of TGFb receptor kinase activity, almost completely prevented the activation of canonical Wnt-signaling, highlighting the key-role of TGFb for the activation of Wnt signaling in fibrosis. We also show that the activation of Wnt signaling directly contributes to the pro-fibrotic effects of TGFb. Canonical Wnt signaling stimulates the release of collagen in vitro and induces massive fibrosis in vivo. Recombinant Dkk-1 strongly reduced the stimulatory effects of TGFb on cultured fibroblasts and decreased the TGFb-induced upregulation of collagen, aSMA and stress fibers by up to 75%. Moreover, transgenic overexpression of Dkk-1 ameliorates fibrosis in mice induced by adenoviral transfection of constitutively active TGF receptor type I with reduction of dermal thickening, myofibroblast counts and hydroxyproline content by 75 ± 7%, 85 ± 5% and 80 ± 11% respectively (p < 0.02 for all). Overexpression of Dkk-1 also exerted potent anti-fibrotic effects in bleomycin induced dermal fibrosis and in Tsk-1 mice.

Conclusion:

Canonical Wnt pathway is activated in SSc and potently stimulates fibroblast activation and tissue fibrosis. TGFb activates canonical Wnt signaling in SSc by decreasing the expression of the Wnt inhibitor Dkk-1. Overexpression of Dkk-1 potently reduces the pro-fibrotic effects of TGFb and prevents fibrosis in different experimental models, demonstrating that the interaction of the canonical Wnt pathway and TGF-b plays a key role in the pathogenesis of fibrotic diseases.

To cite this abstract, please use the following information:
Akhmetshina, Alfiya, Palumbo, Katrin, Bergmann, Christina, Venalis, Paulius, Dees, Clara, Zerr, Pawel, et al; Transforming Growth Factor Beta Mediated Activation of Canonical Wnt Signaling Is Crucial for the Development of Fibrosis In Systemic Sclerosis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2535
DOI:

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