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Abstract Number: 968

Priming of WNT Signalling during Fibrosis Is Mediated By TGF-β Induced Axin-2 Downregulation

Justin Gillespie1, Emma C. Derrett-Smith2, Michael McDermott1, Paul Emery3, Christopher P Denton4 and Francesco Del Galdo3, 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, 2Centre for Rheumatology and Connective Tissue Diseases,, UCL Medical School Royal Free Campus, London, United Kingdom, 3Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 4Centre for Rheumatology and Connective Tissue Disease, UCL Medical School Royal Free Campus, London, United Kingdom

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, systemic sclerosis and transforming growth factor, WNT Signaling

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I

Session Type: Abstract Submissions (ACR)

Background/Purpose

Systemic Sclerosis (SSc) is characterized by autoimmune activation, vasculopathy and tissue fibrosis. Recently, activation of the Wnt/β-catenin signaling pathway in SSc fibroblasts has been linked to the pathogenesis of SSc. However, the relative role of crosstalk between TGF-β and Wnt Pathways in SSc is still to be determined. Here we have aimed to evaluate the Wnt pathway in SSc fibroblasts and the effects of TGF-β on canonical Wnt signalling.

Methods

Dermal fibroblasts from 3 early diffuse cutaneous (dc)-SSc patients and 3 healthy controls (HC) were stimulated with recombinant human (rh)TGF-β and/or rhWnt-3a. mRNA stability was investigated using actimomycin D. mRNA levels were quantified by qRT-PCR and protein expression was measured by western blotting or immunohistochemistry. Canonical Wnt signaling was evaluated by TOPFlash luciferase reporter activity. In- vivoexpression studies were performed on TGF-β-RII DeltaK transgenic mice, which have constitutive activation of the TGF-β pathway in fibroblasts, and wild-type littermates. 

Results

In basal conditions, SSc fibroblasts did not show any increase in TOPFlash reporter activity compared to HC. On the contrary, the expression of Axin2, a Wnt target gene and negative regulator of the Wnt pathway, was reduced at both mRNA (58%; P<0.01) and protein levels. Indeed, SSc fibroblasts had an increased response to rhWnt-3a compared to HC fibroblasts (11.6 fold increase in TOPFlash activity and 2.5 fold in Axin-2mRNA vs. 4.2 and 1.8 fold, respectively, in HC). TGF-β treatment of HC fibroblasts decreased Axin-2 expression to levels similar to SSc fibroblasts, both at mRNA (38.7%; [p<0.001]) and protein levels. This effect was associated with a 3.7 fold increase in mRNA decay. Concordantly, TGF-β-RII DeltaK transgenic mice displayed a reduced expression of Axin-2 in the dermis. Similar to SSc, pretreatment of HC fibroblasts with TGF-β increased their responsiveness to Wnt-3a (16.1 vs. 7.7 fold increase in TOPFlash activity; P<0.01). Depletion of Axin-2 by siRNA was sufficient to mimic the effect of TGF-β pretreatment (P<0.05). Accordingly, XAV939-mediated Axin-2 stabilization ablated the Wnt-3a-induced canonical hyperactivation in ‘TGF-β primed’ fibroblasts.

Conclusion

TGF-β stimulation primes dermal fibroblasts to increase their responsiveness to Wnt ligand-induced canonical signaling. TGF-β mediates the downregualtion of Axin-2, which is required for canonical Wnt signaling hyperactivation in dermal fibroblasts. Our data suggest that the increased Wnt signaling observed in SSc is a consequence of TGF-β signaling and therefore targeting of the TGF-β pathway may also help to resolve the aberrant Wnt signaling observed in SSc.


Disclosure:

J. Gillespie,
None;

E. C. Derrett-Smith,
None;

M. McDermott,
None;

P. Emery,
None;

C. P. Denton,
None;

F. Del Galdo,
None.

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