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Abstract Number: 2709

Secreted Frizzled-Related Protein 4 Can Be Induced By Transforming Growth Factor-β, Is Regulated By Caveolin-1 and Can Induce Non-Canonical Wnt Signaling In Fibroblasts

Justin Gillespie1, Giuseppina Abignano1, Michael McDermott1, Paul Emery1 and Francesco Del Galdo2, 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, 2Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Basic Science, fibroblasts and systemic sclerosis, WNT Signaling

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's: Pathogenesis, Animal Models, Genetics: Novel Signaling Pathways Mediating Fibrosis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic Sclerosis (SSc) is a heterogeneous disease characterized by autoimmune activation, fibroproliferative vasculopathy, and tissue fibrosis of skin and multiple internal organs. Several studies have indicated that both caevolin-1 (CAV-1) and WNT/β-catenin signaling play important roles in the pathogenesis of tissue fibrosis.  Indeed, CAV-1 is downregulated by 40% in SSc skin compared to healthy controls and, intriguingly, tissue expression studies with SSc skin biopsies show both upregulation of canonical WNT ligands1,2 and consistent upregulation of Frizzled-Related Protein 4 (SFRP4), a putative WNT antagonist, at both mRNA at protein level3,4. To evaluate the role CAV-1 and TGFβ on the expression of SFRP4, and the effects of SFRP4 upon WNT signaling in fibroblasts.

Methods: Immortalized primary healthy (HC) and SSc fibroblasts were cultured in 10% DMEM and starved in 0.5% DMEM for 24hrs prior to stimulation with recombinant TGFβ (10ng/ml), WNT-3a/5a (100ng/ml) and/or SFRP4 (100-500ng/ml). Gene expression was quantified by SYBRgreen RTPCR and by western blot. CAV-1 siRNA was transfected at 5μM. Canonical WNT signaling was assessed by TOPFlash luciferase reporter activity. ELISA was used to measure both the level of Phospho-c-JUN from whole cell lysates, and the level of SFRP4 from SSc patient sera.

Results: In SSc fibroblasts, the basal expression of SFRP4 was increased at protein level and also by 264% at mRNA level compared to HC [p<0.001]. TGFβ stimulation upregulated SFRP4 mRNA by 170% [P<0.01] at 48hrs and by 348% [P<0.01] at 72hrs. TGFβ also induced a time-dependent increase of both SFRP4 and α-SMA protein expression, while reducing CAV-1. The siRNA-mediated silencing of CAV-1 was sufficient to induce a time-dependent increase in SFRP4 protein expression. WNT-3a induced a 600% increase in TOPFlash activity, while co-treatment with SFRP4 suppressed this activation by 59%. In contrast, SFRP4 induced a 260% increase [p<0.001] in c-JUN phosphorylation, a non-canonical WNT target, at 10 min in both HC and SSc fibroblasts. This was similar to the activity of the non-canonical WNT-5a ligand. Interestingly, basal Phospho-c-JUN was increased by 180% [P<0.005] in SSc compared to HC fibroblasts. Further, SFRP4 treatment increased COL1A1 expression by 26% in HCs at 500ng/ml, while in SSc fibroblasts SFRP4 induced both COL1A1 and α-SMA by 49-50% with 100-500ng/ml SFRP4, respectively. Additionally, SSc sera levels of SFRP4 inversely correlated with diffusion lung capacity of carbon monoxide % (r=-0.29, P=0.01) and positively with mRSS in patients with normal lung function (r=0.40, p=0.006).

Conclusion: The increased expression of SFRP4 observed in SSc skin biopsies may be a direct consequence of CAV-1 downregulation by TGFβ in tissue fibroblasts. Given the non-canonical WNT activity of SFRP4, a TGFβ primed microenvironment may be responsible for shaping the phenotype of both fibroblasts and neighboring cells, through aberrant WNT pathway activation. Additionally, circulating SFRP4 may have potential as a biomarker of fibrosis. Investigation of the mechanisms linking CAV-1 expression and SFRP4 function will improve our understanding of the pathogenic role that aberrant WNT activation plays in SSc.


Disclosure:

J. Gillespie,
None;

G. Abignano,
None;

M. McDermott,
None;

P. Emery,
None;

F. Del Galdo,
None.

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