Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2734–2745, August 2012
How to Cite
Wei, J., Fang, F., Lam, A. P., Sargent, J. L., Hamburg, E., Hinchcliff, M. E., Gottardi, C. J., Atit, R., Whitfield, M. L. and Varga, J. (2012), Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis & Rheumatism, 64: 2734–2745. doi: 10.1002/art.34424
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 10 FEB 2012 04:39PM EST
- Manuscript Accepted: 2 FEB 2012
- Manuscript Received: 8 SEP 2011
- NIH. Grant Number: AR-42309
- Scleroderma Research Foundation
Fibrosis in human diseases and animal models is associated with aberrant Wnt/β-catenin pathway activation. The aim of this study was to characterize the regulation, activity, mechanism of action, and significance of Wnt/β-catenin signaling in the context of systemic sclerosis (SSc).
The expression of Wnt signaling pathway components in SSc skin biopsy specimens was analyzed. The regulation of profibrotic responses by canonical Wnt/β-catenin was examined in explanted human mesenchymal cells. Fibrotic responses were studied using proliferation, migration, and gel contraction assays. The cell fate specification of subcutaneous preadipocytes by canonical Wnt signaling was evaluated.
Analysis of published genome-wide expression data revealed elevated expression of the Wnt receptor FZD2 and the Wnt target LEF1 and decreased expression of Wnt antagonists DKK2 and WIF1 in skin biopsy specimens from subsets of patients with diffuse cutaneous SSc compared to the other distinct subsets. Immunohistochemical analysis showed increased nuclear β-catenin expression in these biopsy specimens. In vitro, Wnt-3a induced β-catenin activation, stimulated fibroblast proliferation and migration, collagen gel contraction, and myofibroblast differentiation, and enhanced profibrotic gene expression. Genetic and pharmacologic approaches were used to demonstrate that these profibrotic responses involved autocrine transforming growth factor β signaling via Smads. In contrast, in explanted subcutaneous preadipocytes, Wnt-3a repressed adipogenesis and promoted myofibroblast differentiation.
Canonical Wnt signaling was hyperactivated in SSc skin biopsy specimens. In explanted mesenchymal cells, Wnt-3a stimulated fibrogenic responses while suppressing adipogenesis. Taken together, these results indicate that Wnts have potent profibrotic effects, and that canonical Wnt signaling plays an important role in the pathogenesis of fibrosis and lipoatrophy in SSc.