Fibrosis in human diseases and animal models is associated with aberrant Wnt/β-catenin pathway activation. The regulation, activity, mechanism of action and significance of Wnt/β-catenin signaling in the context of systemic sclerosis (SSc) has not been characterized.
Expression of Wnt signaling pathway components in SSc skin biopsies was analyzed. The regulation of profibrotic responses by canonical Wnt/ß-catenin was examined in explanted human mesenchymal cells. Fibrotic responses were studied by proliferation, migration and gel contraction assays. The fate specification of subcutaneous preadipocytes by canonical Wnt signaling was evaluated.
Analysis of published genome-wide expression datasets revealed elevated expression of the Wnt receptor Fzd2 and the Wnt target Lef1, and decreased expression of Wnt antagonists Dkk2 and Wif1 in skin biopsies from subsets of dcSSc patients. Immunohistochemistry showed increased nuclear β-catenin expression in these biopsies. In vitro, Wnt3a induced ß-catenin activation, stimulated fibroblast proliferation, migration, gel contraction and myofibroblast differentiation, and profibrotic gene expression. Genetic and pharmacological approaches were used to demonstrate that these profibrotic responses involved autocrine TGF-β signaling via Smads. In contrast, in explanted subcutaneous preadipocytes Wnt3a repressed adipogenesis and promoted myofibroblast differentiation.
Canonical Wnt signaling was hyperactivated in SSc skin biopsies, and in explanted mesenchymal cells Wnt3a stimulated fibrogenic responses while suppressing adipogenesis. Together, these results indicate that Wnts have potent profibrotic effects and canonical Wnt signaling plays an important role in the pathogenesis of fibrosis and lipoatrophy in SSc.