Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells

Abstract

Introduction 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. Methods 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. Results 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. Conclusions 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.

Wnt Coreceptor Lrp5 Is a Driver of Idiopathic Pulmonary Fibrosis

“…For example, b-catenin signaling can upregulate TGF-b message in some but not all contexts (46,47), and TGF-b signaling can lead to b-catenin signaling through Wnt-dependent (10) and-independent mechanisms (48). In our study, alveolar epithelial type 2 cells and leukocytes isolated from Lrp5 2/2 mice manifest reduced capacity to produce TGF-b protein compared with cells isolated from Lrp5 1/1 mice.…”

Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury

“…Upon activation, fibroblasts differentiate into myofibroblasts, which have a substantially increased potential for the synthesis of ECM, resulting in aggravated fibrosis. Wei and colleagues (38) found that Wnt-3a-induced ␤-catenin activation could stimulate the proliferation and migration of fibroblasts, collagen gel contraction and myofibroblast differentiation, and enhance profibrogenic gene expression. In the present study, we demonstrated that XAV939 could inhibit myofibroblast differentiation and ECM accumulation in vitro and it can also suppress the proliferation of NIH/3T3 fibroblasts.…”

Canonical Wnt signaling in systemic sclerosis

“…These results suggest that canonical Wnt signaling and TGF-β signaling might be mutually reinforcing each other to persistently drive myofibroblast activation in SSc. 30 …”