Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis

Abstract

The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.

Canonical Wnt signaling in systemic sclerosis

“…7,8 Consistently, classical targets of canonical Wnt signaling are elevated in skin samples from SSc patients. 7,20 Similar results were also observed in other fibrotic tissues, such as non-alcoholic liver fibrosis and idiopathic pulmonary fibrosis. 7,25,26 Of note, the increased expression of central canonical Wnt pathway components is also reflected in murine models of SSc, such as the model of bleomycininduced dermal fibrosis and in tight-skin (tsk-1) mice.…”

“…7,11,12 In fibroblasts from SSc patients, the increased expression of the Wnt proteins Wnt1 and Wnt10b along with the decreased expression of endogenous Wnt antagonists such as DKK1, SFRP1 and WIF1 have been observed. 7,20,24 The nuclear accumulation of β-catenin occurs in fibrotic skin from SSc patients compared with healthy controls. 7,8 Consistently, classical targets of canonical Wnt signaling are elevated in skin samples from SSc patients.…”

“…7,20,24 The nuclear accumulation of β-catenin occurs in fibrotic skin from SSc patients compared with healthy controls. 7,8 Consistently, classical targets of canonical Wnt signaling are elevated in skin samples from SSc patients. 7,20 Similar results were also observed in other fibrotic tissues, such as non-alcoholic liver fibrosis and idiopathic pulmonary fibrosis.…”

“…7,25,26 Of note, the increased expression of central canonical Wnt pathway components is also reflected in murine models of SSc, such as the model of bleomycininduced dermal fibrosis and in tight-skin (tsk-1) mice. 7,8 …”

“…2,4 In recent years, morphogen pathways, including Wnt, Hedgehog and Notch, have gained considerable attention as key mediators of fibroblast activation in fibrotic diseases. [7][8][9][10][11][12][13][14][15] Here we review the key role of canonical Wnt signaling in fibrosis, exemplified in SSc as a prototypic fibrosing disorder. Although we will focus on SSc in this review, evidence from other fibrotic diseases confirms the important pathophysiological role of Wnt signaling.…”