β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis

Abstract

Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis. Methods Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4′,6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis. Results The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis. Conclusions The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.

Canonical Wnt signaling in systemic sclerosis

“…8 Similar results were also described in a mouse model characterized by conditional overexpression of a stabilized β-catenin-mutant selectively in fibroblasts of the murine ventral dermis by Hamburg and Atit. 27 In addition, Hamburg-Shields et al 28 recently published that the conditional overexpression of β-catenin in dermal fibroblasts is associated with the increased expression of extracellular matrix genes in vivo.…”

“…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.…”

“…7,8,27 Indeed, genetic inactivation of several different effector molecules within the canonical Wnt signaling pathway ameliorated fibrosis: postnatally induced, fibroblast-specific deletion of β-catenin prevented the development of bleomycin-induced skin fibrosis, a model of the early, inflammatory stages of SSc. 8 Moreover, the transgenic overexpression of DKK1 ameliorated fibrosis in different complementary fibrosis models, including bleomycininduced dermal fibrosis, tsk-1 mice and TBRIact-induced fibrosis. 7 Knockdown of evenness-interrupted, a transmembrane protein at the Golgi and the cell surface required for secretion of Wnt ligands, inhibited the activation of fibroblasts in vitro and reduced experimental fibrosis in vivo.…”

“…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.…”