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

Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). beta-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of beta-catenin in fibroblasts for the development of SSc dermal fibrosis. Methods Nuclear accumulation of beta-catenin in fibroblasts was assessed by triple staining for beta-catenin, prolyl-4-hydroxylase-beta 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 fibroblastspecific depletion were used to evaluate the role of beta-catenin in fibrosis. Results The auhors found significantly increased nuclear levels of beta-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of beta-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of beta-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of beta-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 beta-catenin significantly reduced bleomycin-induced dermal fibrosis. Conclusions The present study findings identify beta-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 beta-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of beta-catenin/Wnt signaling have recently entered clinical trials.