Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis

Abstract

Background and objectivesFibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis.MethodsWe examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I.ResultsPKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures.ConclusionsBlockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

“…We used a porcine pancreatic elastase (PPE)-induced emphysema murine model to test this hypothesis because b-catenin has been shown to protect mice from elastase-induced emphysema (21); and the b-catenin transcriptional inhibitor we studied (PKF118-310) produces hepatic toxicity, which precludes its use in chronic model systems, such as the 6-month CS exposure model of emphysema. We coadministered PKF118-310 (48,49) and PPE to Fam13a 1/1 and Fam13a 2/2 mice and measured emphysema development (50). The optimal dose of PKF118-310 (0.25 mg/kg) tested was chosen based on the significant inhibition of Axin2 expression associated with minimal liver toxicity after acute administration (see Figures E8A-E8C).…”

Canonical Wnt signaling in systemic sclerosis

“…In experimental fibrosis models, treatment with PKF118-310 or ICG-001 prevented the development of bleomycin-and TBRIact-induced dermal fibrosis. 33 Moreover, PKF118-310 or ICG-001 also exerted antifibrotic effects in therapeutic settings with preestablished bleomycin-induced dermal fibrosis. 33 Consistently, Henderson et al 34 described antifibrotic effects of ICG-001 in bleomycin-induced lung fibrosis.…”

“…33 Moreover, PKF118-310 or ICG-001 also exerted antifibrotic effects in therapeutic settings with preestablished bleomycin-induced dermal fibrosis. 33 Consistently, Henderson et al 34 described antifibrotic effects of ICG-001 in bleomycin-induced lung fibrosis. Moreover, antifibroticeffects were described in the ureter-obstruction model of renal interstitial fibrosis.…”

β-catenin as a regulator and therapeutic target for asthmatic airway remodeling

“…In contrast, the inhibitor IQ-1 inhibits b-catenin binding to p300 and, therefore, promotes b-catenin binding and signaling through CBP [86]. ICG-001 has been evaluated in animal models of fibrosis and consistently prevents the profibrotic response, in the lungs, the kidney and the skin [34,87,88]. The effects of IQ-1 still require evaluation in animal models of fibrosis.…”