Canonical Wnt Signaling Drives Myopia Development and Can Be Pharmacologically Modulated

Abstract

The purpose of this study was to evaluate the role of the canonical Wnt signaling in the development of the myopia. METHODS.Plasma from adult patients with myopia, myopic animal models including the adenomatous polyposis coli (APC) gene mutation mouse model, and the form deprivation (FD) induced mouse model of myopia were used. Niclosamide, a canonical Wnt pathway inhibitor, was orally administrated in animal models. Plasma levels of DKK-1 were determined by using enzyme-linked immunosorbent assay. Refraction, vitreous chamber depth (VCD), axial length (AL), and other parameters, were measured at the end of the FD treatment. Canonical Wnt signaling changes were evaluated by Western blot analysis and immunostaining analysis. RESULTS.Plasma level of Wnt inhibitor DKK-1 was markedly decreased in patients with myopia. Meanwhile, the canonical Wnt pathway was progressively activated during myopia development in mice. Moreover, inhibition of canonical Wnt signaling by niclosamide in mouse models markedly reduced lens thickness (LT), VCD, and AL elongation, resulting in myopia inhibition. CONCLUSIONS. Dysregulation of canonicalWnt signaling is a characteristic of myopia and targeting Wnt signaling pathways has potential as a therapeutic strategy for myopia.

Presumed veterinary niclosamide-induced retinal toxicity in a human: a case report

“…In addition, an animal study by a Liu et al . found that niclosamide could effectively inhibit the progression of myopia [ 5 ]. Patients consume 2 g for up to 7 days for the treatment of intestinal parasites.…”

“…This drug kills tapeworms by inhibiting oxidative phosphorylation in the mitochondria and anaerobic adenosine triphosphate (ATP) production [ 1 ]. Recent studies have shown its potential in treating many other diseases including Parkinson’s disease, diabetes, viral and microbial infections, and inhibition of myopia progression [ 2 – 5 ]. In addition, other studies have demonstrated the efficacy of niclosamide in the treatment of various cancers [ 6 ].…”

Association between Vitamin E and myopia in a cross- sectional study of the United States population

“…When abnormalities in reactive oxygen species generation result in an imbalance in redox reactions in the body, vitamin E may modulate the relevant signaling pathways (24)(25)(26). The extracellular regulated protein kinase (ERK)1/2-matrix metalloproteinase (MMP)-2, Wnt, and Akt pathways are involved in the regulation of myopia (27)(28)(29). The Wnt pathway is continuously activated in myopia in mice, causing a decrease in the expression of the Wnt inhibitor DKK-1 (27).…”

“…The extracellular regulated protein kinase (ERK)1/2-matrix metalloproteinase (MMP)-2, Wnt, and Akt pathways are involved in the regulation of myopia (27)(28)(29). The Wnt pathway is continuously activated in myopia in mice, causing a decrease in the expression of the Wnt inhibitor DKK-1 (27). Inhibition of the Wnt pathway after niclosamide treatment eventually leads to a decrease in myopia development, a regulatory function not found with α-tocopherol treatment.…”

Gap junction Delta-2b (gjd2b/Cx35.1) depletion causes hyperopia and visual-motor deficiencies in the zebrafish

“…Considering this, we concluded that the regulation of dopaminergic genes reflected a mechanism in which vmat2 upregulation compensates functional deficits of dopaminergic synapses utilizing D2-receptor family genes. Experimental evidence and genome-wide association studies imply the canonical Wnt signaling pathway in eye development and eye disorders such as myopia (Cheng et al, 2013;Liu et al, 2021). A potential correlation between Cx35.1 and the canonical Wnt-signaling pathway affecting eye-development was testable based on a previous RNA-seq expression analysis showing expression of wingless-type MMTV integration site family and frizzled class receptor genes in 6dpf TL larvae (GEO database entry GSE181853) (Supplementary Table S4).…”