Abstract
BackgroundTransforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. Currently, there are no effective agents targeting TGF-β signaling to diminish corneal fibrosis. Glucosamine (GlcN), which is widely used in the treatment of osteoarthritis, abrogates the morphologic effects of TGF-β2 on retinal pigmented epithelial cells in a mouse disease model. Here, we sought to determine whether GlcN would exert beneficial effects against TGF-β1-induced corneal fibrosis.MethodsIn human corneal fibroblasts (HCFs) treated with GlcN, the expression of Krüppel-like factor 4 (KLF4) and its downstream signaling effects were determined in the presence and absence of TGF-β1 using immunoblot analysis. We further explored GlcN inhibition of fibroblast-to-myofibroblast differentiation via KLF4 siRNA. The effect of cycloheximide on KLF4 protein levels with or without GlcN administration was assessed to determine whether GlcN affects the stability of the KLF4 protein.ResultsIn HCFs, GlcN induced the expression of KLF4, which regulated the maturation and maintenance of the ocular surface. GlcN partially suppressed the TGF-β1-induced expression of alpha-smooth muscle actin (α-SMA) and reduced the collagen contraction capacity in HCFs, suggesting a decrease in fibroblast-to-myofibroblast differentiation. This effect appeared to be mediated through suppression of Smad2 phosphorylation and ERK-dependent signaling. The levels of KLF4 mRNA were increased by GlcN and decreased by TGF-β1 and the TGF-β1-induced α-SMA mRNA expression was upregulated when the KLF4 gene was silenced. GlcN also appeared to stabilize the KLF4 protein, reducing its turnover in corneal fibroblasts.ConclusionThese findings shed light on a novel mechanism by which GlcN suppresses TGF-β1-induced fibroblast-to-myofibroblast differentiation through the upregulation of KLF4 expression. Current strategies for treating corneal fibrosis were not effective. Elevating KLF4 levels through the use of GlcN might provide an effective alternative to alleviate the development and progression of corneal fibrosis.
Highlights
Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis
The findings summarized above illustrate the importance of GlcN and Krüppel-like factor 4 (KLF4) in the pathogenesis of fibrosis, the underlying mechanisms regulating signaling in the transforming growth factor beta (TGF-β) pathway during the pathogenic process of corneal fibrosis remain unclear
In an effort to provide new insight into the clinical application of GlcN for corneal fibrosis, we examine whether the effect of GlcN on TGF-β1-induced corneal fibrosis is mediated by KLF4 in human corneal fibroblasts (HCFs)
Summary
Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. There are no effective agents targeting TGF-β signaling to diminish corneal fibrosis. We sought to determine whether GlcN would exert beneficial effects against TGF-β1-induced corneal fibrosis. Current evidence indicates that the TGF-β-induced activation of interstitial fibroblasts, myofibroblasts, and renal tubule epithelial cells contributes to the pathological process of fibrosis [1]. TGF family members exert fibrogenic effects in the cornea that can adversely affect the regulation of corneal integrity, no promising TGF-β blockers or other therapeutic agents capable of diminishing corneal fibrosis without inducing adverse effects have been reported [5]
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