Mechanical Strain of Corneal Epithelium Influences the Expression of Genes Implicated in Keratoconus

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Abstract
Although mechanical injury to the cornea (e.g. chronic eye rubbing) is a known risk factor for keratoconus progression, how it contributes to loss of corneal integrity is not known. Here, we set out to determine how eye rubbing can influence keratoconus progression by exploring the expression of known disease markers in mechanically stressed corneal epithelial cells. To explore the effects of mechanical stress on the expression of genes implicated in keratoconus (e.g. WNT10A, COL12A1, and TGFB1), we measured their expression using an in vitro model that simulates eye rubbing by cyclic stretching of an immortalized human corneal epithelial cell line (hTCEpi) for 16 hours. We further examined the influence of WNT10A expression in hTCEpi cells using loss-of-function approaches. Mechanical strain led to a marked reduction in WNT10A mRNA and protein expression, as well as decreased collagen XII mRNA and protein expression, in hTCEpi cells. Reduced expression of WNT10A protein in WNT10A knockdown cells resulted in reduced protein expression of collagens I and XII, and reduced mRNA expression of MMP9 and TGFB1. Conversely, primary keratocytes treated with recombinant WNT10A protein increased TGFB1 mRNA expression. We provide a molecular explanation for how mechanical strain results in reduced expression of WNT10A in the corneal epithelium, which, in turn, leads to depletion of collagen type I and XII, and TGFβ1 expression. These results provide a molecular link among mechanical strain, WNT10A expression, and the biomechanical failure of the keratoconus cornea.

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