Abstract
Purpose :
Steroid treatments including the use of dexamethasone (Dex) has been shown to increase the intraocular pressure (IOP) and the risk of ocular hypertension, which can cause the steroid-induced glaucoma. Dex has been reported to alter trabecular meshwork (TM) cell functionality through regulating Wnt signaling, which can lead to irregular TM structure and potentially reduce outward flow of intraocular fluid. To further elucidate the role of Wnt signaling in the Dex-induced glaucomatous phenotype, we studied the mRNA expression patterns across MYOC, AXIN2, and extracellular matrix (ECM) genes (i.e. COL I, COL IV). Furthermore, we used novel Wnt small molecule regulators to investigate whether theses modulators would affect Dex-mediated phenotype on primary human TM cells.
Methods :
Primary human TM cells cultured from corneal-scleral rims were treated with 100 nM Dex, DMSO vehicle, or Dex in combination with Wnt signaling regulators. RNA was isolated and followed by quantitative PCR analysis to measure MYOC, AXIN2, and ECM genes expression.
Results :
Dex-treated TM cells showed increased levels of MYOC, AXIN2 and ECM gene expression compared to their vehicle counterparts. Combination of the Wnt inhibitor targeting Frizzled with Dex abolished the effects of Dex on the TM cells, whereas Wnt activators maintained the Dex-induced phenotype. In contrast, application of a canonical Wnt inhibitor targeting LRP5/6 together with Dex, enhanced the effects of Dex on TM cells.
Conclusions :
Dex-induced phenotypic changes in primary human TM cells are consistent with previously reported phenotypes contributing to ocular hypertension, therefore leading to glaucoma progression. Regulating the activity of Wnt alleviates these Dex-mediated effects indicates that Dex-induced glaucomatous TM cell activities is associated with aberrant Wnt signaling. The different effects that the Frizzled and LRP5/6 inhibitors exhibited on the TM cells suggests that proper balance between canonical and non-canonical Wnt signaling is required to maintain the homeostasis of the TM tissue.
This is a 2020 ARVO Annual Meeting abstract.