Abstract
Purpose :
Maintaining the structural integrity of the trabecular meshwork (TM) is critical for sustaining a balanced intraocular pressure. Use of steroids such as Dexamethasone (Dex), can increase IOP and essentially ocular hypertension, a major risk factor of steroid-induced glaucoma. Dex has been shown to alter trabecular meshwork cell functionality that can lead to irregular TM structure through abnormal Wnt signaling activity and therefore decreased outward flow of intraocular fluid. However, the role of canonical and non-canonical Wnt signaling in the steroid-induced glaucoma is unclear. In this study we use Frizzled receptor inhibitor and LRP receptor inhibitor to investigate howr these modulators targeting canonical or non-canonical Wnt pathway affect Dex-induced phenotypes of 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 the presence of a Frizzled inhibitor (3265-0367) or a LRP5/6 inhibitor (IC15). Samples are examined for their collagen production, matrix contraction and related gene expression.
Results :
Dex-treated TM cells showed increased levels of MYOC, AXIN2 expression and increased collagen production compared to their vehicle counterparts. Application of the Frizzled inhibitor together with Dex, abolished the effects Dex had on the TM cells. However, application of LRP5/6 inhibitor together with Dex, enhanced the effects of Dex on TM cells.
Conclusions :
Our result exhibited Dex induced phenotypic changes in primary human TM cells that were consistent with contributions had been reported to progress the glaucoma. The different effects that the Frizzled and LRP5/6 inhibitors exhibited on the TM cells, suggests that canonical and non-canonical Wnt signaling participates in different roles in glaucoma. We reason that a proper balance of canonical and non-canonical Wnt signaling is required to maintain the homeostatic state of the TM tissue. Prolonged external stress such as steroid treatment, could potentially disrupt such balance, causing abnormal Wnt activity in the TM, and possibly contributing to glaucoma. Therefore, regulating the canonical and non-canonical Wnt signaling may serve as a novel therapeutic strategy in treating steroid-induced glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.