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Editors Selection IGR 17-4

Basic Science: Molecular mechanisms of steroid-induced glaucoma

Comment by Toru Nakazawa on:

56532 Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma, Zode GS; Sharma AB; Lin X et al., Journal of Clinical Investigation, 2014; 124: 1956-1965

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Ocular hypertension and secondary open-angle glaucoma can occur as side effects of glucocorticoid therapy in some patients. However, the molecular mechanisms underlying glucocorticoid-induced glaucoma are poorly understood.

Zode et al. established a mouse model of glucocorticoid-induced glaucoma with topical, ocular administration of 0.1% dexamethasone. In this model, intraocular pressure (IOP) rose and ER stress-associated damage occurred in the retinal ganglion cells in the trabecular meshwork (TM). Withdrawing dexamethasone reduced ER stress and IOP elevation, parallel to human glucocorticoid-induced glaucoma. Additionally, reducing ER stress by deleting the Chop gene or using chemical chaperone treatment prevented IOP elevation in the model, suggesting that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma.

Importantly, the authors found that the unfolded protein response was activated in a primary culture of human dexamethasone-treated TM cells, suggesting that ER stress is a primary event in the TM in glucocorticoid-induced ocular hypertension. Additionally, dexamethasone-induced ER stress in the TM occurred before IOP elevation in the mice, suggesting that ER stress induction is a primary event in IOP elevation in glucocorticoid- induced glaucoma.

These findings suggest important new possibilities for therapeutic strategies. In particular, CHOP may be a therapeutic target for glucocorticoid-induced glaucoma. CHOP expression/ activity inhibitors may have clinical benefit in IOP-lowering treatment.

Interestingly, the authors found that topical dexamethasone induced the accumulation of myocilin (MYOC) protein in the TM of mouse eyes. The authors previously reported that mutant MYOC can accumulate and promote ER stress in the TM in association with IOP elevation.¹ Although the mechanism of MYOC accumulation is still unknown, MYOC contributes to IOP elevation. Thus, patients with mutations in the MYOC gene may have a higher risk of glucocorticoid-induced glaucoma.

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