Dexamethasone-Induced Ocular Hypertension in Mice

Abstract

Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious adverse effect of prolonged GC therapy that can lead to iatrogenic glaucoma and permanent vision loss. An appropriate mouse model can help us understand precise molecular mechanisms and etiology of GC-induced OHT. We therefore developed a novel, simple, and reproducible mouse model of GC-induced OHT. GC-induced myocilin expression in the trabecular meshwork (TM) has been suggested to play an important role in GC-induced OHT. We further determined whether myocilin contributes to GC-OHT. C57BL/6J mice received weekly periocular conjunctival fornix injections of a dexamethasone-21-acetate (DEX-Ac) formulation. Intraocular pressure (IOP) elevation was relatively rapid and significant, and correlated with reduced conventional outflow facility. Nighttime IOPs were higher in ocular hypertensive eyes compared to daytime IOPs. DEX-Ac treatment led to increased expression of fibronectin, collagen I, and a-smooth muscle actin in the TM in mouse eyes. No changes in body weight indicated no systemic toxicity associated with DEX-Ac treatment. Wild-type mice showed increased myocilin expression in the TM on DEX-Ac treatment. Both wild-type and Myoc À/À mice had equivalent and significantly elevated IOP with DEX-Ac treatment every week. In conclusion, our mouse model mimics many aspects of GC-induced OHT in humans, and we further demonstrate that myocilin does not play a major role in DEX-induced OHT in mice. (Am J Pathol 2017, 187: 713e723; http://dx.doi.org/10.1016/j.ajpath.2016 Glucocorticoids (GCs) are one of the most commonly prescribed medications worldwide for the treatment of a plethora of diseases and conditions. Because of their broadspectrum anti-inflammatory and immunosuppressive properties, the worldwide market for GC use is estimated to be >$10 billion per year.1 Approximately 1.2% of US and 0.85% of UK populations are prescribed therapeutic GCs every year.2,3 GCs also remain the mainstay of treatment for a variety of ocular inflammatory diseases involving almost all tissues of the eye, such as eyelids, conjunctiva, cornea, sclera, uvea, retina, and optic nerve. 4 The routes of GC administration in treatment of these disorders can be topical ocular, oral, systemic, intravitreal injections and implants, and periocular injections (including subconjunctival, subtenon, retrobulbar, and peribulbar).5 However, prolonged GC therapy is associated with serious ocular adverse effects, including development of posterior subcapsular cataracts, and the development of GC-induced ocular hypertension (GC-OHT) and iatrogenic open-angle glaucoma.The clinical presentation of GC-induced glaucoma is similar to primary open-angle glaucoma (POAG), and for >50 years, reports have suggested a link between glaucoma and GCs. Development of GC-induced OHT depends on GC dose and duration of treatment, method of administration, potency of GC, and individual susceptibility to GCs. 6e8 There are varying degrees of steroid responsiveness (ie, development of GC-OHT) among individ...

Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension

“…sion as described previously (9). After 1 week of Dex injection, conscious IOP revealed that Dex treatment elevated IOP significantly compared with vehicle-injected mice (data not shown).…”

“…Weekly bilateral periocular injections of vehicle or Dex acetate suspension were given to 3-month-old Smad3 Ϫ/Ϫ and WT littermates. Conscious IOPs were measured as described previously (9). A significant increase in IOP was observed in WT mice after 1, 2, and 3 weeks of Dex treatment compared with vehicle-treated WT mice (Fig.…”

“…It is known that GC-induced ocular hypertension is caused by increased resistance to aqueous humor outflow at the trabecular meshwork (TM) tissue (5,(7)(8)(9). However, the molecular pathological mechanisms of how GC treatment leads to increased outflow resistance at the TM are still unclear.…”

“…Previously, we developed a mouse model of GC-induced ocular hypertension by administering topical Dex eye drops three times daily for several weeks (25). We also recently developed a rapid and sustained GC-induced ocular hypertension mouse model by administrating periocular injections of Dex acetate once a week (9). Using these mouse models and primary human TM cells, we have demonstrated the role of ER stress and increased ECM accumulation in GCinduced ocular hypertension.…”

Glucocorticoid receptor signaling in the eye

“…Prolonged DEX treatment of cultured TM cells increased the production and deposition of fibronectin, glycosaminoglycan and extracellular matrix (ECM) resulting in decreased outflow facility [55, 56]. Moreover, topical ocular treatment with DEX in wild-type mice induced IOP and glaucoma, and increased formation of ECM, actin, and mutant myocilin (MYOC) proteins, which has been shown to induce endoplasmic reticulum stress [57, 58], and these effects were reversed after DEX withdrawal. Interestingly, variability in patients’ responsiveness to GC-induced ocular side effects has been attributed to a lower GRβ-GRα ratio compared to their normal counterparts.…”