In Vitro Correlates of Glucocorticoid Effects on Intraocular Pressure

Polansky, Jon R.; Kurtz, Ron M.; Fauss, Donald J.; Kim, R. Y.; Bloom, Ernest

doi:10.1007/978-3-642-76084-6_3

Cited by 23 publications

(18 citation statements)

References 12 publications

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“…The ability of anti-rTIGR antibody to precipitate both forms agrees with our previous suggestion that the 66-kDa form could be due to glycosylation of the 55-kDa protein (1,2). The predicted N-and O-glycosylation sites identified in the TIGR sequence also support this possibility.…”

Section: Candidate Clone Selection and Induction Characteristics-supporting

confidence: 89%

“…The observation that this domain is highly conserved when the olfactomedin genes of fish, frog, rat, mouse, and human are compared (51) supports its functional significance. 2 Nguyen et al, unpublished data. The olfactomedin domain may play a distinct role compared with other domains of the molecule.…”

Section: Candidate Clone Selection and Induction Characteristics-mentioning

confidence: 91%

“…Previously, we described a highly expressed protein and related glycoprotein (55 and 66 kDa, respectively) found in the media of TM cell culture, but not in other cell types examined, after a prolonged exposure to dexamethasone (DEX) (2). We used this observation to define a cell culture model for "steroidinduced glaucoma" and elevated intraocular pressure due to corticosteroids.…”

mentioning

confidence: 99%

“…The trabecular meshwork inducible glucocorticoid response (TIGR) 1 protein, which has significant homology in its C-terminal domain with olfactomedins, was initially cloned in our laboratories as a candidate gene for glaucoma using differential library screening in a trabecular meshwork cell culture model (1,2). Mutations were recently found in this gene that co-segregated with both juvenile and adult forms of the disease (3).…”

mentioning

confidence: 99%

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Gene Structure and Properties of TIGR, an Olfactomedin-related Glycoprotein Cloned from Glucocorticoid-induced Trabecular Meshwork Cells

Nguyen¹,

Chen²,

Huang³

et al. 1998

Journal of Biological Chemistry

320

257

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Expression of the trabecular meshwork inducible glucocorticoid response (TIGR) gene progressively increases from barely detectable levels to greater than 2% of total cellular mRNA over 10 days exposure of trabecular meshwork (TM) cells to dexamethasone. Cycloheximide blocked most of the TIGR mRNA induction, suggesting a requirement for ongoing protein synthesis. The genomic structure of TIGR (ϳ20 kilobases) consists of 3 exons, and a 5-kilobase promoter region that contains 13 predicted hormone response elements, including several glucocorticoid regulatory elements, and other potentially important regulatory motifs. TIGR cDNA encodes an olfactomedin-related glycoprotein of 504 amino acids with motifs for N-and O-linked glycosylation, glycosaminoglycan initiation, hyaluronic acid binding, and leucine zippers. Recombinant TIGR (rTIGR) showed oligomerization and specific binding to TM cells. Anti-rTIGR antibody detected multiple translational/post-translational forms of TIGR produced by the cells (including secreted 66 kDa/55 kDa glycoproteins/proteins in the media and 55 kDa cellular proteins), whereas Northern blot showed a single mRNA species. The findings suggest potential mechanisms by which TIGR could obstruct the aqueous humor fluid flow and participate in the pathogenesis of glaucoma.The trabecular meshwork inducible glucocorticoid response (TIGR) 1 protein, which has significant homology in its C-terminal domain with olfactomedins, was initially cloned in our laboratories as a candidate gene for glaucoma using differential library screening in a trabecular meshwork cell culture model (1, 2). Mutations were recently found in this gene that co-segregated with both juvenile and adult forms of the disease (3).Glaucoma is a major cause of blindness, with its most prevalent form thought to involve the specialized endothelial cells lining the outflow pathway of the eye, termed the trabecular meshwork (TM) (4, 5). The synthesis and/or degradation of a variety of extracellular molecules in the meshwork are thought to be regulated by the TM cells, and alterations in the type or amount of connective tissue elements have been postulated to explain the increased outflow resistance seen in glaucoma cases (6). However, an understanding of the biochemical changes that actually contribute to this process has remained elusive.Previously, we described a highly expressed protein and related glycoprotein (55 and 66 kDa, respectively) found in the media of TM cell culture, but not in other cell types examined, after a prolonged exposure to dexamethasone (DEX) (2). We used this observation to define a cell culture model for "steroidinduced glaucoma" and elevated intraocular pressure due to corticosteroids. The extracellular induced proteins appeared as reasonable candidates for being involved in steroid glaucoma since the time course and dose response of their induction mimicked the intraocular pressure elevation and increased outflow resistance seen in patients receiving glucocorticoid (GC) therapy (7,8).Coincident with our res...

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Section: Candidate Clone Selection and Induction Characteristics-supporting

confidence: 89%

Section: Candidate Clone Selection and Induction Characteristics-mentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Gene Structure and Properties of TIGR, an Olfactomedin-related Glycoprotein Cloned from Glucocorticoid-induced Trabecular Meshwork Cells

Nguyen¹,

Chen²,

Huang³

et al. 1998

Journal of Biological Chemistry

320

257

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“…MYOC expression and OHT induction occur in response to GCs, and both follow similar time-course and dose-response curves. 26,60,61 Few studies have addressed the potential role of myocilin in GC-induced OHT. Both Shepard et al 62 and Kirstein et al 63 showed that myocilin induction by GCs was because of other transcription factors or remote glucocorticoid response elements and not by sequences in the proximal region of the myocilin gene promoter.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone-Induced Ocular Hypertension in Mice

Patel

Phan

Maddineni

et al. 2017

The American Journal of Pathology

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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...

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Prevention of Corticosteroid-Induced Intraocular Pressure Elevation Using ISV-205

Stewart

2003

Arch Ophthalmol

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Objective:To determine whether a topical ophthalmic diclofenac sodium formulation containing a proprietary polymeric drug delivery system (ISV-205), when dosed concomitantly with 1% prednisolone acetate, is effective in blocking the intraocular pressure (IOP) response in humans.Design: This was a multicenter, prospective, doublemasked, parallel, vehicle-controlled study. We included 136 first-degree relatives of subjects with primary open-angle glaucoma. Subjects were randomized to receive 0.06% or 0.1% ISV-205 or vehicle while concomitantly receiving 1% prednisolone for 6 weeks.Results: During the treatment period, the mean ± SD maximum IOP increase (7.3 ± 6.5 mm Hg for vehicle, 4.9±4.6 mm Hg for 0.06% ISV-205, and 5.9±4.9 mm Hg for 0.1% ISV-205) was significantly less with the 0.06% formulation than with placebo (P=.02). The overall mean change in IOP was 3.6, 2.0, and 2.4 mm Hg in the ve-(REPRINTED) ARCH OPHTHALMOL / VOL 121, NOV 2003 WWW.ARCHOPHTHALMOL.COM 1543

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In Vitro Correlates of Glucocorticoid Effects on Intraocular Pressure

Cited by 23 publications

References 12 publications

Gene Structure and Properties of TIGR, an Olfactomedin-related Glycoprotein Cloned from Glucocorticoid-induced Trabecular Meshwork Cells

Gene Structure and Properties of TIGR, an Olfactomedin-related Glycoprotein Cloned from Glucocorticoid-induced Trabecular Meshwork Cells

Dexamethasone-Induced Ocular Hypertension in Mice

Prevention of Corticosteroid-Induced Intraocular Pressure Elevation Using ISV-205

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