Key symptoms and signs

The elevated intraocular pressure (IOP) and secondary glaucoma due to GC administration mimics the clinical presentation of primary open-angle glaucoma (POAG) in many ways. Affected individuals are unaware that they have ocular hypertension because the IOP increase is painless. The elevated IOP is due to impaired aqueous humor outflow. The IOP elevation causes very similar irreversible optic nerve head cupping and visual field loss. GC-induced ocular hypertension is different from POAG in that the damage to the aqueous outflow pathway is usually reversible upon discontinuation of GC therapy. However, there are instances of permanent IOP elevation in some patients treated with prolonged GC therapy.

A number of factors determine the ocular hypertensive effects of GC therapy. Elevated IOP generally develops weeks to months after GC administration. The degree of IOP elevation also depends on the potency and dose of GC used as well as the frequency of dosing and route of administration. For example, intravitreal injections of the potent GC triamcinolone acetonide have been increasingly used to treat conditions of retinal edema and choroidal neovascularization, resulting in the increased prevalence of GC-induced ocular hypertension. This route of administration can lead to significantly elevated IOP in 10–40% of patients, who often require treatment with glaucoma medications or even filtration surgery. Although infrequent, even the use of intranasal and inhaled GCs can elevate IOP in certain individuals.

Epidemiology

There are population differences in this ocular response to GCs. Normal individuals receiving topical ocular administration of a potent GC for 4–6 weeks could be categorized into three groups: ~5% were high responders (IOP elevation of >15 mmHg or IOP >31 mmHg), 33% were moderate responders (IOP elevation 6–15 mmHg or IOP >20 mmHg), while those remaining were considered nonresponders (no effect of IOP elevation <6 mmHg). In contrast, the majority of POAG patients are high-to-moderate responders, and interestingly, descendants of POAGs are more likely to be GC-responsive compared to the normal population. There may be a genetic predilection for the development of GC-induced ocular hypertension, and this merits additional research.

Treatment

IOP elevation resulting from GC use is treated by halting, decreasing, or removing the source of the steroid, standard ocular hypotensive agents, or, if necessary, surgery. Anecortave acetate (AA) is an IOP-lowering cortisone currently in clinical trials; it lowers IOP in GC-induced ocular hypertensive and in glaucoma patients. It is an analog of cortisol acetate, which has been modified to remove GC activity. Topical ocular administration of AA lowers IOP in dexamethasone (DEX)-induced ocular hypertensive rabbits, and in an open-label, compassionate-use clinical study, topical ocular AA lowered the IOPs of patients with GC-induced ocular hypertension (Clark et al, unpublished oberservation), and in an open-label, compassionate-use clinical study, topical ocular AA lowered the IOPs of patients with GC-induced ocular hypertension. Physician investigational new drug clinical studies suggest that a single anterior juxtascleral depot administration of AA lowers IOPs in patients with ocular hypertension due to intravitreal treatment with potent GCs and in POAG patients. Because of these positive preliminary studies, AA is currently in phase II clinical studies for both GC-induced ocular hypertension and in patients with POAG.

Endogenous glucocorticoids and glaucoma

In addition to the ability of GCs to induce ocular hypertension, the endogenous GC cortisol has also been implicated in the development of POAG. There have been several reports of increased levels of the cortisol in the plasma and aqueous humor of POAG patients compared to age-matched controls. However, others studies have not found this association. Diurnal and stress-induced changes in plasma cortisol levels further complicate potential disease associations. Early reports of increased lymphocyte sensitivity to GCs in POAG patients suggested an increased systemic GC sensitivity, although other studies failed to support this finding. A new study showed that POAG patients were more sensitive to GC-induced cutaneous vasoconstriction compared to age-matched controls, and it will be interesting to see if this initial discovery can be independently verified. In addition, there have been several reports that steroid responsiveness is a risk factor for the development of POAG.

Both the physiologic and pharmacologic effects of GCs are mediated by the GC receptor, which is a ligand-dependent transcription factor. It is therefore not surprising that GCs alter the expression of hundreds of TM cell genes. This altered expression includes both upregulated and downregulated genes in diverse categories and pathways, consistent with the pleotrophic effects of GCs on the TM. As previously discussed, the expression of certain genes involved in extracellular matrix (ECM) metabolism is altered by DEX treatment, including increased expression of ECM (FN1, COL8A, LUM) and proteinase inhibitor genes (SERPINA3), and decreased expression of proteinase genes (MMP1, TPA, ADAMTS5). A number of growth factor pathway genes are also altered, such as decreased expression of insulin-like growth factor (IGF1)-binding protein 2 (IGFBP2), IGF1, hepatocyte growth factor (HGF) and BMP2. Altered expression of several cytoskeletal genes (ACTA2, FLNB, NEBL) may be associated with GC-mediated reorganization of TM cell microfibrils and microtubules. In addition, DEX induced the expression of a number of stress-related genes (e.g., increased expression of SAA1, SAA2, methalothioneins, and ceruloplasmin).

Myocilin (MYOC) was first identified as a major GC-responsive gene and protein in the TM. This gene is one of the most abundantly expressed genes in human TM tissues and is also found in the aqueous humor. In addition to induction in cultured TM cells, GCs also increase MYOC expression in the TM of perfusion-cultured human anterior segments and in monkeys treated systemically with GCs. Although the MYOC promoter contains partial GC response elements (GREs), GC induction of MYOC requires additional RNA and protein synthesis, and therefore this induction is indirect. Although MYOC was originally proposed to be the major mediator of GC-induced ocular hypertension, there is still no compelling evidence showing that it plays any role in this GC-mediated event. In fact, genetically overexpressing or knocking out MYOC in mice had no effect on IOP. However, MYOC was the first glaucoma gene identified and is responsible for approximately 4% of POAG. Glaucomatous mutations in MYOC result in a gain-of-function phenotype, leading to nonsecretion and mistargeting of MYOC, which is normally a secreted glycoprotein. Expression of glaucomatous MYOC also induces the endoplasmic stress response in cultured TM cells.

Effects of GCs on the trabecular meshwork ( Box 19.3 )

The GC-induced decrease in conventional aqueous outflow and GC-induced morphological changes in the TM point to the TM as being the target tissue involved in GC-induced ocular hypertension. TM cells and TM tissues express GC receptors, which are essential for GC responsiveness. As seen in many other tissues, GCs have a wide variety of diverse effects on TM cells and TM tissues ( Table 19.3 ). GCs alter several TM cellular functions, including proliferation, phagocytosis, and cell shape and size ( Table 19.3 ). The potent GC DEX inhibited TM cell proliferation induced by a number of different growth factors, and at least part of this activity was mediated by DEX inhibition of growth factor receptor expression. DEX also inhibited TM cell migration and significantly increased TM cell and nucleus size. In addition, DEX inhibited TM cell phagocytosis in a perfusion culture ex vivo system. DEX also induced ultrastructural changes in cultured TM cells, including proliferation of the Golgi apparatus, stacking of the endoplasmic reticulum, and increased numbers of secretory vesicles, which provides morphological support for the increased ECM deposition seen after DEX treatment.

One of the hallmarks of steroid-induced glaucoma is the deposition of ECM material in the TM. Aqueous humor outflow in the TM is regulated by the ECM. The overall increased deposition of ECM in the TM of steroid-induced ocular hypertensive eyes could be due to increased ECM synthesis and/or decreased degradation. The synthesis of fibronectin, laminin, collagen, and elastin was increased in DEX-treated TM cells. GCs also affect ECM turnover. In addition to decreasing matrix metalloproteinase (MMP) and tissue plasminogen activator expression, GCs also increase the expression of plasminogen activator inhibitor-1 (Clark, unpublished observation) and tissue inhibitors of MMPs. GCs alter TM cell glycosaminoglycan (GAG) metabolism, decreasing hyaluronan and increasing chondroitin sulfate and GAGase-resistant material.

The TM cytoskeleton regulates aqueous humor outflow. The cytoskeleton also regulates a number of cell functions, including proliferation, migration, phagocytosis, and cell size/shape, all of which are affected in TM cells treated with GCs. GC treatment reorganizes the actin cytoskeleton to form cross-linked actin networks (CLANs) in cultured TM cells. CLANs are geodesic dome-like structures, and GC induction of CLANs is unique to TM cells, not occurring in a variety of other ocular and nonocular cells. The dose, time, and potency dependency for GC-induced CLAN formation are very similar to GC-induced ocular hypertension, and like GC-induced ocular hypertension, CLANs in TM cells are reversible after GC withdrawal. DEX-induced CLANs are also seen in perfusion-cultured eyes. Interestingly, very similar cytoskeletal changes, including CLANs, are present in cultured glaucomatous TM cells and in glaucomatous TM tissues. In addition to reorganizing the actin cytoskeleton, DEX treatment of cultured human TM cells alters microtubules to form microtubule tangles. However, we do not know whether DEX directly alters microtubules or whether this microtubule change is indirectly due to CLAN formation. These GC-induced changes in the TM cytoskeleton may make these cells more resistant to cytoskeletal disrupting agents. DEX-treated TM cells were more resistant to microtubule disrupting agent (i.e., ethacrynic acid and ethylene glycol tetraacetic acid)-induced cellular retraction.

Glucocorticoid mechanism of action

The most widely accepted mechanism for transducing GC signals into cellular responses is via a cognate cellular GC receptor (GR) molecule. GR belongs to the family of intracellular ligand-inducible transcription factors termed the steroid/vitamin D/retinoic acid superfamily. The superfamily encompasses the steroid receptor family and the thyroid/retinoid/vitamin D (or nonsteroid) receptor family. The class of steroid hormone receptors includes GR forms α and ß, progesterone receptor (PR) forms A and B, mineralocorticoid receptor (MR), androgen receptor (AR), and estrogen receptor (ER) forms α and ß. Like other members of this receptor superfamily, GR protein is composed of structurally and functionally defined domains. The amino-terminal part of the protein contains a major transactivation domain responsible for gene activation, whereas the central part includes a highly conserved cysteine-rich DNA-binding domain, composed of two highly conserved zinc fingers. The zinc fingers consist of two zinc ions coordinated with eight cysteine residues to form two peptide loops, which bind cooperatively to half-sites in specific palindromic sequences in the promoter regions, known as GC response elements (GRE), and this specific DNA association induces receptor dimerization. The moderately conserved carboxy-terminal includes ligand-binding domain, which possesses the essential property of hormone recognition and ensures both specificity and selectivity of the physiologic response. This region also contains sequences that are involved in nuclear translocation, receptor dimerization, heat shock protein (Hsp) 90 binding, and transactivation.

The classic model for steroid/thyroid hormone action involves a ligand-induced conformational change in the receptor that allows the receptor–hormone complex to bind to its cognate hormone response element (HRE) in the promoter region of a target gene. The interaction of the activated receptor with the basal transcriptional apparatus alters transcription of hormone-sensitive genes. The ligand-binding domain can be thought of as a molecular switch that, upon binding ligand, shifts the receptor to a transcriptionally active state.

Alternative GR transcripts

The full-length human GR has two isoforms, GRα and GRβ, which originate from the same gene by alternative splicing of the GR primary RNA transcript. There is also alternative translation initiation from a downstream, in-frame ATG codon. Alternative translation initiation produces two GR protein products, the longer protein (777 amino acids), initiated from the first ATG codon (Met 1), termed as GR-A, and the shorter protein (751 amino acids), termed as GR-B. A and B receptor isoforms have been consistently identified for both GRα and GRß in various tissues and cell lines. When expressed in vitro in mammalian cells, the A and B forms are generated in approximately equivalent levels from a single cDNA. However, the GR-B form appears to be more susceptible to degradation and is more effective than GR-A in gene transactivation, but not in transrepression.

GRα

GRα is the major GR transcript that has GC-binding activity. Because of its predominant expression, ligand-binding activity, and transcriptional function, most of the physiological and pharmacological effects of GCs are directly mediated by GRα. GRα is expressed in most human tissues and cell lines. Unlike most members of the steroid receptor superfamily, GRα resides predominantly in the cytoplasm of cells in the absence of ligand as a multiprotein heterocomplex that contains Hsp 90, Hsp70, immunophilin, and several other proteins. Hormone binding to GRα causes a conformation change and activation of GRα. The activated GRα can alter gene expression via GRE-dependent (classical) and GRE-independent (nonclassical) mechanisms.

GRE-dependent pathway

Activated GRα translocates to the nucleus via retrograde transport along microtubules. Once in the nucleus, GRα can bind to specific palindromic DNA sequences (GRE) as a homodimer on the promoter region of target genes, where it interacts with the basal transcription apparatus to induce transcription of the target genes. In addition, GRα also functions as a negative regulator of transcription in a specific subset of GC-responsive genes, which contain a negative GRE (nGRE).

GRE-independent pathway

There is an additional way for GRα to inhibit rather than activate gene expression. GRα can inhibit the expression of genes that do not contain nGRE. GCs are known to suppress the expression of proinflammatory cytokines, which are key regulators of the immune response. However, the majority of proinflammatory genes that are suppressed by GCs lack nGRE in their promoter regions. Instead, GRα physically interacts with other transcription factors to prevent them from binding to their response elements of genes. The powerful GC-mediated anti-inflammatory actions and immune suppression are mediated via this GRE-independent pathway.

GRß

In contrast, GRß was thought to be a nucleus-localized orphan receptor lacking ligand-binding activity and gene transcription regulation and, hence, it was suggested that GRß was generally of little physiological importance. However, there is increasing evidence that this view is incorrect. GRß can act as a dominant negative regulator to antagonize the function of GRα. Increased GRß expression has been associated with a variety of GC-insensitive conditions. We reported that decreased expression of GRß in glaucomatous TM cells was associated with increased GC sensitivity in glaucoma. These reports suggest a potential physiological consequence to changes in GRß expression. In addition, GRß has been reported to bind a ligand and has the ability to regulate gene expression on its own, suggesting that GRß may regulate GC responsiveness beyond its ability to manipulate the function of GRα. GRß may compete with GRα for GRE binding because GRß has an intact DNA-binding domain. Alternatively, GRß may complex with activated GRα to form transcriptional impaired GRα-GRß heterodimers, as has been demonstrated in corticosteroid-insensitive cells ( Figure 19.1 ).

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