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JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 23, Number 5, 2007


© Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2006.0067

The Etiology of Steroid Cataract

ERIC R. JAMES

ABSTRACT

Steroid-induced posterior subcapsular cataracts (PSCs) exhibit three main distinctive char-
acteristics: (i) association only with steroids possessing glucocorticoid activity, (ii) involve-
ment of aberrant migrating lens epithelial cells, and (iii) a central posterior location. The first
characteristic suggests a key role for glucocorticoid receptor activation and subsequent
changes to the transcription of specific genes. Glucocorticoid receptor activation is associated
in many cell types with proliferation, suppressed differentiation, a reduced susceptibility to
apoptosis, altered transmembrane transport, and enhancement of reactive oxygen species ac-
tivity. Glucocorticoids may be capable of inducing changes to the transcription of genes in
lens epithelial cells that are related to many of these cellular processes. This review examines
the various mechanisms that have been proposed to account for the development of PSC in
the context of recent DNA array studies. Additionally, given that the glucocorticoid receptor
can also engender wide-ranging indirect activities, glucocorticoids could also indirectly affect
the lens through the responses of other cells within the ocular compartment and/or through
effects on cells at more remote locations. These indirect mechanisms, which, for example,
could be mediated through alterations to the intraocular levels of growth factors that nor-
mally orchestrate lens development and maintain lens homeostasis, are also discussed. Al-
though the mechanism of steroid cataract induction remains unknown, glucocorticoid-induced
gene transcription events in lens epithelial cells, and also other intraocular or systemic cells,
likely interact to generate steroid cataracts. Finally, although evidence for glucocorticoid-pro-
tein adduct formation in the lens is inconclusive, the generation of such adducts cannot yet
be discounted as a contributing factor and must necessarily be retained in discussions of the
etiology of steroid cataract.

INTRODUCTION play important roles in cancer chemotherapy and


organ transplantation. However, a significant risk

G LUCOCORTICOIDS ARE HIGHLY EFFECTIVEanti-in-


flammatory agents that are widely used in
the management of many clinical conditions, in-
exists for development of serious complications
when glucocorticoids are administered for an ex-
tended period at relatively high doses; these com-
cluding allergy and asthma, rheumatoid arthritis, plications place limits on the utility of an other-
and other autoimmune diseases, and they also wise highly effective class of therapeutic agents.

Sanaria, Inc, Rockville, MD, and Department of Ophthalmology, College of Graduate Studies, Medical University
of South Carolina, Charleston, SC.
The author of this work claims no proprietary interest in any product, or conflicts of interests, or financial disclo-
sures. This work was supported, in part, by NIH EY-13786 and EY-14793 and an unrestricted grant to Storm Eye In-
stitute, Medical University of South Carolina (Charleston, SC) from Research to Prevent Blindness (New York, NY).

403
404 JAMES

One of the ocular complications of steroid treat- and were found in 29% of those on a moderate
ment is the development of cataracts, specifically regimen of corticosteroid (50–99 mg/day cortisol)
posterior subcapsular cataracts (PSCs).1–5 and in 75% of those receiving a high dose of
Clinical prevalence studies of the different types steroid (100 mg/day cortisol or 3 mg/day
of cataracts have indicated approximately 5%–15% dexamethasone). (A dose of 3 mg of dexametha-
are classified as PSC,6–9 with PSC comprising as sone equates to approximately 0.1 M in a 75-kg
much as 40% of those cataract cases that require person, assuming complete uptake, producing an
surgery.10 Although steroid use is the primary risk accumulated continuous exposure of approxi-
factor for PSC, PSC can be related to other risk fac- mately 0.3 M at an in vivo half-life of 45 h). The
tors, in particular aging and diabetes. cataracts in this study were described as sharply
The first study to report a link between steroid defined “black spots or thread-like opacities” seen
administration and PSC1 described the essential against the red fundus and located in the lens cor-
morphologic characteristics and noted a strong tex immediately adjacent to the posterior lens cap-
correlation with the dose of steroids administered sule in the center of the field of vision.1 Subse-
and with the duration of treatment. It was soon quent studies have variously described “small,
recognized that the extended application of glu- yellow-white, highly refractile” cataracts with as-
cocorticoids by any route, including intraocu- sociated “small, scattered punctate vacuoles”
larly, topically, or systemically, can potentially combining to form a granular conglomerate.14
lead to the development of PSC. Aerosolized in- Steroid-induced PSCs contain superficial corti-
tranasally administered glucocorticoids used in cal vacuoles, leading them to be categorized as
asthma therapy, however, are generally given at “vacuolated PSC.” A proportion of age-related
much lower doses or are in a form that is rapidly PSC, diabetic PSC, and PSC associated with re-
metabolized by the liver, and thus the intranasal tinitis pigmentosa may also be classified as vac-
route is not normally associated with PSC devel- uolated PSC.15 However, at least in the early
opment.11,12 stages of their formation, these other forms of
Because steroid-induced PSCs result from the vacuolated PSC appear to be clinically different
administration of a single, well-known, and rela- from steroid-induced PSC, with the exception of
tively well-characterized class of chemothera- diabetic PSC, which have been described as in-
peutic agents, it might be supposed that elucida- distinguishable from steroid-induced PSC.15
tion of the mechanism triggering the formation of
these cataracts would have been straightforward; Characteristics of steroid cataract
however, this has not been the case. A number of
potential mechanisms have been proposed to ac- There are three main defining characteristics
count for steroid cataracts, including several of of steroid-induced PSC: (i) an association only
those implicated in age-related cataracts. But with steroids that possess glucocorticoid activity;
there are problems in translating these general (ii) the posterior migration of aberrant lens ep-
mechanisms of cataract formation into an expla- ithelial cells from the lens equator to the poste-
nation of the development of steroid-induced rior lens pole; and (iii) their location (initially) in
PSC. The various possible mechanisms that have, a sharply defined, limited central area of the pos-
until now, been considered as inducers of steroid terior subcapsular region. The first characteristic
cataracts have been reviewed most recently by suggests that the development of steroid-induced
Jobling and Augusteyn.13 Information reported PSC involves glucocorticoid receptor activation,
since that review, however, provides a different whereas the second attribute suggests that the
perspective and suggests alternative potential normal cellular proliferation and differentiation
mechanisms for the induction of steroid cataracts. of lens epithelial cells has been perturbed. Until
recently, these two characteristics had received
little attention. Instead, the prevailing opinion
Clinical presentation of steroid-induced PSC
was that oxidation of lens proteins and changes
Steroid-induced PSCs were originally de- to lens hydration (both mechanisms implicated in
scribed in a study where 17 patients being treated the development of other forms of cataract) in-
systemically for rheumatoid arthritis developed duced steroid cataract. Alternatively, it was pos-
bilateral PSC.1 These steroid-induced PSC ap- tulated that the direct binding of steroids to lens
peared after approximately 1 year of treatment, proteins was responsible.
STEROID CATARACT 405

The previously proposed mechanisms for receptor to the nucleus, and receptor dimeriza-
steroid cataract induction have been discussed in tion at glucocorticoid response element (GRE)
detail by Jobling and Augusteyn,13 who con- binding sites in the promoter regions of specific
cluded that they were unlikely to play more than genes.26,27 Many genes contain GRE (or negative
subsidiary roles. Moreover, these mechanisms GRE) sites and the enhanced (or repressed) ex-
did not appear to be compatible with the re- pression of these genes resulting from glucocor-
stricted and focal central posterior subcapsular ticoid receptor activation are referred to as clas-
location of steroid cataracts. With regard to the sical or “Type I” glucocorticoid receptor effects.
first two characteristics of steroid PSC, these sug- Additionally, ligand-bound monomeric gluco-
gest that glucocorticoid receptor activation and corticoid receptors can form protein-protein in-
subsequent changes to gene transcription are the teractions with other transcription factors, which
key initiating events. interfere with (or enhance) the transcription of
In vivo, glucocorticoids administered by vari- genes regulated by these factors; these are re-
ous routes can lead to the development of steroid ferred to as “Type II” glucocorticoid receptor ef-
cataracts, in part because of their widespread dis- fects. Examples of significant Type II effects are
semination throughout the body. Thus, the in- the interaction of the glucocorticoid receptor with
duction of PSC could be: (i) through direct action the transcription factors, nuclear factor kappa-B
of glucocorticoids on glucocorticoid receptors in (NF-B) and activator protein-1 (AP-1), poten-
the lens epithelial cells or (ii) through the indirect tially affecting the transcription of a large num-
activation of glucocorticoid receptors in a variety ber of genes.28–31 One of the main anti-inflam-
of other cell types, such as those in the ciliary matory actions of glucocorticoids is ascribed to
body.13 Alternatively, the induction could in- their repression of NF-B-induced proinflamma-
volve a combination of direct and indirect effects. tory genes in cells of the immune system.32,33
Glucocorticoid receptor activation is also reg-
Lens glucocorticoid receptor ulated by cofactor interactions at two transcrip-
tional activation/function sites on the glucocorti-
Prior to Jobling and Augusteyn’s13 review, sev- coid receptor. Cofactors include the Hsp90-linked
eral pieces of evidence had indicated that lens ep- complex of proteins that sequester the inactive
ithelial cells exhibit activity consistent with the unliganded monomeric receptor in the cyto-
presence of a glucocorticoid receptor.16–19 Dick- plasm, kinases, and coactivators and corepressors
erson and colleagues20 had noted, furthermore, associated with gene transcription.34 Each cell
that the reduction in lens glutathione (GSH) type may contain a specific suite of cofactors and
content that followed glucocorticoid treatment glucocorticoid-receptor activation can, therefore,
was inhibited by the glucocorticoid antagonist, result in a distinct cell type–specific response.35–37
RU486, thereby implying the presence of func- For example, glucocorticoid administration in-
tional glucocorticoid receptors in lens epithelial duces lymphocytes to undergo apoptosis38,39; in
cells. Convincing evidence for a glucocorticoid re- contrast, glucocorticoids have an anti-apoptotic
ceptor in the lens was still lacking, however, lead- effect on several other cell types.40,41 Activated
ing some to doubt its existence.13,21 Indeed, the glucocorticoid receptors can also elicit nonge-
conclusions drawn by Jobling and Augusteyn13 nomic effects in cells, but these are not usually
in their review were derived, in part, from the ab- specific for “classical” glucocorticoid receptors42
sence, at that time, of clear definitive data for the and occur within a more rapid time frame, sug-
expression of a glucocorticoid receptor in the lens. gesting that this nongenomic mode of action is
More recent studies22–24 have demonstrated that unlikely to be relevant to the induction of steroid
the lens contains a glucocorticoid receptor and, cataracts, which usually take many months to de-
furthermore, that the lens glucocorticoid receptor velop.
is functional,22 with the capability of inducing or
repressing the transcription of genes known to be
Glucocorticoid-modified gene expression in lens
associated with glucocorticoid receptor activation
epithelial cells
in other cell types.22,25
Glucocorticoid receptor activation involves DNA microarray hybridization data obtained
glucocorticoid binding to the cytoplasmically lo- from cultured lens epithelial cells exposed to glu-
cated receptor, translocation of this ligand-bound cocorticoids have (not surprisingly) indicated
406 JAMES

that a broad range of transcripts are up- or down- treated lens epithelial cells. However, any of
regulated relative to unexposed control cells.25,43 the observed up- or downregulated transcripts
When lens epithelial cells were exposed to 1 M could, of course, be candidates for participation
glucocorticoid for 24–48 h, 57 and 92 transcripts, in the induction and development of steroid
respectively, were upregulated by more than 2- cataract.
fold, whereas 50 and 42 transcripts, respectively, Overall, at the early time points of 4 and 16 h,
were downregulated. Changes in transcript lev- no clear pattern of altered gene expression
els at 4 and 16 h were investigated by Gupta and emerged from the DNA array data, nor was it
colleagues,43 also using dexamethasone at 1 M, possible to identify a specific functional category
who reported 93 transcripts were upregulated of transcripts affected by glucocorticoid treat-
and 43 were downregulated by 1.5-fold or more ment.43 The data at 48 h demonstrated a slightly
at 4 h and 30 transcripts were upregulated and higher statistical significance,25 which may indi-
56 were downregulated by 1.5-fold or more at cate that these changes are more robust and more
16 h. representative of longer term alterations to gene
Those transcripts whose expression was up- expression in lens epithelial cells. If this is so, then
regulated (by at least 1.5-fold at 4 or 16 h or 2- the 134 transcripts altered at 48 h, and particu-
fold at 24 and 48 h at two or more of these four larly, the 27 transcripts altered at 48 h together
time points), or downregulated (by at least 1.5- with one or more additional time points (Table 1)
fold at 4 or 16 h or 2-fold at 24 and 48 h at two may include the most significant cohort.
or more of their time points),25,43 are shown in At 48 h, the altered transcripts represented
Table 1. The levels of 41 transcripts were modi- genes involved predominantly in signal trans-
fied at two or more time points, 9 transcripts were duction, transcription factor activity, cytoskele-
changed at three or more time points, but only 2 ton/ECM and adhesion, membrane transport,
transcripts were altered at all four time points. and cell cycle development.25 This later time
These latter two transcripts were for glucocorti- point is arguably also more representative of rel-
coid-induced lucine zipper protein (GILZ; also evant changes in transcript expression because it
known as delta sleep–inducing peptide immuno- includes, in addition to Type I effects, the sec-
reactor) and for nexin (plasminogen activator in- ondary downstream effects induced by glucocor-
hibitor-1, PAI-1). Continuous upregulation of ticoid-mediated modifications to the levels of ex-
GILZ between 3 and 48 h of dexamethasone treat- pression of transcription factors, such as GILZ
ment (relative to untreated controls) was demon- and also Type II glucocorticoid receptor–medi-
strated by real-time quantitative PCR22 and an ated effects.
upregulation of PAI-1 at 4 and 16 h was con-
firmed by conventional reverse transcriptase–
Lens epithelial cell migration
polymerase chain reaction (RT-PCR).43 Upregu-
lation of a specific transcript does not necessarily Lens epithelial cells underlie the lens capsule
translate into protein expression of course, but anterior to the equator, but are normally absent
this is a necessary precursor event, in most in- from the posterior subcapsular region between
stances, and can be used as a likely indicator of the lens equator and the posterior lens pole. The
upregulated protein expression. lens grows slowly throughout life; new lens fibers
Several diverse activities have been attributed are added to the lens cortex by proliferation of
to both GILZ and PAI-1 in different cell types. the narrow band of epithelial cells in the germi-
For GILZ, these include its activity as a tran- nal and transitional zones at the lens equator, and
scription factor and its role in the regulation of the differentiation of these cells into fiber cells.
several cellular processes, including transmem- This process has been well documented and fol-
brane sodium transport, suppression of apopto- lows an ordered and carefully regulated pro-
sis, modification of NF-B and AP-1 activity, and gression bearing the hallmarks of prematurely ar-
inhibition of differentiation.29,44–50 PAI-1 is an rested apoptosis. The sequence of events includes
acute-phase protein, which functions as a regu- the enhanced expression of proapoptotic Bcl-2
lator of apoptosis, an inhibitor of cellular differ- family proteins, depressed expression of anti-
entiation and cell adhesion and a promoter of cell apoptotic Bcl-2 proteins, and caspase-3 activa-
migration and insulin resistance.51–54 It is not yet tion,55–58 culminating in the disassembly of the
known, however, whether these attributes of organelles and the nucleus and removal of the
GILZ and PAI-1 are exhibited in glucocoticoid- DNA by a caspase-3-activated DNase II.59
STEROID CATARACT 407

TABLE 1. GENE TRANSCRIPTS SIGNIFICANTLY ALTERED BY GLUCOCORTICOID TREATMENT


(1 M DEXAMETHASONE) AT TWO OR MORE TIME POINTS POST-TREATMENT

Fold-change from control

Accession no. Gene name 4h 16 h 24 h 48 h

AL110191 glucocorticoid-induced leucine zipper protein 5.56 5.97 3.06 3.84


AL574210 nexin, plasminogen activator inhibitor type 1, member 1 2.61 3.01 2.49 2.38
AA576961 pleckstrin homology-like domain, family A, member 1 1.62 1.73 2.51
S69738.1 chemokine (C-C motif) ligand 2 5.76 2.03 3.89
NM_000602.1 nexin, plasminogen activator inhibitor type 1, member 1 3.15 2.42 2.37
NM_001706.1 B-cell CLL/lymphoma 6 (zinc finger protein 51) 2.18 2.21 2.49
NM_001038.1 sodium channel, nonvoltage-gated 1 alpha 11.94 2.09 3.98
NM_001627.1 activated leukocyte cell adhesion molecule 2.41 2.13 2.15
NM_004417.2 dual specificity phosphatase 1 3.35 2.30 2.02
NM_002616 period homolog 1 (Drosophila) 6.01 4.59
NM_014033 DKFZP586A0522 protein 2 2.47 2.85
AK026720.1 hypothetical protein LOC283537 2.97 3.28
NM_020353.1 phospholipid scramblase 4 2.84 2.19
AL136842.1 CDC42 effector protein (Rho GTPase binding) 3 2.66 2.08
AL13686.1 LCCL domain containing cysteine-rich secretory protein 2 4.16 2.49
NM_014033.1 DKFZP586A0522 protein 2.85 2.12
NM_002620.1 platelet factor 4 variant 1 1.95 2.05
NM_002658.1 plasminogen activator, urokinase 1.41 2.99
M73554.1 cyclin D1 (PRAD1: parathyroid adenomatosis 1) 1.61 2.57
NM_005737.2 ADP-ribosylation factor-like 7 1.95 2.23
NM_000346.1 SRY (sex determining region Y)-box 9 1.73 2.18
(campomelic dysplasia, autosomal sex-reversal)
AI791860 ESTs 5.64 6.89
NM_014059.1 RGC32 protein 4.18 5.16
NM_002852.1 pentaxin-related gene, rapidly induced by IL-1 beta 3.52 6.26
AK026720.1 hypothetical protein LOC283537 3.28 4.60
NM_005410.1 selenoprotein P, plasma, 1 3.23 7.34
AW137148 Homo sapiens cDNA FLJ11382 fis, clone HEMBA 1000504 3.06 2.04
AI992251 Homo sapiens, clone IMAGE:4151609, mRNA 3.00 4.25
NM_021122.2 fatty-acid-coenzyme A ligase, long-chain 2 2.95 2.20
M61906.1 phosphoinositide-3-kinase, p85 alpha regulatory subunit 2.57 2.87
BF438302 basic transcription element binding protein 1 2.54 2.12
NM_001854.1 collagen, type XI, alpha 1 2.45 3.45
J04177 collagen, type XI, alpha 1 2.36 3.99
NM_002193.1 inhibin, beta B (activin AB beta polypeptide) 2.20 3.45
NM_020353.1 phospholipid scramblase 4 2.19 2.19
NM_001206.1 basic transcription element binding protein 1 2.01 2.68
AL049435.1 Homo sapiens mRNA; cDNA DKFZp586B0220 2.60 2.21
U19495.1 chemokine (C-X-C motif) ligand 12 (stromal cell–derived factor 1) 2.05 2.79
D32039.1 chondroitin sulfate proteoglycan 2 (versican) 2.15 2.06
NM_016076.1 CGI-146 protein 2.76 2.04
D12625.1 neurofibromin 1 (neurofibromatosis, von Recklinghausen 2.74 2.09
disease, Watson disease)

Note. Included are those transcripts that were found to be up- or down-regulated by more than 2-fold at 24 and/or
48 h25, and those modified by more than 1.5-fold at 4 and/or 16 h.43
CLL, chronic lymphocytic leukemia; ESTs, expressed sequence tags; IL, interleukin.

In PSC, particularly steroid-induced PSC, the The numbers of these migrating cells was not
proliferation and differentiation of lens epithelial large,17 except in the lenses of pediatric pa-
cells appears to be disrupted. Histologic studies tients,14,61 in which they tended to be located pre-
of steroid cataracts describe the presence, at the dominantly at the margin of the PSC.60
posterior lens pole, of nucleated cells with the The presence of nucleated and degenerating
characteristics of epithelial cells, together with cells, posterior to the lens equator and at the pos-
rounded Wedl or bladder cells, which contain de- terior lens pole in steroid-induced PSC, is con-
generating nuclei and few organelles, and which sistent with the disruption of normal equatorial
share many characteristics with fiber cells.14,15,60 lens epithelial cell proliferation and differentia-
408 JAMES

tion. These aberrant epithelial cells must be sub- gether with the histologic similarity between
jected to influences that cause them to migrate steroid-induced PSC and diabetes-related PSC,
posteriorly, but no one has yet provided evidence these observations concur with the possibility
for why the cell migration should be directed to- that there could be common elements to the
ward the posterior pole; perhaps the cells are fol- mechanisms underlying the initiation of diabetic
lowing the path of least resistance, or perhaps PSC and steroid-induced PSC.
they are following biochemical cues. Neverthe- The prominent basic hallmarks of diabetes—
less, histologic studies,61 experiments with lens hyperglycemia, abnormal or ablated insulin pro-
explant cultures,23 and limited experience with duction or the cellular responses to insulin, and
animal models appear to substantiate that one of disruption of the growth hormone insulin-like
the earliest events in the induction of steroid growth factor (GH-IGF) axis70–72—are also noted
cataracts is the posteriorly directed migration of following extended systemic glucocorticoid treat-
lens epithelial cells away from the lens equator. ment.73–77 Hyperglycemia can result not only
Any of a large number of proteins involved in from a reduction in insulin availability following
cell cycle control, cell differentiation, cell adhe- damage to the pancreatic -cells (Type I) (or from
sion, cell signaling, and other processes could po- insulin resistance [Type II]), but also from en-
tentially be involved in triggering lens epithelial hancement of gluconeogenesis through the mech-
cells to migrate posteriorly. Lyu and colleagues23 anism normally regulated by cortisol. Moderate
suggested that cell migration away from the levels of glucocorticoids are used therapeutically
equatorial region in explanted rat lenses exposed to counteract the hypoglycemia induced by in-
to glucocorticoid is linked to a reduction in E- sulin overproduction, whereas excess exogenous
cadherin, a protein involved in cell adhesion to glucocorticoids can induce hyperglycemia.78,79
the extracellular matrix and in the -catenin/Wnt PSCs, in general, demonstrate an association with
cellular signaling pathway. However, whereas E- enhanced circulating levels of glucose,80–82 and
cadherin protein levels appeared to be reduced, ocular glucose levels appear to be elevated fol-
the levels of E-cadherin mRNA transcription lowing glucocorticoid treatment.83
were unaffected; these results suggest that if a Enhanced levels of glucose are linked in the eye
link exists between glucocorticoids and E-cad- to an increased production of reactive oxygen
herin, it is likely to be indirect, perhaps mediated species (ROS) and to the formation of advanced
through modified protein degradation. A causal glycation end (AGE) products. AGE modifications
relationship between glucocorticoid administra- to lens crystallins and lens cell membrane trans-
tion, E-cadherin protein levels, and migration of port proteins have been implicated in age-related
lens epithelial cells has yet to be substantiated. cataracts and also in some diabetic cataracts.84–87
Some posterior migration of epithelial cells has However, there is as yet no evidence for similar
also been noted in age-related PSC,15 in diabetic enhanced levels of AGEs occurring in steroid-in-
PSC,60 and the lenses of diabetic mice.62 These ob- duced cataracts, and there are no data to indicate
servations lend support to the notion that there a causative link between glucocorticoids, ocular
may be an indirect, possibly metabolic, compo- glucose levels, and PSC development.
nent to steroid cataract induction that involves al-
terations to the lens environment. Jobling and Growth factors
Augusteyn13 favored an alteration to the normal
gradient of growth factors, and in particular, fi- Jobling and Augusteyn13 appear to have been
broblast growth factor-2 (FGF-2), as the stimulus the first to propose that the induction of PSC may
for continued lens epithelial cell proliferation and be rooted in changes in intraocular growth fac-
their posteriorly directed migration. tors. A number of growth factors play a role in
regulating lens epithelial cell proliferation and
their differentiation into fiber cells: these include
Glucocorticoids, diabetes, and PSC
FGF-2, insulin, insulin-like growth factor-1 (IGF-
Diabetes, in particular Type I (juvenile) dia- 1), epidermal growth factor (EGF), transforming
betes, carries a significant risk for PSC develop- growth factor-beta (TGF-), lens epithelium–de-
ment.63–68 There may also be synergy between di- rived growth factor (LEDGF), platelet-derived
abetes and glucocorticoid treatment, leading to growth factor (PDGF), and bone morphogenetic
earlier, more aggressive PSC development.69 To- proteins (BMPs).88–99
STEROID CATARACT 409

The effects of glucocorticoids on the ocular lev- even if glucocorticoid treatment does not lead di-
els of growth factors (that may be derived either rectly to reduced FGF-2 and/or enhanced IGF-1
from endogenous or systemic sources) are un- levels within the eye, there could be significant
known. However, because the production of effects mediated through glucocorticoid-induced
growth factors can be modified by glucocorti- changes to IGF binding proteins, to insulin/IGF-
coids, it is reasonable to speculate that glucocor- 1 levels, and/or FGF-2 signaling.
ticoids could disrupt the normal balance of The levels of circulating IGF-1 and the activity
growth factors or their gradients within the ocu- of IGF-1 in the tissues are regulated by a family
lar compartments. of seven IGF binding proteins (IGFBPs).120–126
In several different cell types, glucocorticoids The expression of specific IGFBPs are modified
inhibit the production or activity of TGF-, by diabetes and by glucocorticoid administra-
EGF, PDGF, and BMP.30,100,101 The effect of glu- tion.127–130 DNA array data for glucocorticoid-
cocorticoid treatment on FGF-2 production by treated lens epithelial cells indicate that there is
cells varies, and both enhancement and reduc- a moderate increase in the transcription of IGFBP-
tion have been reported from different cell 2 (by 1.9-fold at 48 h of glucocorticoid treatment)
types.102–105 The proliferation of lens epithelial and decrease in the transcription of IGFBP-5 and
cells at the lens equator and their subsequent dif- -6 (by 4.1-fold and 2.4-fold, respectively at 48
ferentiation into fiber cells has been shown to be h).25 The activities of the IGFBPs are complex and
affected by FGF-2 concentration.106 The lower can vary with a number of factors, including the
concentrations of FGF-2 in the anterior chamber level of IGF-1 expression. Moreover, there may
promote lens epithelial cell proliferation, whereas be antagonistic as well as compensatory overlap
higher concentrations, found in the posterior between the activities of individual IGFBPs.124,126
chamber, encourage differentiation into fiber IGFBP-2 is thought to function by conveying IGF-
cells.107,108 Jobling and Augusteyn13 proposed 1 to those cells specifically expressing IGF recep-
that if the posterior chamber concentration of tors131 and enhanced IGFBP-2 expression is asso-
FGF-2 fell below that required to induce fiber cell ciated with promoting cell growth; the levels of
differentiation, the lens epithelial cells would IGFBP2 are elevated substantially in lens epithe-
proliferate at the lens equator and migrate poste- lial cells during the early development of the
riorly. Jobling and Augusteyn13 also hypothe- lens.131 Cell growth, proliferation, and migration
sized that the ciliary body is the main source of are usually inhibited by IGFBP-6. IGFBP-5 ex-
intraocular growth factors, and that the abnormal hibits a dual response-enhancing proliferation
production of growth factors induced by gluco- and migration but also inhibiting proliferation at
corticoid treatment leads to the dysregulation of a molar ratio of 2:1 with IGF-1. IGFBP-5 expres-
lens epithelial cell proliferation and differentia- sion is also enhanced concomitantly with cell dif-
tion. However, there are no data yet to substan- ferentiation and apoptosis.132–136 In the eyes of
tiate these hypotheses. diabetic rats, IGFBP-5 expression was upregu-
FGF-2 expression suppresses the production of lated and IGFBP-6 was downregulated, with the
IGF-1 by cells109–111; if FGF-2 levels in the poste- overall net effect of enhancing the activity of
rior chamber are reduced, then IGF-1 levels might IGF-1.137 If the transcript levels noted for gluco-
be expected to increase. IGF-1 also affects lens ep- corticoid-treated lens epithelial cells in vitro also
ithelial cell proliferation and differentiation,112 occur in vivo in the lens, then these glucocorti-
and it has been noted that in mice overexpress- coid-induced changes might also be expected to
ing IGF-1, the developing lens exhibits an ex- encourage lens epithelial cell proliferation while
panded equatorial transitional zone and per- suppressing differentiation into fiber cells.
turbed lens polarization.113 The level of IGF-1 is
normally relatively low in the vitreous and ap-
Glucocorticoid modifications to
proximately half the concentration found in the
signal transduction
aqueous,114 producing a gradient of increasing
concentration from the posterior to the anterior Growth factor signaling pathways are modi-
segment. The enhanced IGF-1 concentrations in fied in the lenses of diabetic rats,138 and it is prob-
the vitreous associated with diabetes115–119 sug- able that glucocorticoid administration could
gest that the ocular concentration gradient may lead to similar changes. The actions of growth fac-
be reduced or reversed in this disease. However, tors are mediated through specific cell-surface re-
410 JAMES

ceptors that signal primarily through the mito- MAPK pathways. Glucocorticoids can lead to
gen-activated protein kinase (MAPK) and the changes in the levels of expression of the p85 reg-
phosphoinositide-3 kinase (PI-3K) signal trans- ulatory and p110 catalytic subunits of PI-3K. In
duction pathways. Activation of the insulin re- DNA array studies of lens epithelial cells that had
ceptor (IR) or the IGF-1 receptor (IGF-1R) leads, received 48 h of glucocorticoid treatment,25 the
through the recruitment and cleavage of the in- transcription of the PI-3K p85 subunit was up-
sulin receptor substrate proteins (IRS-1 through regulated by 2.9-fold and a 1.4-fold downregula-
IRS-4), to the activation of PI-3K and subse- tion of the p110 subunit was noted. The ratio of
quently to protein kinase-B (PKB/Akt) activa- p85 to p110 subunits is critical to the ability of PI-
tion139 (and possibly the enhancement of MAPK 3K to function normally,155 and altered PI-3K sig-
pathway signaling). Serum/glucocorticoid-in- naling efficiency, induced by a disrupted subunit
duced kinase (SGK), which is upregulated in lens ratio, has been suggested to account for the glu-
epithelial cells by glucocorticoid treatment,22 cocorticoid-mediated inhibition of differentiation
shares many of the attributes of PKB/Akt, in- of chondrocytes.156
cluding the ability to be activated by the PI-3K The three MAPK pathways, extracellular-reg-
pathway,41,140–143 as well as by the MAPK sig- ulated kinase (ERK), Jun-N-terminal kinase/
naling pathway through FGF-2 stimulation.144 stress-activated protein kinase (JNK/SAPK) and
Activities ascribed to SGK include a role in cell p38 MAPK, are differentially affected by gluco-
cycle progression, cellular proliferation, protec- corticoids. Glucocorticoids partially inhibit ERK
tion from apoptosis, and ion channel regula- in lung fibroblasts without affecting JNK/SAPK
tion.144–149 Additionally, the enhanced expression or p38 MAPK.157 On the other hand, in trabecu-
of SGK results in the inhibition of systemic in- lar meshwork cells, glucocorticoids can enhance
sulin secretion specifically by the enhanced ac- ERK activation and cell proliferation.158 In lym-
tivity of the voltage-gated Kv1.5 channel.146,149 phoid cells, glucocorticoids specifically stimulate
The outcome of IR and IGF-1R activation is p38 MAPK activation.159 Diabetes appears to pro-
modulated, depending on the availability of IRS- duce significant perturbation to MAPK signaling
1150,151; high IRS-1 concentrations are mitogenic in the lens138; however, whether such effects are
and antiapoptotic, whereas low IRS-1 concentra- also induced in the lens by glucocorticoids has
tions mediate cellular differentiation. Glucocorti- not yet been explored.
coids can significantly alter the levels of expres- PI-3K and MAPK signaling can be further
sion of the IRS isoforms.152 In this regard, DNA modulated by cross-talk between these and other
array data indicate that both IRS-1 and IRS-2 tran- signaling pathways.160–162 In the lens, activation
scription are moderately enhanced by dexam- of Ras (an upstream activator of the ERK path-
ethasone (by 1.8- and 2.8-fold, respectively, at 48 way), MEK1 (the immediate upstream activator
h) in lens epithelial cells.25 of ERK), SAPK/JNK, and p38 can all affect the
PKB/Akt (and SGK) also promote cell survival activation of PI-3K.163 ERK can, in turn, activate
and function to protect cells against apoptosis the p70 serine/threonine kinase (p70-S6K), the
mediated, in part through the phosphorylation of latter being a proproliferative signaling kinase in
the FOXO family of transcription factors,145,152 lens epithelial cells.164 The degree of Akt activa-
and through the stimulation of NF-B activity.153 tion can affect the activation state of glycogen-
Cells obtained from human posterior subcapsu- synthase kinase-3 (GSK-3), which then can affect
lar cataracts, including those linked to diabetes, the stability of -catenin, which could modulate
exhibit a reduced propensity to undergo apopto- the -catenin/Wnt signaling pathway and also
sis by the intrinsic apoptotic pathway when stim- affect cell differentiation.165
ulated with staurosporine.154 These observations In summary, studies of glucocorticoid-medi-
suggest that glucocorticoid treatment could be ated modification to signal transduction path-
promoting an antiapoptotic response in lens ep- ways in other cell types, and limited DNA array
ithelial cells. Such a response could provide an data with lens epithelial cells indicate that the po-
additional mechanism for suppressing the differ- tential exists for signaling pathways in lens ep-
entiation of lens epithelial cells at the equator and ithelial cells to be altered by glucocorticoid treat-
promoting epithelial cell proliferation. ment. An analysis of the effects of glucocorticoid
Glucocorticoid administration also affects treatment on PI-3K and MAPK pathways, possi-
other component proteins of the PI-3K and bly along the lines of the studies on the lenses of
STEROID CATARACT 411

streptozotocin-treated diabetic rats conducted by nist, RU486.20 Both of these observations indicate
Zatechka and colleagues,138 would provide par- that GSH depletion must be linked to the activa-
ticularly useful information. tion of the glucocorticoid receptor. Glucocoticoid-
mediated reduction of lens GSH could involve al-
terations to the expression of transcripts for any
Oxidation and lens hydration
of those proteins involved in the mechanisms of
Two of the general mechanisms implicated in GSH loss indicated above. However, the most di-
the induction of age-related and other forms of rect mechanism might be a reduction in the lev-
cataracts are oxidation of lens proteins and dis- els of those enzymes involved in GSH synthesis.
ruption of the level of lens hydration. These GSH is synthesized from cysteine by two en-
mechanisms have previously been suggested to zymes, the rate-limiting -glutamylcysteine syn-
possibly be important in steroid cataract induc- thase (-GCS) and glutathione synthetase (GS).174
tion. Reduction in the concentration of reduced The -GCS enzyme exists as a heterodimer com-
GSH is a common feature of cataractous lenses prising a 73-kDa heavy subunit (-GCS-HS) and
resulting from a wide range of causes. This phe- a 28-kDa light subunit (-GCS-LS).175 The ex-
nomenon would be expected to promote oxida- pression of -GCS-HS, which contains the en-
tion of lens proteins and has been studied quite zyme’s catalytic activity, is regulated through the
extensively; however, little is known about the in- binding of AP1,176 whose activity can be modu-
fluence of steroid treatment on the oxidation of lated by glucocorticoids. Studies have demon-
lens proteins. GSH is integral to the action of sev- strated that glucocorticoid receptor activation by
eral antioxidant systems, including, in particular, dexamethasone inhibits -GCS-HS mRNA ex-
glutathione peroxidase/glutathione reductase. pression in alveolar epithelial cells by blocking
Glutathione peroxidase utilizes GSH as a proton the -GCS-HS AP1 promoter.177 Reduced levels
donor, generating oxidized-GSH (GSSG) in the of activity of both -GCS and GS have been re-
process of converting hydrogen peroxide (H2O2) ported from human cataract lens samples,178 and
to water, and a reduction in lens GSH concentra- were particularly significant for lenses with PSC.
tion would impair the efficiency of H2O2 detoxi- (The mechanism(s) involved in the generation of
fication and could lead to the oxidation of lens these PSC was not defined and the possible in-
proteins. H2O2-mediated damage to lens epithe- clusion of steroid-induced PSC in these data is
lial cells is regarded as a key event in the devel- unknown.) However, gene chip analyses25,43 and
opment of age-related cataract.166 quantitative real-time PCR (E.R.J., unpublished
It has been assumed that the mechanisms re- data) could not detect any significant alterations
sponsible for depletion of lens GSH in steroid-in- in -GCS-HS transcript levels in in vitro cultured
duced PSC are similar to those causing GSH de- lens epithelial cells exposed to dexamethasone,
pletion in other forms of cataracts, these being: (i) suggesting that GSH depletion is probably not a
the inhibition of GSH-reductase activity leading result of the disruption of GSH synthesis in the
to a reduction in the ability of GSH regeneration lens. The mechanism underlying the reduction in
from GSSG167–169; (ii) efflux of GSH from the lens GSH following glucocorticoid treatment
lens170,171; (iii) sequestration of GSH by incorpo- needs to be resolved nevertheless, as glucocorti-
ration into mixed disulfide aggregates associated coid administration is associated with a reduction
with the action of oxidants172,173; (iv) enhanced in lens GSH, and a contribution to steroid-in-
consumption of GSH in the process of detoxify- duced PSC from elevated ROS levels remains fea-
ing ROS; and (v) a downregulation of GSH syn- sible.
thesis. If enhanced ROS activity plays a role in steroid
Evidence to support most of these mechanisms cataract formation, antioxidants would be ex-
of GSH reduction in relation to steroid treatment, pected to aid in their prevention. The generalized
however, is absent. The observations by Dicker- opacification noted by Ohta and colleagues,179
son and colleagues20 with in vitro cultured lenses that followed steroid administration to lenses in
indicated that a reduction in lens GSH was only culture, could be prevented by the administration
associated with steroids possessing glucocorti- of vitamin E. The lack of any similarity between
coid activity. Additionally, the reduction in GSH this generalized opacification and PSC notwith-
concentration could be prevented by preexposing standing, the addition of vitamin E did not pre-
the lenses to the glucocorticoid-receptor antago- vent GSH depletion,179 which suggests that en-
412 JAMES

hanced GSH efflux is the most probable cause of mational change facilitating SH cross-linking and
the glucocorticoid-associated reduction of GSH. subsequent oxidation. As Dickerson and cowork-
Altered lens hydration has been implicated as ers20,196 indicate, this hypothesis is conceptually
an initiator of, or a contributor to, age-related and similar to that originally proposed to cause age-
diabetic cataracts180 and may follow initial dam- related cataract.
age induced by oxidative stress.181 In cortical di- Dickerson and colleagues,20 along with Jobling
abetic cataract, an increase in lens water content and Augusteyn,199 have pointed out that the
and vacuolation of fiber cells is preceded by other steroid-protein adduct hypothesis assumes that: (i)
changes that include an increase in ROS with a cataractogenic steroids must have a hydroxyl-
concomitant depletion of GSH and ascorbate, group adjacent to the reactive carbonyl; (ii) any
possibly resulting in this case from a higher rate steroid with ketol activity should be capable of in-
of consumption of these antioxidants. It is possi- ducing cataracts; and (iii) the ability to produce
ble that glucocorticoid administration could lead cataracts must not be a function of “glucocorticoid
directly to changes in lens hydration through activity.” The studies of Dickerson and cowork-
modification of the levels of expression of cell- ers20 did not support this hypothesis, as proges-
surface membrane channels that are important in terone (a steroid lacking the C-21-OH and which
regulating intracellular ions and water.181–184 For has no glucocorticoid activity) formed adducts
example, both the alpha1 and beta1 Na/K- with the greatest avidity, whereas crystallin mod-
ATPase gene promoter-regions contain GREs, and ification by dexamethasone (a C-21-OH-contain-
systemic glucocorticoid treatment directly affects ing steroid) proceeded extremely slowly.193 With
the level of expression of Na/K-ATPase and wa- dexamethasone, the adducts formed were largely
ter balance in other cell types.185,186 Levels of the soluble in water, in contrast to progesterone-in-
alpha1 Na/K-ATPase transcript were increased duced adducts, which were only soluble in urea.190
by 4-fold at 48 h in glucocorticoid-treated lens ep- Aspirin pretreatment, which promotes acetylation
ithelial cells.25 In addition, five members of the of amino groups, did not reduce the limited de-
cystic fibrosis transmembrane conductance regu- gree of dexamethasone binding to crystallin, but
lator/multidrug resistance–associated proteins significantly reduced progesterone binding.
(CTFR/MRP) and two members of the organic an- Whereas steroid-protein adducts have been
ion transporting polypeptide family of trans- reported from samples obtained from steroid-
porters (Oatp) are able to transport GSH187 and at induced PSC,190 the quantities formed are
least two of these, MRP2 and CTFR, are known to small191,196; in addition, the adducts do not ap-
be upregulated by glucocorticoid administra- pear to compromise lens crystallin conformation.
tion.188 The transcript for one of these, OatP2, was Nevertheless, Lyu and colleagues23 have pre-
moderately elevated (by 2.4-fold at 48 h) in lens sented evidence for the colocalization of dexa-
epithelial cells exposed to dexamethasone. This methasone with opacities observed in vitro in cul-
area of cellular physiology coupled to gene ex- tured, dexamethasone-treated rat lenses, at the
pression in relation to glucocorticoid treatment high dose of 5 M. The nature of this association
and cataract formation is yet to be explored. was not investigated and it is not certain that it
represents the formation of adducts. As noted by
Jobling and Augusteyn,13 an unresolved issue ex-
Protein-steroid binding
ists: if adduct formation is involved in steroid
The hypothesis that steroid-induced PSC occur cataract formation, why would these adducts be
by the binding of steroids to lens proteins to gen- restricted to the terminal ends of the lens fibers
erate steroid-protein adducts has probably re- at the posterior lens pole? This unlikely restricted
ceived the most attention as a potential cause of location for adduct formation assisted Jobling
steroid-induced PSC.189–198 Originally ascribed to and Augusteyn13 in concluding that steroid-pro-
Bucala and colleagues,189 this hypothesis sug- tein adduct formation is an improbable mecha-
gests the C-20 carbonyl-group of the steroid nism to account for the induction of steroid
forms a Schiff base with a lysine residue -amino cataracts. Nevertheless, as there is evidence for
group of lens crystallin. A hydroxyl-group on the some steroid adduct formation and for some colo-
steroid’s adjacent C-21 is then induced to form a calization of PSC with steroids, this mechanism
ketoimine product, covalently binding the steroid might contribute to the development of steroid
to the crystallin, which then undergoes a confor- cataracts.
STEROID CATARACT 413

CONCLUSIONS tain, in particular because the data were gener-


ated following short exposure times to glucocor-
Despite the long-recognized association of glu- ticoid in vitro, and because in vivo steroid cataracts
cocorticoids with PSCs, the mechanism(s) re- require many months of glucocorticoid adminis-
sponsible for inducing steroid cataracts remains tration to develop. Hopefully, a clearer picture re-
unknown. Glucocorticoids administered locally garding the altered expression of relevant genes
(to the eye) or systemically (at a distance from in lens epithelial cells will emerge from extended
the eye) are both effective in inducing steroid glucocorticoid treatment studies, preferably us-
cataracts. It is possible, therefore, to present a case ing patient-derived PSC material.
for steroid-induced cataracts as being the result Demonstration of an active glucocorticoid re-
of the direct action of glucocorticoids on lens ep- ceptor in the lens has altered the perception of
ithelial cells but also for an indirect action, as fa- what mechanism(s) may underlie the develop-
vored by Jobling and Augusteyn13 through ment of steroid cataract. The data from DNA ar-
changes to, for example, the levels of intraocular ray studies encourage the consideration of sev-
growth factors. eral feasible hypotheses, but as yet, there are very
Recent studies have demonstrated the defini- few supportive data. Defining and characterizing
tive existence of a glucocorticoid receptor alpha the effects of glucocorticoid receptor activation on
in lens epithelial cells, whose activation results in signal transduction mechanisms in lens epithelial
changes in gene expression. Glucocorticoid re- cells will likely be one of the important next steps
ceptor activation (in other cell types) is associ- in unraveling the mechanism of steroid cataract
ated, in particular, with changes to gene expres- induction. Monitoring the intraocular environ-
sion that are linked to alterations in: (i) cell ment of the lens following exposure to glucocor-
proliferation and differentiation, (ii) apoptosis, ticoid for changes in the levels of growth factors
(iii) gluconeogenesis, (iv) expression and activity also promises to yield additional useful data. The
of growth factors, and (v) modifications to signal issues of ROS activity and lens cell membrane
transduction pathways. Changes to the levels of permeability changes also require further resolu-
transcription of genes involved in these processes tion in light of observed modifications to gene
have been observed in the DNA array studies and transcription.
supplementary investigations performed with The etiology of steroid cataract induction will,
cultured lens epithelial cells.25,43 However, the in all probability, turn out to be comprised of both
relevance of these individual changes is uncer- direct effects of glucocorticoids on lens epithelial

FIG. 1. Steroid cataract formation: Pathways/factors potentially contributing to the formation of steroid-induced
posterior subcapsular cataracts following glucocorticoid treatment. Likely prominent pathways are shown in black,
with possible secondary contributing pathways in grey. GC, glucocorticoid; GSH, glutathione; ROS, reactive oxygen
species; PSC, posterior subcapsular cataract; Na, sodium).
414 JAMES

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Figure 1, acting together on the lens over an ex- 17. Wenk, E.J., Hernandez, M.R., Weinstein, B.I., et al.
Glucocorticoid receptor binding in bovine lens. In-
tended period of time.
vest Ophthalmol. Vis. Sci. 22:599–605, 1982.
18. Stokes, J., Noble, J., and Brett, L. Distribution of glu-
cocorticoid and mineralocorticoid receptors and
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