ARTICLE |
Correspondence to: Alexander V. Ljubimov, Cedars-Sinai Medical Center, Davis-5069, 8700 Beverly Boulevard, Los Angeles, CA 90048..
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Summary |
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Corneas of diabetic patients have abnormal healing and epithelial adhesion, which may be due to alterations of the corneal extracellular matrix (ECM) and basement membrane (BM). To identify such alterations, various ECM and BM components and integrin receptors were studied by immunofluorescence on sections of normal and diabetic human corneas. Age-matched corneas from 15 normal subjects, 10 diabetics without diabetic retinopathy (DR), and 12 diabetics with DR were used. In DR corneas, the composition of the central epithelial BM was markedly altered, compared to normal or non-DR diabetic corneas. In most cases the staining for entactin/nidogen and for chains of laminin-1 (1ß1
1) and laminin-10 (
5ß1
1) was very weak, discontinuous, or absent over large areas. Other BM components displayed less frequent changes. The staining for
3ß1 (VLA-3) laminin binding integrin was also weak and discontinuous in DR corneal epithelium. Components of stromal ECM remained unchanged even in DR corneas. Therefore, distinct changes were identified in the composition of the epithelial BM in DR corneas. They may be due to increased degradation or decreased synthesis of BM components and related integrins. These alterations may directly contribute to the epithelial adhesion and wound healing abnormalities found in diabetic corneas. (J Histochem Cytochem 46:10331041, 1998)
Key Words: diabetic retinopathy, corneal epithelium, basement membrane, integrins, VLA-3, laminin chains, entactin/nidogen, type IV collagen isoforms, extracellular matrix, immunofluorescence
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Introduction |
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Diabetes mellitus, both insulin-dependent (IDDM, or Type I) and non-insulin-dependent (NIDDM, or Type II), causes loss of vision not only from major abnormalities of the retina and lens but also from the alterations in the cornea, tear film, eyelids, iris, ciliary body, and cranial nerves (
These and other defects are likely to result from alterations in epithelial adhesion, migration, differentiation, and renewal. Extracellular matrix (ECM) and BM components acting through cell surface adhesive receptors, integrins (
Consequently, the purpose of this investigation was to identify the specific changes in individual BM and ECM components and in integrins that occur in the diabetic human cornea, with special reference to DR. Such a study was a necessary first step in understanding of the molecular mechanisms of corneal epithelial abnormalities in diabetes. Because of lack of pertinent data, we needed to study many BM components and integrins to single out those that were specifically altered in diabetes and DR. We conclude that corneas from patients with DR have specific alterations in the distribution of major epithelial BM components, entactin/nidogen, laminin-1 and laminin-10, and of an integrin receptor, 3ß1 (VLA-3), reported to bind to these components. In contrast, corneas from diabetic patients without DR showed such alterations much less frequently. This suggests that, as retinal diabetic disease worsens, concomitant alterations of the corneal epithelial BM occur in parallel. Our study therefore provides the necessary background information for future investigations of the role of changes in specific BM components and integrins in DR-associated corneal dysfunction.
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Materials and Methods |
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Tissue
Human autopsy corneas were obtained within 30 hr after death from the National Disease Research Interchange (Philadelphia, PA). They included age-matched corneas from 15 non-diabetic individuals (normal group), 10 diabetics without DR, referred to as non-DR diabetics (four IDDM and six NIDDM), and 12 diabetics with DR (nine IDDM and three NIDDM). All corneas were bisected, embedded in OCT (Miles; Elkhart, IN), and cryostat sections were studied.
Immunohistological Analysis
Indirect immunofluorescent staining of cryostat sections, their treatment with urea to reveal type IV collagen epitopes, and photography were performed as described (1(IV) chain, tenascin-C, fibrillin-1), markedly decreased staining (Figure 6,
3ß1, ß1 integrins), discontinuity (Figure 2, laminin
1, entactin/nidogen; Figure 4,
3(IV) chain) and absence of staining (Figure 2, laminin
5, ß1) were taken into account only if they were reproducible on serial sections and/or with different antibodies (e.g., to different chains of laminin).
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Antibodies
Well-characterized antibodies were used to 1
6 chains of Type IV collagen, to
1,
2,
4, ß1, ß2, and
1 chains of laminin, to laminin-5 (
3ß3
2), to entactin/nidogen, to fibronectin eighth Type III repeat, to Types VI, VII, XII, and XIV collagen, and to perlecan and bamacan core proteins (
5 chain of laminin was from Chemicon International. This antibody was previously believed to react with laminin
1 chain and was only recently shown to recognize the
5 chain instead (
5ß1 integrin heterodimer,
3ß1 integrin heterodimer (clone M-KID 2), to
6 (clone NKI-GoH3),
3 (clone P1B5),
2,
1 (clone FB12 to I domain), ß1 (clone HB1.1), and ß4 (clone 3E1) integrin subunits, and cross-species-absorbed fluorescein- and rhodamine-conjugated secondary antibodies were from Chemicon International.
Statistical Analysis
This was performed using a double-sided Fisher's exact test (InStat software program; GraphPad Software, San Diego, CA).
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Results |
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Laminin Chain Distribution in Normal Human Corneas
Human cornea can be topographically divided into the central part, which has the collagenous Bowman's layer under the epithelial BM, and the peripheral corneoscleral limbus, which harbors epithelial stem cells but does not have Bowman's layer (1 chain was recently shown to react with a ubiquitous
5 chain instead (
1 chain, we have previously used an 11D5 antibody (see
5 chain. Therefore, the distribution of laminin chains in the normal human cornea first had to be revisited using other antibodies with a properly defined
-chain specificity. Such antibodies became available only very recently (
In normal adult corneas, the laminin 5 chain-specific antibody 4C7 yielded the same staining pattern as 11D5: the epithelial central and limbal BM, limbal blood vessels, and the endothelial face of Descemet's membrane (DM) were strongly positive (Figure 1). Laminin
1 chain was present in the epithelial BM throughout the cornea, and on the endothelial face of DM (Figure 1). Limbal blood vessels exhibited weak to no staining (not shown). Some keratocyte staining was observed for both the
1 and
5 chains (Figure 1). The
4 chain could not be detected with the antibody used (Figure 1). These and previous data (
1ß1
1), laminin-5 (
3ß3
2), laminin-6 (ß1
1), and laminin-10 (
5ß1
1), with more isoforms in the limbus (see
Basement Membrane Abnormalities in Diabetic Retinopathy Corneas
In the corneoscleral limbus, all ECM and BM components studied had a normal distribution in all non-DR diabetic or DR corneas. In addition, the corneal stromal components decorin, bamacan, and Types I, III, V, VI, and XII collagen were unchanged compared to normal corneas (not shown). However, profound alterations were revealed at the level of the epithelial BM in the central part of DR corneas.
In most DR cases, staining for chains of laminin-1 and laminin-10, 1 (nine of 12 cases),
5 (10 of 12 cases), ß1 (10 of 12 cases) and
1 (eight of 10 cases), and for entactin/nidogen (seven of 11 cases) was very weak, discontinuous, or absent from parts or whole central epithelial BM (Figure 2; Table 1). In contrast, these components displayed strong and continuous staining in normal corneas (Figure 1 and Figure 2). The incidence of the abnormal distribution of laminin-1, laminin-10, or entactin/nidogen in the DR group was significantly higher (p<0.03) than in either non-DR diabetic or normal group. Laminin chains
2 and ß2 did not appear in the central epithelial BM or DM of non-DR diabetic or DR corneas and were seen only in the limbal BM, similar to normal corneas (not shown). In about half of the DR cases, alterations similar to laminin-1 and entactin/nidogen were observed in the central epithelial BM for
3 and
4 Type IV collagen chains (Figure 3; Table 1), although differences from the non-DR diabetic group were not significant. Laminin-5, Type VII collagen,
5 and
6 chains of Type IV collagen (Figure 4; Table 1), and perlecan (not shown) were rarely altered even in DR corneas. In the epithelial BM, fibronectin was also normal in most cases.
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In DM, the only consistent change in DR group was the absence of fibronectin (both total and cellular, six of nine cases, Figure 5), which was found at the stromal aspect of DM in normal corneas (1
2 Type IV collagen abnormally deposited in the epithelial BM, fibrillin-1 deposited in BM and stroma, and tenascin-C mainly deposited in stroma (Figure 5). The deposition of these components may be related to diabetes-associated corneal edema, because they also appeared in human corneas with bullous keratopathy, an edematous blistering disease (
Epithelial Integrin Alterations in Diabetic Retinopathy Corneas
The next question was to determine whether the observed alterations of laminin-1, laminin-10, and entactin/nidogen in DR corneal epithelial BM were accompanied by changes in the expression of specific integrin receptors on corneal cells that bind to these components. To this end, we studied the distribution of chains of most of the known laminin-binding inte-grins, including 6,
3 (also reported to bind entactin/nidogen),
2,
1, ß4, and ß1. One of these integrin chains,
1, was not found in any of the central corneas studied (not shown). In addition, corneas were stained for the fibronectin receptor
5ß1, which served as a negative control because its ligand did not change in the epithelial BM of diabetic corneas. Because diabetic changes mainly concerned the epithelial BM, we will discuss below primarily the epithelial patterns of studied integrins. The endothelium and keratocytes of non-DR diabetic and DR corneas were positive for
5ß1,
6,
3,
2, and ß1 integrins, similar to normal corneas (not shown).
In normal corneas, the epithelial patterns of studied integrins and their subunits were identical to previously described patterns (3ß1 integrin was markedly weaker or discontinuous compared to non-DR diabetic or normal corneas (Figure 6; Table 1). Changes were more pronounced in suprabasal layers and on the basal surface of basal epithelial cells. In some DR corneas these alterations were local, whereas in other corneas they were seen in the majority of the epithelial cells. Identical results were obtained with antibodies recognizing the whole integrin heterodimer (Figure 6) or its
3 chain (not shown). The staining for ß1 integrin was also weaker than normal or discontinuous in more than half of DR corneas (Figure 6; Table 1), unlike non-DR diabetic corneas. In contrast, the distribution of
6, ß4 (Figure 6) and
5ß1 (not shown) integrins did not change in either non-DR diabetic or DR corneas compared to normal corneas. Because the ß1 integrin subunit, unlike
6 and ß4, appeared to be reduced in DR corneas, the epithelial
6 subunit may mostly be part of
6ß4 rather than of
6ß1 integrin.
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Discussion |
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Diabetic retinopathy is a severe ocular diabetic complication and a major cause of legal blindness. Although diabetes affects mostly the retina and iris (
Diabetic nephropathy and retinopathy bring about profound changes in the ECM and BM in kidney and retina, respectively. Glomerular, retinal, and vascular BMs are thickened in diabetics and exhibit alterations in the expression of laminins, collagens, fibronectin, tenascin-C, proteoglycans, and some integrins (
We show here that the epithelial BM composition in DR corneas is significantly altered. Major epithelial BM components, entactin/nidogen, laminin-1, and laminin-10, were markedly diminished in DR corneas as revealed by specific immunofluorescence. Alterations in other BM components, laminin-5, Type IV collagen isoforms, Type VII collagen, and fibronectin, were less pronounced and less common.
The next step was to analyze in DR corneas the fate of integrins that bind laminin and entactin/nidogen. Only one integrin studied, 3ß1 (VLA-3), was significantly altered in the epithelium of DR corneas compared to both normal and non-DR diabetics (Table 1). This integrin has been reported to bind both isolated entactin/nidogen and laminins (
3Aß1, is expressed in cornea, because the other variant,
3Bß1, has a restricted tissue distribution (
Laminin-binding integrin 1ß1 (not shown) was not found in the corneal epithelium. Laminin-binding integrins
2ß1 and
6ß4 were generally not altered in DR corneas (Table 1). This might be due to preferential binding of
2ß1 integrin to collagen and of
6ß4, to laminin-5 (
7ß1 laminin binding integrin (
The observed alterations in major human corneal epithelial BM components and in their binding 3ß1 integrin appear to be DR-specific. In fact, in corneas from patients with bullous keratopathy, laminin and entactin/nidogen abnormalities were less severe and less common (similar to non-DR diabetics), and both
3ß1 and ß1 integrins retained a normal distribution (not shown). In addition, BM and integrin alterations were significantly more pronounced and more common in DR corneas than in non-DR diabetic corneas (Table 1). It should be noted that no similar alterations have been reported in retinas of DR patients or in kidneys of diabetic nephropathy patients. In contrast, there was an increased expression of BM proteins and integrins (
What could be the mechanisms of such alterations and why would they develop late in the course of the disease, with the advent of DR and proliferative DR? One possibility is that BM and/or integrin synthesis is decreased because of the action of growth factors abnormally expressed in the diabetic eye. Growth factor modulation of laminin-1, entactin/nidogen, and 3ß1 integrin expression was shown in other systems (
Another possibility is that, in DR corneas, BM components and/or integrins may be altered because of their increased degradation by proteinases elevated in these corneas. Several lines of evidence support this hypothesis. Cultured diabetic human retinal endothelial cells have abnormal expression of matrix metalloproteinase-2 (MMP-2), which can cleave laminin (
The laminin 1 chain is involved in the formation of stable complexes with entactin/nidogen (
1 chain-containing laminin-1 and laminin-10 in the epithelial BM of DR corneas could trigger coordinate alterations in entactin/nidogen. If proteolysis is involved in the DR corneal alterations, it may first affect entactin/nidogen, which is easily proteolysed (
Interaction of corneal epithelial cells with BM components is known to modulate integrin expression patterns (3ß1 integrin expression by gene knockout has been recently shown to disrupt epidermal BM assembly (
3ß1 integrin by some DR-activated factors may cause BM alterations observed in DR corneas. One such mechanism may be an increase in the expression of matrix metalloproteinases that degrade
3ß1 BM ligands (
The concerted reduction of expression of entactin/nidogen, laminin-1, laminin-10, and of their binding 3ß1 integrin in DR corneas may severely impair the adhesive and migratory properties of corneal epithelial cells. Such alterations in corneal cellBM adhesion may be the mechanism underlying clinically observed diabetic abnormalities in epithelial barrier function, adhesion, epithelial integrity and wound healing. Finding ways to inhibit or retard corneal BM and integrin downregulation may prove useful in the development of novel therapeutics aimed at alleviating the symptoms of diabetic keratopathy.
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Footnotes |
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1 Presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, FL, May 1997.
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Acknowledgments |
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Supported by the Iris and B. Gerald Cantor Foundation, the Discovery Fund for Eye Research, and the Skirball Program for Molecular Ophthalmology.
We thank Profs J.R. Couchman (University of Alabama, Birmingham, AL), E. Engvall (The Burnham Institute, La Jolla, CA), and A.F. Michael (University of Minnesota, Minneapolis, MN) for providing antibodies. Antibodies to laminin ß2 chain produced by Dr J. Sanes and to Type IV collagen 1
2 chains produced by Dr H. Furthmayr were obtained from the Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa (Iowa City, IA), under contract N01-HD-2-3144 from the NICHD.
Received for publication December 18, 1997; accepted May 12, 1998.
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