Changes in the Extracellular Matrix of the Human Optic Nerve Head in Primary Open-Angle Glaucoma

doi:10.1016/S0002-9394(14)75984-7

American Journal of Ophthalmology

Volume 109, Issue 2, February 1990, Pages 180-188

https://doi.org/10.1016/S0002-9394(14)75984-7 Get rights and content

Using immunofluorescent staining, we were able to characterize the changes in composition and distribution of the macromolecules making up the extracellular matrix of the lamina cribrosa of the glaucomatous human optic nerve head. In tissue adjacent to the glaucomatous cups, there was marked disorganization and loss of fibers of elastin within the cores of the cribriform plates. Collagen type VI, normally sparse, increased in quantity considerably throughout the lamina cribrosa in glaucomatous eyes with all degrees of damage. Collagen type IV and other basement membrane macromolecules appeared to extend into nerve bundles, presumably filling in spaces previously occupied by nerves. There was no appreciable change in the postlaminar region, which indicates the specificity of the extracellular matrix changes in the lamina cribrosa. Our results indicate that changes in the extracellular matrix play an important role in the progression of the glaucomatous process and may be a causative agent of the disease.

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Située au sein du canal scléral, la lame criblée est une structure tamisée qui sépare les portions intraoculaire et rétrobulbaire du nerf optique. Identifiée comme site principal des dommages axonaux retrouvés dans la neuropathie optique glaucomateuse, l’étude de la lame criblée suscite depuis des années un réel intérêt. De nombreuses études ont ainsi exploré les caractéristiques histologiques et morphologiques de la région laminaire chez le sujet sain comme chez le sujet glaucomateux. Plus récemment, le développement des systèmes d’optique adaptative et des nouvelles générations d’OCT a permis de réaliser de grands progrès dans la compréhension de la physiopathologie du glaucome, et ont ouvert de nouvelles pistes dans l’amélioration des procédés diagnostiques à notre disposition.
Located within the scleral canal, the lamina cribrosa is a sieve-like structure separating the intraocular and retrobulbar portions of the optic nerve. Identified as the main site of axonal damage in glaucomatous optic neuropathy, the study of the lamina cribrosa has been of great interest for many years. Numerous studies have explored the histological and morphological characteristics of the laminar region in healthy subjects as well as glaucoma patients. More recently, the development of adaptive optics systems and new generations of OCT has allowed great progress in the understanding of the pathogenesis of glaucoma and has opened new perspectives for the improvement of diagnostic procedures.
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Citation Excerpt :
Acute IOP changes lead to changes in PLT thickness,30,31 whereas we evaluated the effects of chronic elevation of IOP on LC and PLT in eyes receiving medical treatment with no history of glaucoma surgery. In patients with chronically elevated IOP, the PLT is under constant stress and strain, leading to extracellular matrix remodeling.32–34 In advanced glaucoma patients, laminar compliance is decreased because of decreased retinal ganglion cell axons and increased tissue stiffness resulting from tissue remodeling.26
To investigate characteristics of the lamina cribrosa (LC) and prelaminar tissue (PLT) in eyes of patients with primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and pseudoexfoliation glaucoma (PXG) using enhanced depth imaging (EDI) OCT.
Observational case-control study.
A total of 116 eyes from 116 participants with POAG (n = 30 eyes), PACG (n = 29 eyes), or PXG (n = 29 eyes) and 28 healthy eyes.
Participants underwent a complete ophthalmologic examination in addition to corneal pachymetry, standard achromatic perimetry, peripapillary retinal nerve fiber layer (RNFL) OCT, and EDI OCT, as well as measurement of LC, PLT thickness, and LC depth.
Lamina cribrosa measurement, PLT thickness, and LC thickness.
Average LC thickness was significantly different among the 4 groups with the thinnest values in the PXG group. Prelaminar tissue also was significantly thinner in PXG eyes. The POAG eyes demonstrated the largest LC depths (P < 0.05), whereas PACG and healthy eyes demonstrated the smallest LC depths (P < 0.05). Mean deviation on standard achromatic perimetry and average thickness on peripapillary RNFL OCT were associated significantly with LC and PLT thickness.
Pseudoexfoliation glaucoma eyes demonstrate reduced LC and PLT thickness compared with POAG, PACG, and healthy eyes. Lamina cribrosa depth was larger in POAG eyes as compared with PXG, PACG, and healthy eyes. These findings may account for the peculiar appearance of the optic nerve head in PXG eyes.
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The meninges not only surround the brain and the spinal cord but also the optic nerve. Meningeal-derived extracellular matrix (ECM) is a crucial component of the pial basement membrane, glia limitans and important for maintenance of optic nerve axon integrity, homeostasis and retinal ganglion cell health. To get closer insight into optic nerve meningeal-derived ECM composition, we performed proteomic analysis of the sheep optic nerve subarachnoid space (SAS). Candidate components were confirmed in cultures of primary human meningothelial cells (phMECs) and human optic nerve samples. Sheep optic nerve SAS samples were analysed by LC-MS, identified proteins were matched to their human orthologs and filtered using gene lists representing all major ECM components. To validate these findings digital droplet PCR (ddPCR) to evaluate mRNA expression of all candidate components identified was performed on cultures of phMECs. In addition, one protein per major ECM group was stained on human optic nerve sections and on phMEC cultures. Employing LC-MS, 1273 proteins were identified and subjected to bioinformatic analysis. Gene ontology analysis revealed six out of forty-four collagen types (1A1, 1A2, 3A1, 6A2, 6A3 and 14A1), three out of eleven laminin subunits (A4, B2, C1) and six out of twenty-seven hyaluronan binding proteins (CD44, versican (VCAN), C1q binding protein, neurocan (NCAN), brevican (BCAN) and hyalaluronan proteoglycan link protein 2 (HAPLN2)) were present in our cohort. DdPCR in phMEC cell culture confirmed presence of all candidate components except NCAN, BCAN and HAPLN2. Immunohistochemistry (IHC) staining on human optic nerve sections and immunofluorescence (IF) staining on in vitro cultured phMECs showed strong immunopositivity for collagen-typeI-α1 (COL1A1), lamininγ1 (LAMC1), and VCAN. Fibronectin (FN1) was exclusively present in cultures of phMECs. Using a combined bioinformatics and immunohistological approach, we describe the ECM composition of the optic nerve subarachnoid space. As this space plays an important role in maintaining optic nerve function, a better understanding of ECM composition in this delicate environment might be key to further pathophysiological insight into optic nerve degeneration and associated disorders.
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Reprint requests to M. Rosario Hernandez, D.D.S., Eye Research Institute, 20 Staniford St., Boston, MA 02114.

This study was supported in part by National Eye Institute research grant EY-06416, the New England Glaucoma Research Foundation, Inc. (Boston), the Glaucoma Foundation (New York), and the Foundation for Glaucoma Research (San Francisco).

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Changes in the Extracellular Matrix of the Human Optic Nerve Head in Primary Open-Angle Glaucoma

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Coll. Relat. Res.

Ophthalmology

Surv. Ophthalmol.

J. Am. Acad. Dermatol.

Hum. Pathol.