The composition of wide-spaced collagen in normal and diseased Descemet's membrane

Levy, Simon G.; Moss, J.; Sawada, Hajime; Dopping-Hepenstal, Patricia J.C.; Mccartney, A. C. E.

doi:10.3109/02713689609017610

Cited by 91 publications

(64 citation statements)

References 29 publications

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“…In FECD corneas, DM becomes thickened with irregularly deposited wide-spaced COL8 aggregates. 4 In the normal cornea, a smooth monolayer of CECs, uniform in size and shape, is present along the DM. CECs form a selective barrier to the aqueous fluid 5 with the activity of sodium-potassium ATPase and carbonic anhydrase on the apical surface maintaining physiologic hydration and clarity of the cornea.…”

Section: Conclusion the Col8a2mentioning

confidence: 99%

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

Meng

Matthaei

Ramanan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We compared the cellular phenotypes and studied the role of autophagy in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD) using two a2 collagen VIII (Col8a2) knock-in mouse models and human FECD tissues. METHODS.In vivo corneal endothelial cell (CEC) counts and morphology were analyzed by clinical confocal microscopy. Ultrastructural analysis of CECs was performed by transmission electron microscopy. Real-time PCR and Western blotting were performed using total RNA, and protein extracted from mouse CECs and human CECs obtained from FECD and autopsy patients.RESULTS. Both Col8a2 mouse models exhibited hallmarks of FECD; however, the Col8a2 L450W/L450W mice exhibited a milder phenotype compared to the Col8a2 Q455K/Q455K mice. Both models exhibited upregulation of the unfolded protein response (UPR) as evidenced by dilated rough endoplasmic reticulum (RER), and upregulation of UPR-associated genes and proteins. Real-time PCR of Col8a2 L450W/L450W and Col8a2 Q455K/Q455K CECs at 40 weeks revealed a 2.1-fold (P < 0.05) and a 5.2-fold (P < 0.01) upregulation of the autophagy marker Dram1, respectively. Real-time PCR of human FECD endothelium revealed a 10.4-fold upregulation of DRAM1 (P < 0.0001) compared to autopsy controls. CONCLUSIONS. The Col8a2L450W/L450W and Col8a2

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Section: Conclusion the Col8a2mentioning

confidence: 99%

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

Meng

Matthaei

Ramanan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Collagen VIII is a short-chain, nonfibrillar, extracellular matrix component with a composition that varies between tissues 29,30 and there is evidence that it may serve a structural role 31 or be involved in cellular differentiation. 30 In FCD, it appears to accumulate at higher levels within Descemet's membrane in the posterior collagenous zone, 31,32 which appears to contribute structurally to the guttae. The ␣1 and ␣2 chains of collagen VIII assemble in vivo as trimers by their collagen helix domains, and form a hexagonal lattice.…”

Section: Disease Mechanismsmentioning

confidence: 99%

Inheritance of a NovelCOL8A2Mutation Defines a Distinct Early-Onset Subtype of Fuchs Corneal Dystrophy

Gottsch

Sundin

Liu³

et al. 2005

Invest. Ophthalmol. Vis. Sci.

191

179

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PURPOSE.To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS.DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS.Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS.A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD. (Invest Ophthalmol Vis Sci. 2005;46:1934 -1939) DOI: 10.1167/iovs.04-0937 F uchs corneal dystrophy (FCD) is a primary disorder of the endothelium that leads to progressive edema of the corneal stroma (OMIM 136800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). Visual disability from this disease is currently the major reason for corneal transplantation.1 The initial stages of FCD typically begin in the fifth through seventh decades of life and are characterized by localized thickening of Descemet's membrane and the development of nodular excrescences called guttae. This early phase is followed by long-term decreases in the density and ion transport functions of the overlying corneal endothelial cells, which allows excess water to accumulate in the cornea.2-8 Several reports, including the original description by Fuchs, have indicated that two to three times as many females as males are affected by the disease. 2,7,9 As many as 50% of clinical cases of FCD may show familial clustering, 9 and the disease generally follows an autosomal dominant pattern of inheritance. 10 -15 Nearly all these families show inheritance of late-onset FCD, whereas rare cases 12,14 show disease onset as early as the first decade, with extensive corneal edema by the third ...

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“…15 This type of collagen forms 3D networks 16,17 and is proposed to participate in angiogenesis. 18 Studies on the proliferation and migration of SMCs in the rat balloon injury model provide evidence that type VIII collagen plays a role in promoting migration but not proliferation of SMCs.…”

mentioning

confidence: 99%

Expression of Type VIII Collagen After Cholesterol Diet and Injury in the Rabbit Model of Atherosclerosis

Plenz

Dorszewski

Breithardt

et al. 1999

ATVB

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Abstract-This study presents an analysis of the expression of type VIII collagen mRNA in response to cholesterol diet and balloon injury in the rabbit iliac artery. The design of the animal experiments was as follows: 28 male New Zealand White rabbits were divided into the 3 different treatment groups. Group 1 received regular chow; group 2 was fed with a 1% cholesterol diet for 6 weeks and normal chow for 5 weeks; and group 3 underwent balloon injury, then 6 weeks of a 1% cholesterol diet, which was followed by 5 weeks of normal chow. The expression pattern of type VIII collagen mRNA was compared with that of the fibrillar collagen types I and III, transforming growth factor-␤1, a factor known to exert the most potent stimulatory effect on collagen synthesis in vitro, and matrix metalloproteinase 1, a collagen-degrading enzyme. The cholesterol diet resulted in an upregulation of type VIII collagen, fibrillar collagens, transforming growth factor-␤1, and matrix metalloproteinase I in the adventitia. Although the number of type VIII collagen mRNA-expressing cells in the media increased, no significant difference in overall expression levels was detectable by northern blot analysis. The ratio of medial smooth muscle cells expressing type VIII collagen mRNA to those expressing type I and type III collagen mRNA (CVIII:CI:CIII) changed from 1:1.88:0.03 in the normal media to 1:0.78:0.29. When cholesterol feeding was preceded by balloon injury, type VIII collagen mRNA expression concomitant with the fibrillar collagens was further upregulated over and above that level reported after cholesterol diet alone. In general, low levels of transforming growth factor-␤1 mRNA correlated with high expression of matrix metalloproteinase I. Our study indicates that a cholesterol diet resulted in a balanced reorganization of the collagen composition but did not result in marked collagen accumulation. This may provide an extracellular environment that favors migration and proliferation processes during early atherogenesis. It also demonstrates that type VIII collagen is highly expressed and deposited at later stages, and this may be linked to processes such as tissue reorganization during vascular repair and plaque stabilization. Key Words: rabbit Ⅲ balloon injury Ⅲ extracellular matrix remodeling Ⅲ collagen Ⅲ collagenase Ⅲ transforming growth factor-␤ Ⅲ stenosis A therosclerosis involves pathological changes in the normal structure and function of the arterial wall that depend critically on interactions between vessel wall cells and their extracellular environment. The principal vascular cell type responsible for extracellular matrix (ECM) metabolism is the smooth muscle cell (SMC). 1,2 Medial SMCs, expressing the contractile phenotype, are embedded in an ECM composed of basement membrane molecules, elastin, and collagens. 3 These cells show low proliferative activity and do not migrate. During early atherogenesis, SMCs differentiate from the contractile to the synthetic phenotype. This transition is accompanied by the onset of SMC...

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The composition of wide-spaced collagen in normal and diseased Descemet's membrane

Cited by 91 publications

References 29 publications

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

Inheritance of a NovelCOL8A2Mutation Defines a Distinct Early-Onset Subtype of Fuchs Corneal Dystrophy

Expression of Type VIII Collagen After Cholesterol Diet and Injury in the Rabbit Model of Atherosclerosis

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