International Journal of Keratoconus and Ectatic Corneal Diseases

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VOLUME 5 , ISSUE 2 ( May-August, 2016 ) > List of Articles

RESEARCH ARTICLE

Abnormal Regulation of Extracellular Matrix and Adhesion Molecules in Corneas of Patients with Keratoconus

Yelena Bykhovskaya, Anastasia Gromova, Helen P Makarenkova, Yaron S Rabinowitz

Citation Information : Bykhovskaya Y, Gromova A, Makarenkova HP, Rabinowitz YS. Abnormal Regulation of Extracellular Matrix and Adhesion Molecules in Corneas of Patients with Keratoconus. Int J Kerat Ect Cor Dis 2016; 5 (2):63-70.

DOI: 10.5005/jp-journals-10025-1123

Published Online: 01-08-2016

Copyright Statement:  Copyright © 2016; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Aim

To identify changes in the expression of genes coding for extracellular matrix (ECM) proteins in patients with noninflammatory corneal disorder keratoconus (KC), patients with corneal scarring, and normal controls.

Materials and methods

Total ribonucleic acid extracted from corneal tissue of 13 KC patients, 2 patients with corneal scaring, and 4 normal controls was analyzed using Human Extracellular Matrix & Adhesion Molecules Profiler Polymerase Chain Reaction Array. Statistically significant changes in gene expression were identified using the Data Analysis software.

Results

Comparison of KC and control corneas with thresholds of 1.5 or greater fold change and a p-value of 0.05 or lower revealed 21 differentially expressed genes: 16 genes were downregulated and 5 were upregulated. Among transcripts downregulated in KC patients, we identified thrombospondin 1, disintegrin and metalloproteinase with thrombospondin motif 1, secreted phosphoprotein 1, several collagens, and integrins. We found transforming growth factor beta-induced (TGFBI or BIGH3) gene was the most significantly upregulated transcript.

Conclusion

The development of KC results in deregulation of gene expression of ECM and adhesion molecules.

Clinical significance

Downregulation of collagens and upregulation of TGFBI repeatedly identified in KC patients may be used as clinical markers of the disease.

How to cite this article

Bykhovskaya Y, Gromova A, Makarenkova HP, Rabinowitz YS. Abnormal Regulation of Extracellular Matrix and Adhesion Molecules in Corneas of Patients with Keratoconus. Int J Kerat Ect Cor Dis 2016;5(2):63-70.


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  1. Keratoconus. Surv Ophthalmol 1998 Jan-Feb;42(4):297-319.
  2. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet 2013 Feb;45(2):155-163.
  3. Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. Invest Ophthalmol Vis Sci 2013 Apr 12;54(4):2696-2704.
  4. Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Invest Ophthalmol Vis Sci 2012;53(7):4152-4157.
  5. Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp Eye Res 2012 Nov;104:74-81.
  6. Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus. Invest Ophthalmol Vis Sci 2015 Jan;56(1):578-586.
  7. Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus. Invest Ophthalmol Vis Sci 2014 Sep;55(9):5629-5635.
  8. Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus. Mol Vis 2009 Dec 20;15: 2848-2860.
  9. Evaluation of possible relationship between COL4A4 gene polymorphisms and risk of keratoconus. Cornea 2015 Mar;34(3):318-322.
  10. Abnormalities of the extracellular matrix in keratoconus corneas. Cornea 1997 May;16(3):345-351.
  11. Alterations of extracellular matrix components and proteinases in human corneal buttons with INTACS for post-laser in situ keratomileusis keratectasia and keratoconus. Cornea 2008 Jun;27(5):565-573.
  12. Differential epithelial and stromal protein profiles in keratoconus and normal human corneas. Exp Eye Res 2011 Apr;92(4):282-298.
  13. The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. J Proteomics 2013 Jul 11;87:122-131.
  14. Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. Invest Ophthalmol Vis Sci 2011 Aug;52(9):6181-6191.
  15. Identification of differentially expressed genes in keratoconus epithelium analyzed on microarrays. Invest Ophthalmol Vis Sci 2003 Jun;44(6):2466-2476.
  16. Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity. Mol Vis 2015 Jan;21:12-25.
  17. Evaluation of differentially expressed genes identified in keratoconus. Mol Vis 2009 Nov 28;15:2480-2487.
  18. Downregulation of betaactin gene and human antigen R in human keratoconus. Invest Ophthalmol Vis Sci 2012 Jun;53(7):4032-4041.
  19. Molecular changes in selected epithelial proteins in human keratoconus corneas compared to normal corneas. Mol Vis 2006 Dec 20;12:1615-1625.
  20. Epstein-Barr virus transformation of cryopreserved lymphocytes: prolonged experience with technique. Am J Hum Genet 1991 Aug;49(2):467.
  21. Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease. Hum Mol Genet 2008 Dec 15;17(24):3987-4000.
  22. Comparison of upstream regulators in human ex vivo cultured cornea limbal epithelial stem cells and differentiated corneal epithelial cells. BMC Genomics 2013 Dec 17;14:900.
  23. ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 2001 Jan;33(1):33-44.
  24. Expression of extracellular matrix proteins fibulin-1 and fibulin-2 by human corneal fibroblasts. Curr Eye Res 2007 Jun;32(6):481-490.
  25. Are proteinases the reason for keratoconus? Curr Eye Res 2010 Mar;35(3):185-191.
  26. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin Experiment Ophthalmol 2001 Dec;29(6):340-344.
  27. Corneal integrins and their functions. Exp Eye Res 2006 Jul;83(1):3-15.
  28. Integrin beta1 is necessary for the maintenance of corneal structural integrity. Invest Ophthalmol Vis Sci 2011;52(11):7799-7806.
  29. Co-operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival. Dev Biol 2009 Feb 15;326(2):403-417.
  30. Characterization of corneal stromal stem cells with the potential for epithelial transdifferentiation. Stem Cell Res Ther 2013 Jun 24;4(3):75.
  31. Proteome profiling of wild type and lumican-deficient mouse corneas. J Proteomics 2011 Sep 6;74(10):1895-1905.
  32. Transforming growth factor-beta signaling pathway activation in Keratoconus. Am J Ophthalmol 2011 May;151(5):752-759.e2.
  33. Gene expression profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin 5. Invest Ophthalmol Vis Sci 2005 Apr;46(4):1239-1246.
  34. Genetics of corneal endothelial dystrophies. J Genet 2009 Dec;88(4):487-494.
  35. Over expression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice. Mol Vis 2008 Jun 13;14:1129-1137.
  36. The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population. Gene 2012 Jul 15;503(1):137-139.
  37. Keratoepithelin in secondary corneal amyloidosis. Graefes Arch Clin Exp Ophthalmol 2006 Jun;244(6):725-731.
  38. Keratoconus associated with corneal stromal amyloid deposition containing TGFBIp. Cornea 2009 Jun;28(5):589-593.
  39. Colocalization of increased transforming growth factor-beta-induced protein (TGFBIp) and Clusterin in Fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2009 Mar;50(3):1129-1136.
  40. Extracellular matrix alterations in late-onset Fuchs’ corneal dystrophy. Invest Ophthalmol Vis Sci 2014 Jun;55(6):3700-3708.
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