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(Investigative Ophthalmology and Visual Science. 2005;46:3604-3615.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-1507
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Proteinase and Growth Factor Alterations Revealed by Gene Microarray Analysis of Human Diabetic Corneas

Mehrnoosh Saghizadeh,1,2 Andrei A. Kramerov,1 Jian Tajbakhsh,2 Annette M. Aoki,1 Charles Wang,2,3 Ning-Ning Chai,3 Julia Y. Ljubimova,4 Takako Sasaki,5 Gabriel Sosne,6 Marc R. J. Carlson,2 Stanley F. Nelson,2 and Alexander V. Ljubimov1,2

1From the Ophthalmology Research Laboratories, 3Research Institute Microarray Core, and 4Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California; 2David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; 5Max-Planck-Institut für Biochemie, Martinsried, Germany; and 6Departments of Ophthalmology, and Anatomy and Cell Biology, Wayne State University, Detroit, Michigan.

PURPOSE. To identify proteinases and growth factors abnormally expressed in human corneas of donors with diabetic retinopathy (DR), additional to previously described matrix metalloproteinase (MMP)-10 and -3 and insulin-like growth factor (IGF)-I.

METHODS. RNA was isolated from 35 normal, diabetic, and DR autopsy human corneas ex vivo or after organ culture. Amplified cRNA was analyzed using 22,000-gene microarrays (Agilent Technologies, Palo Alto, CA). Gene expression in each diabetic corneal cRNA was assessed against pooled cRNA from 7 to 9 normal corneas. Select differentially expressed genes were validated by quantitative real-time RT-PCR (QPCR) and immunohistochemistry. Organ cultures were treated with a cathepsin inhibitor, cystatin C, or MMP-10.

RESULTS. More than 100 genes were upregulated and 2200 were downregulated in DR corneas. Expression of cathepsin F and hepatocyte growth factor (HGF) genes was increased in ex vivo and organ-cultured DR corneas compared with normal corneas. HGF receptor c-met, fibroblast growth factor (FGF)-3, its receptor FGFR3, tissue inhibitor of metalloproteinase (TIMP)-4, laminin {alpha}4 chain, and thymosin ß4 genes were downregulated. The data were corroborated by QPCR and immunohistochemistry analyses; main changes of these components occurred in corneal epithelium. In organ-cultured DR corneas, cystatin C increased laminin-10 and integrin {alpha}3ß1, whereas in normal corneas MMP-10 decreased laminin-10 and integrin {alpha}3ß1 expression.

CONCLUSIONS. Elevated cathepsin F and the ability of its inhibitor to produce a more normal phenotype in diabetic corneas suggest increased proteolysis in these corneas. Proteinase changes may result from abnormalities of growth factors, such as HGF and FGF-3, in DR corneas. Specific modulation of proteinases and growth factors could reduce diabetic corneal epitheliopathy.




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