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(American Journal of Pathology. 2001;158:723-734.)
© 2001 American Society for Investigative Pathology

Regular Article

Overexpression of Matrix Metalloproteinase-10 and Matrix Metalloproteinase-3 in Human Diabetic Corneas

A Possible Mechanism of Basement Membrane and Integrin Alterations

Mehrnoosh Saghizadeh*, Donald J. Brown*, Raquel Castellon*, Marilyn Chwa*, Gang H. Huang*, Julia Y. Ljubimova{dagger}, Shari Rosenberg*, Konstantin S. Spirin*, Raisa B. Stolitenko*, Wakako Adachi{ddagger}, Shigeru Kinoshita{ddagger}, Gillian Murphy§, L. Jack Windsor{ddagger}, M. Cristina Kenney* and Alexander V. Ljubimov*

From the Ophthalmology Research Laboratories*
and Neurosurgical Institute,{dagger}
Burns and Allen Research Institute, Cedars-Sinai Medical Center, University of California Los Angeles Medical School Affiliate, Los Angeles, California; the Department of Ophthalmology,{ddagger}
Kyoto Prefecture University of Medicine, Kyoto, Japan; the School of Biological Sciences,§
University of East Anglia, Norwich, England; and the School of Dentistry,{ddagger}
Indiana University, Indianapolis, Indiana

We have previously described decreased immunostaining of nidogen-1/entactin; laminin chains {alpha}1, {alpha}5, {beta}1,{gamma}1; and epithelial integrin {alpha}3{beta}1 in human diabetic retinopathy (DR) corneas. Here, using 142 human corneas, we tested whether these alterations might be caused by decreased gene expression levels or increased degradation. By semiquantitative reverse transcription-polymerase chain reaction, gene expression levels of the {alpha}1, {alpha}5, and {beta}1 laminin chains; nidogen-1/entactin; integrin {alpha}3 and {beta}1 chains in diabetic and DR corneal epithelium were similar to normal. Thus, the observed basement membrane and integrin changes were unlikely to occur because of a decreased synthesis. mRNA levels of matrix metalloproteinase-10 (MMP-10/stromelysin-2) were significantly elevated in DR corneal epithelium and stroma, and of MMP-3/stromelysin-1, in DR corneal stroma. No such elevation was seen in keratoconus corneas. These data were confirmed by immunostaining, zymography, and Western blotting. mRNA levels of five other proteinases and of three tissue inhibitors of MMPs were similar to normal in diabetic and DR corneal epithelium and stroma. The data suggest that alterations of laminins, nidogen-1/entactin, and epithelial integrin in DR corneas may occur because of an increased proteolytic degradation. MMP-10 overexpressed in the diabetic corneal epithelium seems to be the major contributor to the observed changes in DR corneas. Such alterations may bring about epithelial adhesive abnormalities clinically seen in diabetic corneas.




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