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G. Pino, D.J. Dwivedi, Z. Nathu, J.A. West–Mays; Matrix Metalloproteinase 2 and 2/9 Specific Inhibitors Suppress TGF–ß–induced Anterior Subcapsular Cataracts in Rats . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4699.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:We have shown that Matrix Metalloproteinase (MMP) activity is involved in anterior subcapsular cataract (ASC) formation in that co–treatment with the broad MMP inhibitor,GM6001, suppresses TGF–ß–induced cataractous changes including epithelial to mesenchymal transition (EMT) of the lens epithelium (ARVO 2004; 1039). In the current study, we further determine whether additional MMP specific inhibitors (MMPIs) can suppress ASC. Methods:Excised rat lenses were either left untreated or treated with TGF–ß (2ng/ml), or TGF–ß and one of the following inhibitors: GM6001 (25µM), MMP–2 specific inhibitor (OA–Hy cis–9–Octadecenoyl–N–hydroxylamide Oleoyl–N–hydroxylamide) or MMP–2/–9 specific inhibitor ((2R)–[(4–Biphenylylsulfonyl)amino]–N–hydroxyl–3–phenylpropionamide). Cataracts were observed microscopically and MMP–2 and MMP–9 activity and expression were measured using gelatin zymography and Western Blot analysis. Results:Following 6 days of treatment with TGF–ß distinct anterior subcapsular plaques had formed in the rat lens. In comparison, lenses co–treated with TGF–ß and the MMP–2 or the MMP–2/–9 specific inhibitors (10µM) for 6 days did not exhibit visible subcaspular plaques. These findings were similar to that observed for the broad inhibitor GM6001. The presence of plaques in TGF–ß treated lenses correlated with increased levels of both MMP–2 and –9 proteins. In comparison, lenses co–cultured with GM6001 and TGF–ß for 6 days exhibited a reduction (similar to control levels) of MMP–9 and MMP–2 protein levels compared to those treated with TGF–ß alone. Lenses co–treated with TGF–ß and the specific MMPIs also resulted in attenuation of MMP–9 protein levels to less than that of TGF–ß treated lenses. However, treatment with the MMPIs resulted in little to no attenuation of MMP–2. Conclusions: Our current data further support a role for MMP–2 and –9 as mediators of ASC since their abrogation, via specific MMPIs, results in suppression of supcapsular plaque formation. Further studies will examine the effects of these MMPIs on TGFß–induced signaling events.
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