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T Anthony, JD Lindsey, RN Weinreb; Latanoprost Effects on TIMP-1 and TIMP-2 in Human Ciliary Muscle Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4082.
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Purpose: To determine the effect of latanoprost treatment on the tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-2 in cultured human ciliary muscle (HCM) cells. Methods: Confluent serum-starved HCM cells were exposed to increasing concentrations of latanoprost acid (LA, 1 nM - 10 µM) for 6, 18 and 24 hrs. TIMP-1 and TIMP-2 mRNA transcripts were evaluated using RT-PCR. Gelatin zymography was used to measure changes in the amount of matrix metalloproteinases (MMPs) in the culture medium. Data was quantified using densitometry and statistically analyzed using the Student's Newman-Keuls test. Results: TIMP-1 and TIMP-2 mRNA transcripts were detected in untreated HCM cells. There was no significant effect on TIMP-1 mRNA levels after 6 hrs of LA treatment. However, TIMP-1 mRNA levels were increased by 45±17% and 54±13% in cultures exposed for 18 hours to 1 µM and 10 µM LA, respectively (n = 3). After 24 hrs exposure to LA, TIMP-1 mRNA levels were dose-dependently increased at each test concentration (1 nM - 10 µM). These increases ranged from 21±7% to 37±15%. In contrast, 6 hr LA exposure increased TIMP-2 mRNA expression by up to 11.3 0.2% (n = 3). However, no significant induction of TIMP-2 mRNA was observed at either 18 or 24 hrs (n = 3). Zymographic analysis of the media from these cultures confirmed dose-dependent increases of MMP-1 at 6, 18 and 24 hours, whereas dose-dependent increases in MMP-2 were seen only after 24 hrs exposure to LA (n = 3). Conclusion: Because LA increased both TIMP-1 and TIMP-2 mRNA in HCM cells, each may contribute to the regulation of increased MMP within the uveoscleral outflow pathway following exposure to latanoprost. Further study will be needed to see whether the 5-fold smaller maximal increase of TIMP-2 mRNA than TIMP-1 mRNA means a lesser role for TIMP-2 than for TIMP-1. Supported in part by NEI EY05990 (RNW), the Drown Foundation (JDL), NRSA EY07047 (TLA) and by the Hewitt Foundation for Medical Research. None.
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