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Prostaglandin FP agonists alter metalloproteinase gene expression in sclera
Robert N Weinreb1, James D Lindsey, George Marchenko
1Hamilton Glaucoma Center and Department of Ophthalmology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 9209-0946, USA. weinreb@eyecenter.ucsd.edu
Purpose:
The present study was undertaken to determine whether exposure of the sclera to prostaglandin (PG)F(2alpha) or to the PGF(2alpha) analogue latanoprost acid alters mRNA for matrix metalloproteinases.
Method:
Fifteen human eye bank eyes were studied. Circular pieces of sclera were either immediately preserved in a stabilization reagent or cultured in low-serum DMEM/F-12 medium. The cultures were treated for 24 hours with medium supplemented with PGF(2a), latanoprost acid, or vehicle. Total RNA was then isolated, and the expression of mRNA for matrix metalloproteinase (MMP)-1, -2, -3, -8, -9, -10, and -12 were determined by real-time PCR. All results were normalized according to the GAPDH mRNA in each sample. Altered mRNA expression after PG treatments also was evaluated with microarrays containing 19 MMP genes and 4 tissue inhibitor of matrix metalloproteinase (TIMP) genes.
Results:
Real-time PCR results showed that 24 hours of exposure to 100 nM PGF(2alpha) significantly increased mRNA for MMP-1 and -9 (P < 0.06 Wilcoxon test) and that exposure to 100 nM latanoprost acid significantly increased mRNA for MMP-9 (P < 0.06 Wilcoxon test). Array analysis demonstrated increases of MMP-3 and -10 mRNA after exposure to 100 nM latanoprost and further increases after exposure to 200 nM latanoprost. The array results also showed that latanoprost induced dose-dependent increases in the expression of TIMP-1, -2, and -3 mRNA in the scleral cultures.
Conclusions:
PGF(2alpha) and latanoprost acid induce coordinated alterations of MMP gene transcription in scleral organ cultures. These results indicate that PGs can directly trigger MMP gene transcription changes within the sclera. These changes support a role for increased MMPs in the enhancement of uveoscleral outflow that occurs after topical treatment with latanoprost.
Insights
Prostaglandin (PG)F(2alpha) and latanoprost acid increase matrix metalloproteinase (MMP) gene transcription in scleral organ cultures. This suggests PGs directly influence MMP gene expression in the sclera, potentially enhancing uveoscleral outflow.
Area of Science:
- Ocular biology
- Molecular biology
- Biochemistry
Background:
- Prostaglandins (PGs) play a role in ocular physiology.
- Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix remodeling.
- Latanoprost is a prostaglandin analogue used to treat glaucoma.
Purpose of the Study:
- To investigate the effect of prostaglandin F(2alpha) (PGF(2alpha)) and latanoprost acid on matrix metalloproteinase (MMP) mRNA expression in human sclera.
- To determine if PGs directly alter MMP gene transcription in scleral tissue.
Main Methods:
- Human eye bank eyes were used to obtain scleral tissue.
- Scleral explants were cultured and treated with PGF(2alpha) or latanoprost acid.
- Real-time PCR and microarray analysis were employed to quantify mRNA levels of various MMPs and tissue inhibitors of metalloproteinases (TIMPs).
Main Results:
- Exposure to PGF(2alpha) and latanoprost acid significantly increased mRNA for MMP-1 and MMP-9.
- Latanoprost induced dose-dependent increases in MMP-3 and MMP-10 mRNA.
- Latanoprost also increased the expression of TIMP-1, TIMP-2, and TIMP-3 mRNA in a dose-dependent manner.
Conclusions:
- Prostaglandin F(2alpha) and latanoprost acid can directly induce changes in MMP gene transcription within the sclera.
- These findings support a role for increased MMPs in the PGF(2alpha)-mediated enhancement of uveoscleral outflow.
