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Acute Effects of PGF₂ on MMP-2 Secretion from Human Ciliary Muscle Cells: A PKC- and ERK-Dependent Process

¹From the Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, and the ²Department of Endocrinology, Medical University of South Carolina, Charleston, South Carolina.

PURPOSE. Studies were designed to evaluate the cellular mechanisms associated with prostaglandin (PG)F₂-induced matrix metalloproteinase (MMP)-2 secretion from human ciliary muscle (HCM) cells.

METHODS. The secretion and activity of MMP-2 was determined by Western blot analysis and zymography, using conditioned medium and HCM cells. ERK1/2 activity was measured by in-gel kinase assay and Western blot analysis with anti-phospho-ERK1/2 antibodies.

RESULTS. PGF₂ increased the secretion of MMP-2 in a dose-dependent manner with an EC₅₀ of 2.7 x 10^–8 M. The addition of 1 µM PGF₂ also increased MMP-2 secretion in a time-dependent manner with maximum secretion occurring at 4 hours after administration. At 4 hours, the maximum increase in MMP-2 secretion and activity were 112% ± 32% and 88% ± 18%, respectively. The secretory action of PGF₂ was inhibited by pretreatment with a protein kinase C (PKC) inhibitor, chelerythrine chloride; the FP receptor antagonist, AL-8810; and the MEK inhibitor, PD-98059. The addition of PGF₂ and latanoprost acid increased ERK1/2 activity by 117% ± 12% and 75% ± 9%, respectively. The PGF₂- and latanoprost-acid–induced ERK1/2 activation was blocked by the presence of PKC inhibitors and downregulation of PKC by prolonged incubation with a phorbol ester.

CONCLUSIONS. These data provide evidence that FP receptor activation leads to an increase in the secretion and activation of MMP-2 through PKC- and ERK1/2-dependent pathways. FP-agonist–induced activation of ERK1/2 was blocked by PKC inhibitors, indicating that PKC activation is required for ERK1/2 activation and MMP-2 secretion from HCM cells. In the ciliary muscle, the functional responses to ERK1/2 activation include secretion of MMP-2, supporting the hypothesis that increases in uveoscleral outflow facility induced by PG administration involves the secretion and activation of MMP-2.

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