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Editors Selection IGR 10-4

Medical treatment: MMP

Comment by James Lindsey on:

12518 Acute effects of PGF₂α on MMP-2 secretion from human ciliary muscle cells: a PKC- and ERK-dependent process, Husain S; Jafri F; Crosson CE, Investigative Ophthalmology and Visual Science, 2005; 46: 1706-1713

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Increasing evidence suggests the role of matrix metalloproteinases (MMPs) in the intraocular pressure-lowering actions of certain prostaglandins (PGs) and their analogues is complex. For example, early studies found MMP-2, an enzyme that can cleave several major extracellular matrix components, was significantly elevated in the medium of cultured human ciliary smooth muscle cells following exposure to FP-receptor agonists. However, another study found these treatments did not increase MMP-2 gene transcription.

Addressing this apparent paradox, Husain et al. (422) have obtained new evidence that clarify this response. Specifically, they show that this MMP-2 release by ciliary muscle cells is dependent upon activation of the signal transduction mediators protein kinase C and ERK1/2. This response was unaffected by inhibition of transcription, but was inhibited by coincubation with an FP-receptor antagonist. Moreover, proMMP-2 release into the medium peaked within 4 hours and was accompanied by proMMP-2 conversion to active MMP-2. The experiments were well designed and the results were generally convincing. Because the FP-receptor antagonist AL-8810 also can act as a weak FP agonist (Griffin BW et al. J Pharmacol Exp Ther 1999; 290: 1278-1284), dose-response analysis of the effects of this FP-receptor antagonist would have been helpful. Also, additional studies using agonists with greater specificity for the FP receptor than PGF2 would have strengthened the results.

Together, the observations indicate that cellular signaling events triggered by FP receptor activation lead to release of existing MMP-2 from cellular stores into the medium within several hours. This raises the possibility that PG-mediated MMP-2 release in vivo could occur soon enough to coincide with the initial phase of IOP reduction that occurs following topical treatment with pressure-lowering FP-receptor agonists. MMP-2 cleavage of fibrillar collagens incorporated into extracellular matrix often is minimal without prior cleavage events mediated by other MMPs. Hence, further work is needed to determine whether increased MMP-2 release directly contributes to the IOP-lowering effect induced by FP agonists.

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