Purpose: Matrix metalloproteinase (MMP)-mediated turnover of extracellular matrix (ECM) affects outflow resistance in the uveoscleral pathway. The balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs) governs the rate of ECM turnover in many tissues. The hypothesis was that a differential effect on MMPs and TIMPs in ciliary body smooth muscle (CBSM) cells would relate to the relative intraocular pressure-lowering effectiveness of the prostaglandin analogues (PGAs) bimatoprost, latanoprost, and unoprostone.
Methods: Human CBSM cells isolated from donor corneoscleral rims were incubated for 24 hours with control (0.015% ethanol in DMEM) or the free acid forms of bimatoprost (0.01 or 0.1 microg/mL), latanoprost (0.03 or 0.3 microg/mL), or unoprostone (0.145 or 1.45 microg/mL). Western blot analysis determined the relative protein concentrations of MMP-1, -2, -3. -9, and -24 as well as TIMP-1 through -4. Zymography measured the relative activity levels of MMP-1, -2, -3, and -9.
Results: All PGAs increased MMP-1, -3, and -9. Bimatoprost and latanoprost did not change MMP-2. Unoprostone decreased MMP-2 (21% +/- 3%). On zymography, MMP-1 and -2 did not change. Bimatoprost and latanoprost increased MMP-9 activity by 75% +/- 27% and 75% +/- 24%, respectively. MMP-3 activity was not detected on zymography. All PGAs increased TIMP-3, but only unoprostone increased TIMPs1 and -4 by 100% +/- 20% and 61% +/- 11%, respectively. TIMP-2 was unchanged by bimatoprost and latanoprost, but decreased by unoprostone (35% +/- 8%).
Conclusions: Decreased MMP-2 with concurrent increases of TIMP-1 and -4 by unoprostone may explain the lower clinical efficacy of unoprostone. The MMP/TIMP balance relates to the observed intraocular pressure-lowering effectiveness in clinical studies with PGAs.