Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells.
OBJECTIVE
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.
Ooi
Yen Hoong
YH
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.
Oh
Dong-Jin
DJ
Rhee
Douglas J
DJ
D000577:Amides / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000069580:Bimatoprost; D015153:Blotting, Western; D002478:Cells, Cultured; D002924:Ciliary Body / Q000187:drug effects* / Q000378:metabolism; D003008:Cloprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D000077338:Latanoprost; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D000577:Amides; D000959:Antihypertensive Agents; D011461:Prostaglandins F, Synthetic; D019714:Tissue Inhibitor of Metalloproteinases; D003008:Cloprostenol; C072630:isopropyl unoprostone; D000077338:Latanoprost; D015237:Dinoprost; D020782:Matrix Metalloproteinases; D000069580:Bimatoprost