PROSTAGLANDINS INCREASE PROMMP-1 AND PROMMP-3 SECRETION BY HUMAN CILIARY SMOOTH-MUSCLE CELLS

Purpose. The mechanism by which prostaglandin(PG)F-2 alpha increases u veoscleral outflow and lowers intraocular pressure in primates is not known. In cultured human ciliary muscle cells, PGF(2 alpha) induces th e expression of the protooncogene c-fos which is known to induce the t ranscription of genes such as matrix metalloproteinase-1 (MMP-1) and M MP-3 in other cell systems. As these enzymes are initially secreted as proenzymes, the present study was undertaken to determine if PG treat ment induces ciliary muscle cells to secrete either proMMP-1 or proMMP -3. Methods. Human ciliary smooth muscle cells were grown to confluenc e in monolayer eel cultures and then treated with PGF(2 alpha), 17-phe nyltrinor-PGF(2 alpha), or 11-deoxy-PGE(1). Medium harvested at variou s times after treatment was assayed for proMMP-1 and proMMP-3 content using sandwich ELISAs. Results. Three days after adding 10 nM PGF(2 al pha), proMMP-1 and pro-MMP-3, concentrations in the culture medium wer e increased by 254 +/- 33% (mean +/- SE) and 128 +/- 13%, respectively . Compared with vehicle controls, 24 h treatment with 200 nM PGF(2 alp ha), 17-phenyltrinor-PGF(2 alpha), or PGE(1), increased proMMP-1 by 11 6 +/- 29%, 169 +/- 26%, and 273 +/- 16%, respectively. In parallel exp eriments, proMMP-3 was increased by 99 +/- 18%, 82 +/- 24%, and 214 +/ - 16%, respectively. Conclusions. These results suggest that induction of MMPs in situ following topical PG treatment may degrade ciliary mu scle extracellular matrix and possibly contribute to increased uveoscl eral outflow, as well.