Prostaglandins increase proMMP-1 and proMMP-3 secretion by human ciliary smooth muscle cells.
OBJECTIVE
The mechanism by which prostaglandin(PG)F2 alpha increases uveoscleral outflow and lowers intraocular pressure in primates is not known. In cultured human ciliary muscle cells, PGF2 alpha induces the expression of the protooncogene c-fos which is known to induce the transcription of genes such as matrix metalloproteinase-1 (MMP-1) and MMP-3 in other cell systems. As these enzymes are initially secreted as proenzymes, the present study was undertaken to determine if PG treatment induces ciliary muscle cells to secrete either proMMP-1 or proMMP-3.


METHODS
Human ciliary smooth muscle cells were grown to confluence in monolayer cell cultures and then treated with PGF2 alpha, 17-phenyltrinor-PGF2 alpha, or 11-deoxy-PGE1. Medium harvested at various times after treatment was assayed for proMMP-1 and proMMP-3 content using sandwich ELISAs.


RESULTS
Three days after adding 10 nM PGF2 alpha, proMMP-1 and proMMP-3, concentrations in the culture medium were increased by 254 +/- 33% (mean +/- SE) and 128 +/- 13%, respectively. Compared with vehicle controls, 24 h treatment with 200 nM PGF2 alpha, 17-phenyltrinor-PGF2 alpha, or PGE1, increased proMMP-1 by 116 +/- 29%, 169 +/- 26%, and 273 +/- 16%, respectively. In parallel experiments, 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 muscle extracellular matrix and possibly contribute to increased uveoscleral outflow, as well.
Lindsey
J D
JD
Department of Ophthalmology, University of California San Diego, La Jolla 92093, USA.
Kashiwagi
K
K
Boyle
D
D
Kashiwagi
F
F
Firestein
G S
GS
Weinreb
R N
RN
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D015237:Dinoprost / Q000494:pharmacology*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D020781:Matrix Metalloproteinase 1; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology
C092396:17-phenyltrinorprostaglandin E2; D004792:Enzyme Precursors; D011459:Prostaglandins E, Synthetic; D015237:Dinoprost; D017364:Collagenases; D008666:Metalloendopeptidases; C048047:prostromelysin; D020781:Matrix Metalloproteinase 1; D000527:Alprostadil; D015232:Dinoprostone; C034008:11-deoxyprostaglandin E1