Selenium's effects on MMP-2 and TIMP-1 secretion by human trabecular meshwork cells.
OBJECTIVE
Because of the observed increase in incidence of glaucoma among some individuals taking selenium as a dietary supplement, the present study was undertaken to investigate mechanisms of selenium-induced changes in homeostasis of human trabecular meshwork (HTM) cells. Specifically, the impact of selenium on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of metalloproteinases; TIMPs), and the second messengers that regulate MMP expression was investigated in an HTM cell culture model.


METHODS
HTM cell cultures were treated with an organic selenium compound (methyl seleninic acid), and changes in secretion and activity of MMPs and TIMPs were analyzed by Western blot and zymography. Changes in extracellular-signal-related kinases 1 and 2 (ERK1/2) and phospho-ERK1/2 levels were monitored by Western blot analysis of whole-cell lysates prepared from selenium-treated cells. Photographs of cultures over time were used to document selenium-induced changes in cell morphology.


RESULTS
Treatment of HTM cells with selenium for 24 hours at doses ranging from 1 to 10 micro M caused a dose-dependent decrease in the secretion of MMP-2 and TIMP-1. Treatment for 6 hours revealed a significant decrease in MMP-2 and TIMP-1 at the highest dose. MMP-1, -3, and -9 and TIMP-2 were either not detected or their secretion was not consistently influenced by selenium treatment. Selenium treatment caused a significant decrease in ERK1/2 phosphorylation, but no change in overall ERK protein levels. Selenium treatment resulted in dose-dependent, reversible changes in HTM cell-matrix associations.


CONCLUSIONS
Selenium-induced changes in MMP-2/TIMP-1 secretion may alter the balance of extracellular matrix turnover in the conventional outflow pathway and cause an increase in intraocular pressure that eventually leads to glaucoma.
Conley
Shannon M
SM
Department of Ophthalmology, University of Arizona, Tucson, Arizona 85711, USA. sconley@u.arizona.edu
Bruhn
Roberta L
RL
Morgan
Parham V
PV
Stamer
W Daniel
WD
D015153:Blotting, Western; D002264:Carboxylic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002264:Carboxylic Acids; D016566:Organoselenium Compounds; D019715:Tissue Inhibitor of Metalloproteinase-1; C473453:seleninic acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2