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M. Aga, M.J. Kelley, T.S. Acott; Role of Mitogen Activated Protein Kinases (MAPK) in Mediating Increased Expression of Matrix Metalloproteinase–2 (MMP–2)Following Mechanical Stretching of Trabecular Meshwork Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1355.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Trabecular meshwork (TM) cells appear to sense increased intraocular pressure (IOP) as mechanical stretching and may partially maintain IOP homeostasis by initiating extracellular matrix turnover. Stress and chemical mediators have been implicated in the activation of the three MAPK signal transduction pathway: extracellular signal–regulated kinases 1/2(ERK1/ERK2); c–jun–N terminal kinases 1/2 (JNK1/JNK2); and p38 in other systems. Earlier studies in our lab identified other signaling pathways involved in the regulation of MMP–2 levels, however, the role of MAPKs in this process is not known. Consequently, we assessed the role of MAPK pathways in porcine TM cells in response to mechanical stretch. Methods: Porcine TM cells were subjected to mechanical stretch for 0–4 hrs or 24 hrs. TM cells were pretreated with either the inhibitors of the MEK/ERK pathway (U0126 and PD98059) or the p38 inhibitor (SB202190) 30 min prior to initiating stretch. Cellular extracts were analyzed by Western immunoblot using various phospho–specific antibodies. MMP–2 levels in the media were determined by gelatin zymography. Results: Mechanically stretching TM cells activated all three MAPKs within 5 min of treatment. Phosphorylation of ERK1/ERK2 peaked at 5 minutes, then decreased over time and was barely detectable at 2 or 4 hrs. JNK1/JNK2 phosphorylation was maximal by 15 minutes and was undetectable after 60 min. Phosphorylation of p38, which was weaker than that of either ERK or JNK, was maximal by 5 or 10 min and diminished by 60 minutes. Stretching TM cells for 24 hrs increased MMP–2 expression. Interestingly, pretreatment with the MEK inhibitors further potentiated MMP–2 expression. The p38 inhibitor, SB202190, however, had no effect on MMP–2 levels. Conclusions: Mechanical stretching of TM cells triggered activation of all three MAPKs within a few minutes of treatment. Stretching TM cells for 24 h leads to the enhanced expression of MMP–2, which is further augmented in the presence of MEK inhibitors. This suggests cross talk or an inverse regulation of MMP–2 expression by the MEK/ERK pathway.
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