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W Cui, MR Bryant, PJ McDonnell; Signal Transduction Pathways For The Expression Of Genes For Mmp And Timp Induced By Stretching Human Fetal Scleral Fibroblasts . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2467.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:We previously found that integrin subunits α2, α5 and ß1 mediate signal transduction for the expression of genes for MMP-1 and MMP-2 induced by stretching human fetal scleral fibroblasts (HFSF). The purpose of this study is to determine a second signal transduction pathway for the expression of genes for MMP-1, MMP-2, TIMP-1, and TIMP-2. Methods:Prior to stretching the cells in vitro, we selectively inhibited protein kinase C (PKC), protein kinase A (PKA), extracellular signal-regulated kinase (ERK), tyrosine kinase (TK); disrupted cytoskeletal elements (microfilament, microtubule, and intermediate filaments), blocked cellular membrane L-type voltage-sensitive calcium channels (VSCC) or mechanosensive cation channel (MSCC). Gene expression was measured with RT-PCR and Southern blot. Results:Inhibiting PKC, TK, or ERK decreased stretch-induced MMP-1 gene expression. Disrupting microfilaments or blocking MSCC also decreased MMP-1 gene expression. For MMP-2, disrupting intermediate filaments, inhibiting PKC, or blocking MSCC or VSC decreased stretch-induced gene expression. Inhibiting PKC, TK, or ERK, disrupting microfilaments or blocking VSCC inhibited stretch-induced TIMP-1 gene expression. For TIMP-2, only inhibiting PKC or ERK inhibited stretch-induced gene expression. Conclusion:Our results indicate that protein kinases, ion channels and the cytoskeleton are involved in the stretch-induced mechanotransduction of MMP and TIMP gene expression. Among the signaling molecules, PKC is the most active because it affects the signal transduction for MMP-1, MMP-2, TIMP-1 and TIMP-2. PKA and microtubules are not involved in the stretch-induced signal transduction for the measured MMPs and TIMPs.
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