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목적 : Previously, we reported statins can modulate transforming growth factor-beta 2 (TGF-β2)-induced expression of extracellular matrix (ECM)-related proteins in human astrocytes of the lamina cribrosa (LC) in the optic nerve head (ONH). Here we investigated modulation of matrix metalloproteinases (MMPs), which is involved in ECM maintenance and remodeling by TGF-β2 and statins in ONH astrocytes.
방법 : Primary astrocytes, cultured from the LCs of human donor ONHs, were treated with recombinant TGF-β2 at 5 ng/mL. To test the effects of statin, cells were pretreated with three types of statin at 5 μg/mL for 1 h followed by TGF-β2. Astrocyte culture media were subjected to western blotting for MMP-2/-9 levels and to zymography for MMP-2/-9 activities. As a downstream modulator of TGF-β2, phosphorylation levels of myosin light chain (MLC) was determined by western blotting and immunocytochemistry.
결과 : In human ONH astrocytes, MMP-2 and MMP-9 levels were up-regulated by TGF-β2. Pretreatment with statins (i.e., simvastatin, lovastatin, and atorvastatin) effectively inhibited TGF-β2-mediated expression of MMP-2 and MMP-9. In addition to expression, statins inhibited TGF-β2-mediated MMP-2 and MMP-9 activities as well. Levels of tissue inhibitors of metalloproteinase two (TIMP2) were correlated with MMP-2 and MMP-9 activity. Finally, TGF-β2 induced phosphorylation of MLC, which is RhoA/ROCK dependent, and this phosphorylation was down-regulated by pretreatment with statins.
결론 : We found that statins inhibited TGF-β2-mediated regulation of MMPs, likely through inhibition of a RhoA/ROCK signaling pathway. Considering the role of MMPs in ECM remodeling, this study supports the beneficial effect of statins on ECM remodeling that takes place in the LC of ONHs.
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