Induction of tissue inhibitor of matrix metalloproteinase-2 by cholesterol depletion leads to the conversion of proMMP-2 into active MMP-2 in human dermal fibroblasts |
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Authors: | Sangmin Kim Jang-Hee Oh Youngae Lee Jeongyoon Lee Kwang Hyun Cho and Jin Ho Chung |
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Institution: | 1Department of Dermatology, Seoul National University College of Medicine, Laboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National University Hospital, Institute of Dermatological Science, Seoul National University, Seoul 110-744, Korea.;2Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. |
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Abstract: | Cholesterol is one of major components of cell membrane and plays a role in vesicular trafficking and cellular signaling. We investigated the effects of cholesterol on matrix metalloproteinase-2 (MMP-2) activation in human dermal fibroblasts. We found that tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) expression and active form MMP-2 (64 kD) were dose-dependently increased by methyl-β-cyclodextrin (MβCD), a cholesterol depletion agent. In contrast, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation were suppressed by cholesterol repletion. Then we investigated the regulatory mechanism of TIMP-2 expression by cholesterol depletion. We found that the phosphorylation of JNK as well as ERK was significantly increased by cholesterol depletion. Moreover, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation was significantly decreased by MEK inhibitor U0126, and JNK inhibitor SP600125, respectively. While a low dose of recombinant TIMP-2 (100 ng/ml) increased the level of active MMP-2 (64 kD), the high dose of TIMP-2 (≥ 200 ng/ml) decreased the level of active MMP-2 (64 kD). Taken together, we suggest that the induction of TIMP-2 by cholesterol depletion leads to the conversion of proMMP-2 (72 kD) into active MMP-2 (64 kD) in human dermal fibroblasts. |
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Keywords: | cholesterol extracellular signal-regulated MAP kinases JNK mitogen-activated protein kinases matrix metalloproteinase 2 tissue inhibitor of metalloproteinase-2 |
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