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.
10.3858/emm.2010.42.1.004
- Author:
Sangmin KIM
1
;
Jang Hee OH
;
Youngae LEE
;
Jeongyoon LEE
;
Kwang Hyun CHO
;
Jin Ho CHUNG
Author Information
1. Department 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 110-74
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
cholesterol;
extracellular signal-regulated MAP kinases;
JNK mitogen-activated protein kinases;
matrix metalloproteinase 2;
tissue inhibitor of metalloproteinase-2
- MeSH:
Anthracenes/pharmacology;
Butadienes/pharmacology;
Cells, Cultured;
Child;
Child, Preschool;
Cholesterol/metabolism/*physiology;
Cyclodextrins/pharmacology;
Enzyme Inhibitors/pharmacology;
Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/physiology;
Fibroblasts/*drug effects/*metabolism/ultrastructure;
Humans;
Immunoblotting;
Immunoprecipitation;
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/physiology;
Matrix Metalloproteinase 2/*metabolism;
Microscopy, Electron, Transmission;
Nitriles/pharmacology;
Tissue Inhibitor of Metalloproteinase-2/*metabolism
- From:Experimental & Molecular Medicine
2010;42(1):38-46
- CountryRepublic of Korea
- Language:English
-
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-beta-cyclodextrin (MbetaCD), 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 (> or = 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.
