on February 13, 2003
Published online before print February 13, 2003, doi: 10.1161/01.ATV.0000060891.31516.24
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Submitted on December 3, 2002
Accepted on January 30, 2003
Oncostatin M, an Interleukin-6 Family Cytokine, Upregulates Matrix Metalloproteinase-9 Through the Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase Pathway in Cultured Smooth Muscle Cells
Tsuyoshi Nagata ;
From the Cardiovascular Research Institute and Internal Medicine III (T.N., H.K., R.S., M.K. T.I), Kurume University School of Medicine, Kurume; and Department of Immunology (A.Y.), Research Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
* To whom correspondence should be addressed. E-mail: naikai{at}med.kurume-u.ac.jp.
Objectives--Matrix metalloproteinase (MMP)-9 is implicated in extracellular matrix (ECM) degradation of atherosclerotic lesions. Oncostatin M (OSM) regulates ECM metabolism in various kinds of cells. Thus, we sought to investigate whether OSM regulates MMP-9 expression in cultured rat aortic smooth muscle cells (SMCs) and, if so, to determine the signaling pathway for MMP-9 induction by OSM.
Methods and Results--Competitive reverse transcriptase polymerase chain reaction showed that OSM upregulated MMP-9 mRNA expression, peaking at 4 hours and returning to unstimulated levels by 24 hours. Gelatin zymography revealed that MMP-9 activity was increased in the conditioned medium after the 24-hour OSM treatment. Immunoblot analysis demonstrated that OSM transiently induced extracellular signal-regulated kinase (ERK)1/2 and STAT3 phosphorylations with a peak at 15 and 5 minutes, respectively. A MEK1 inhibitor, PD98059, not only blocked ERK1/2 phosphorylation but also abolished the OSM-induced MMP-9 upregulation, whereas the MMP-9 induction was not affected by overexpressing dominant-negative STAT3. In addition, OSM slightly upregulated MMP-2 and downregulated tissue inhibitors of MMP-1 and -3 through different mechanisms from that in case of MMP-9.
Conclusions--OSM upregulates MMP-9 expression in SMCs through the MEK-ERK but not STAT3 pathway.
Key words: oncostatin M • matrix metalloproteinase • muscle • smooth • signal transduction
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