期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 42, 期 9, 页码 1350-1358出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.01.035
关键词
reactive oxygen species; integrins; matrix metalloproteinase; antioxidants; signal transduction; mitogen-activated protein kinase; nuclear factor-kappa B
资金
- NIAMS NIH HHS [AR49003, R37 AR049003, R01 AR049003, R01 AR049003-05] Funding Source: Medline
The objective of the present study was to determine if reactive oxygen species (ROS) are required as secondary messengers for fibronectin fragment-stimulated matrix metalloproteinase (MMP) production in human articular chondrocytes. Cultured cells were stimulated with 25 mu g/ml of the alpha 5 beta 1 integrin-binding 110-kDa fibronectin fragment (FN-f) in the presence and absence of various antioxidants including Mn(III) tetrakis (4-benzoic acid)porphyrin (MnTBAP). FN-f stimulation significantly increased intracellular levels of ROS in articular chondrocytes. Pretreatment of cells with 250 mu M MnTBAP or 40 mM N-acetyl-L-cysteine, but not inhibitors of nitric oxide synthase, completely prevented FN-f-stimulated MMP-3, -10, and -13 production. MnTBAP also blocked FN-f-induced phosphorylation of the MAP kinases and NF-kappa B-associated proteins and blocked activation of an NF-kappa B promoter-reporter construct. Overexpression of catalase, superoxide dismutase, or glutathione peroxidase also inhibited FN-f-stimulated MMP-13 production. Preincubation of chondrocytes with rotenone, an inhibitor of the mitochondrial electron transport chain, or nordihydroguaiaretic acid (NDGA), a selective 5-lipoxygenase inhibitor, partially prevented FN-f-stimulated MMP-13 production and decreased MAP kinase and NF-kappa B phosphorylation. These results show that increased production of ROS but not nitric oxide as obligatory secondary messengers in the chondrocyte FN-f signaling pathway leads to the increased production of MMPs, including MMP-13. (c) 2007 Elsevier Inc. All rights reserved.
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