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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2011-2-23
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pubmed:abstractText |
Proinflammatory cytokines such as interleukin-1 beta (IL-1?) and tumor necrosis factor alpha (TNF-?) enhance degradation of cartilage-specific, type II collagen by matrix metalloproteinase-13 (MMP-13). We investigated the previously unknown role of H-Ras and reactive oxygen species (ROS) in the cytokine induction of MMP-13 gene expression in human articular chondrocytes by using pharmacological inhibitors, RNA interference (RNAi) and antioxidants. Manumycin A, an inhibitor of H-Ras farnesylation by farnesyltransferase, suppressed IL-1?- and TNF-?-induced MMP-13 mRNA and protein expression. Small interfering RNA (siRNA)-mediated H-Ras silencing down-regulated MMP-13 mRNA and protein induction by IL-1? and TNF-?. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase/NOX) inhibitor, diphenyleneiodonium (DPI) suppressed cytokine-induced MMP-13 expression and superoxide production. Apocynin, another NOX inhibitor, also diminished MMP-13 induction. Deoxyglucose an antimetabolite of glucose metabolism reduced MMP-13 increase. Role of NOX-mediated ROS production was reaffirmed by the observation that the antioxidants, trolox, nordihydroguaiaretic acid (NDGA), quercetin and resveratrol downregulated cytokine-induced MMP-13 mRNA and protein expression. These results provide strong pharmacological and genetic evidence for the implication of H-Ras and NADPH oxidase-generated superoxide production in MMP-13 gene regulation by IL-1? and TNF-?. These proteins could be potentially targeted for therapeutic inhibition of MMP-13-driven cartilage erosion by using H-Ras and NOX inhibitors and antioxidants.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antioxidants,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/HRAS protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 13,
http://linkedlifedata.com/resource/pubmed/chemical/NADPH Oxidase,
http://linkedlifedata.com/resource/pubmed/chemical/Onium Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Polyenes,
http://linkedlifedata.com/resource/pubmed/chemical/Polyunsaturated Alkamides,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins p21(ras),
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Reactive Oxygen Species,
http://linkedlifedata.com/resource/pubmed/chemical/Superoxides,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/diphenyleneiodonium,
http://linkedlifedata.com/resource/pubmed/chemical/manumycin
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1096-0384
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pubmed:author |
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pubmed:copyrightInfo |
Copyright © 2011 Elsevier Inc. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
507
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
350-5
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pubmed:meshHeading |
pubmed-meshheading:21211511-Antioxidants,
pubmed-meshheading:21211511-Chondrocytes,
pubmed-meshheading:21211511-Cytokines,
pubmed-meshheading:21211511-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:21211511-Humans,
pubmed-meshheading:21211511-Inflammation,
pubmed-meshheading:21211511-Interleukin-1beta,
pubmed-meshheading:21211511-Joints,
pubmed-meshheading:21211511-Matrix Metalloproteinase 13,
pubmed-meshheading:21211511-NADPH Oxidase,
pubmed-meshheading:21211511-Onium Compounds,
pubmed-meshheading:21211511-Polyenes,
pubmed-meshheading:21211511-Polyunsaturated Alkamides,
pubmed-meshheading:21211511-Proto-Oncogene Proteins p21(ras),
pubmed-meshheading:21211511-RNA, Messenger,
pubmed-meshheading:21211511-Reactive Oxygen Species,
pubmed-meshheading:21211511-Superoxides,
pubmed-meshheading:21211511-Tumor Necrosis Factor-alpha
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pubmed:year |
2011
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pubmed:articleTitle |
Involvement of H-Ras and reactive oxygen species in proinflammatory cytokine-induced matrix metalloproteinase-13 expression in human articular chondrocytes.
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pubmed:affiliation |
Department of Medicine, University of Montreal, Notre-Dame Hospital, 1560 Sherbrooke East, Montreal, Quebec, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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