Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis

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Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis

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dc.contributor.author Pakozdi, Angela
dc.contributor.author Amin, Mohammad A
dc.contributor.author Haas, Christian S
dc.contributor.author Haines, G Kenneth
dc.contributor.author Santos, Lanie L
dc.contributor.author Morand, Eric F
dc.contributor.author Koch, Alisa E
dc.contributor.author Martinez, Rita J.
dc.contributor.author David, John R.
dc.date.accessioned 2011-05-10T00:29:29Z
dc.date.issued 2006
dc.identifier.citation Pakozdi, Angela, Mohammad A. Amin, Christian S. Haas, Rita J. Martinez, G. Kenneth Haines, Lanie L. Santos, Eric F. Morand, John R. David, and Alisa E. Koch. 2006. Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis. Arthritis Research & Therapy 8(4): R132. en_US
dc.identifier.issn 1478-6354 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4885955
dc.description.abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis. In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentration-dependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCδ inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCδ, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.relation.isversionof doi:10.1186/ar2021 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779381/pdf/ en_US
dash.license LAA
dc.title Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Arthritis Research & Therapy en_US
dash.depositing.author David, John R.
dc.date.available 2011-05-10T00:29:29Z
dash.affiliation.other SPH^Immunology and Infectious Diseases TPH en_US
dash.affiliation.other HMS^Medicine-Brigham and Women's Hospital en_US

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