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Arthritis Research and Therapy

, 8:R132

First Online: 26 July 2006Received: 22 February 2006Revised: 19 June 2006Accepted: 26 July 2006


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.

AbbreviationsAIAantigen-induced arthritis

BCAbicinchoninic acid

CO2carbon dioxide

COX2cyclo-oxygenase 2

DAPI4-6-diamidino-2-phenylindole dihydrochloride

DMSOdimethyl sulfoxide

ECLenhanced chemiluminescence

ED50Median Effective Dose

ELISAenzyme-linked immunosorbent assay

FBSfetal bovine serum




Jakjanus kinase

JNKc-jun N-terminal kinase

MAPK-ERKmitogen-activated protein kinase extracellular-signal-regulated kinase

mBSAmethylated bovine serum albumin

MIFmacrophage migration inhibitory factor

MMPmatrix metalloproteinase

MT-MMPmembrane-type matrix metalloproteinase

NF-κBnuclear factor-κB

OCToptimal cutting temperature compound

PAGEpolyacrylamide gel electrophoresis

PBSphosphate-buffered saline

PDTCpyrrolidine dithiocarbamate

PI3Kphosphatidylinositol 3-kinase

PKAprotein kinase A

PKCprotein kinase C

RArheumatoid arthritis

SAPKstress-activated kinase

SEMstandard error of the mean

STATsignal transducer and activator of transcription

TBSTTris-buffered saline Tween

TNF-αtumor necrosis factor-α

ZIAzymosan-induced arthritis.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2021 contains supplementary material, which is available to authorized users.

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