title: Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.
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 PKCdelta inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCdelta, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA.
authors.affiliation: University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Pakozdi
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Amin
authors.forename: Christian S
authors.initials: CS
authors.lastname: Haas
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Martinez
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Lanie L
authors.initials: LL
authors.lastname: Santos
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: John R
authors.initials: JR
authors.lastname: David
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007596:Joints / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation; D015054:Zymosan
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D015054:Zymosan; D016392:Proto-Oncogene Proteins pp60(c-src); D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2