PMID- 16872482
OWN - NLM
STAT- MEDLINE
DCOM- 20070220
LR  - 20220224
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 8
IP  - 4
DP  - 2006
TI  - Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 
      production in rheumatoid arthritis.
PG  - R132
AB  - 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.
FAU - Pakozdi, Angela
AU  - Pakozdi A
AD  - University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 
      48109, USA.
FAU - Amin, Mohammad A
AU  - Amin MA
FAU - Haas, Christian S
AU  - Haas CS
FAU - Martinez, Rita J
AU  - Martinez RJ
FAU - Haines, G Kenneth 3rd
AU  - Haines GK 3rd
FAU - Santos, Lanie L
AU  - Santos LL
FAU - Morand, Eric F
AU  - Morand EF
FAU - David, John R
AU  - David JR
FAU - Koch, Alisa E
AU  - Koch AE
LA  - eng
GR  - R01 AI040987/AI/NIAID NIH HHS/United States
GR  - R01 AR048267/AR/NIAMS NIH HHS/United States
GR  - AI40987/AI/NIAID NIH HHS/United States
GR  - AR48267/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Macrophage Migration-Inhibitory Factors)
RN  - 0 (Recombinant Proteins)
RN  - 9010-72-4 (Zymosan)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/chemically induced
MH  - Arthritis, Rheumatoid/*metabolism/pathology/physiopathology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Joints/metabolism
MH  - Macrophage Migration-Inhibitory Factors/deficiency/*metabolism/pharmacology
MH  - Matrix Metalloproteinase 2/*biosynthesis/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphorylation/drug effects
MH  - Protein Kinase C-delta/metabolism
MH  - Proto-Oncogene Proteins pp60(c-src)/metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Signal Transduction
MH  - Synovial Membrane/metabolism/pathology
MH  - Time Factors
MH  - Up-Regulation
MH  - Zymosan
PMC - PMC1779381
EDAT- 2006/07/29 09:00
MHDA- 2007/02/21 09:00
PMCR- 2006/07/26
CRDT- 2006/07/29 09:00
PHST- 2006/02/22 00:00 [received]
PHST- 2006/06/19 00:00 [revised]
PHST- 2006/07/26 00:00 [accepted]
PHST- 2006/07/29 09:00 [pubmed]
PHST- 2007/02/21 09:00 [medline]
PHST- 2006/07/29 09:00 [entrez]
PHST- 2006/07/26 00:00 [pmc-release]
AID - ar2021 [pii]
AID - 10.1186/ar2021 [doi]
PST - ppublish
SO  - Arthritis Res Ther. 2006;8(4):R132. doi: 10.1186/ar2021.