Expression of membrane-type 1 matrix metalloproteinase in rheumatoid synovial cells.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is thought to be a putative regulator of pro-gelatinase A (MMP-2) in the rheumatoid synovium. In this study, we examined the effects of IL-1beta, one of the inflammatory cytokines, on the expression of MT1-MMP and the activation of pro-MMP-2 using rheumatoid synovial cells. We also studied the effects of KE-298 (2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid), a new disease-modifying anti-rheumatic drug (DMARD), on MT1-MMP expression of rheumatoid synovial cells. Type B synovial cells (fibroblast-like synovial cells) were cultured with KE-298 (25-100 microg/ml) in the presence of IL-1beta for 48 h. Activation of pro-MMP-2 secreted from synovial cells was analysed by gelatin zymography. Reverse transcription-polymerase chain reaction (RT-PCR) methods were used to detect MT1-MMP mRNA. MT1-MMP protein expression on synovial cells was examined by anti-MT1-MMP immunoblot. An active form of MMP-2 was demonstrated in the culture media conditioned by IL-1beta-stimulated synovial cells. In addition, MT1-MMP mRNA and protein expression of rheumatoid synovial cells were increased by IL-1beta treatment. KE-298 blocked this IL-1beta-induced pro-MMP-2 activation and MT1-MMP expression, but did not affect IL-1beta-induced tissue inhibitor of metalloproteinase-2 (TIMP-2) secretion from rheumatoid synovial cells. These findings indicate that activation of rheumatoid synovial cells by IL-1beta results in the induction of MT1-MMP expression. Given that MT1-MMP promotes matrix degradation by activating pro-MMP-2, these results suggest a novel mechanism whereby cytokine may contribute to articular destruction in rheumatoid arthritis (RA). KE-298 may prevent this process by down-regulating MT1-MMP expression.
Honda
S
S
First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
Migita
K
K
Hirai
Y
Y
Origuchi
T
T
Yamasaki
S
S
Kamachi
M
M
Shibatomi
K
K
Fukuda
T
T
Kita
M
M
Hida
A
A
Ida
H
H
Aoyagi
T
T
Kawakami
A
A
Kawabe
Y
Y
Oizumi
K
K
Eguchi
K
K
D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013583:Synovial Membrane / Q000201:enzymology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D015533:Transcriptional Activation
D018501:Antirheumatic Agents; D004792:Enzyme Precursors; D007375:Interleukin-1; D010666:Phenylpropionates; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase; C078547:esonarimod