TNF-alpha-mediated expression of membrane-type matrix metalloproteinase in rheumatoid synovial fibroblasts.
Degradation of the extracellular matrix plays an important role in rheumatoid articular destruction. Rheumatoid synovial fibroblasts secrete a large amount of matrix-degrading metalloproteinases (MMPs), which initiate tissue damage by proteolytic degradation of collagens and proteoglycans. Cytokines, such as interleukin-1 alpha, -1 beta or tumour necrosis factor (TNF)-alpha, are potent inducers of MMPs in rheumatoid synovial fibroblasts, MMPs are synthesized and secreted as latent pro-enzymes and their activation is achieved by proteolytic cleavage or the propeptide domain at the N-terminus of the molecule. Thus, the interaction of the pro-enzymes with specific activators determines the enzymatic activity in the extracellular space. In the present study, we identified a novel mechanism for the activation of pro-MMP-2, which can be achieved through the interaction of the inflammatory cytokine, TNF-alpha, with synovial fibroblasts. Although MMP-2 is constitutively secreted by synovial fibroblasts as a pro-enzyme, stimulation of fibroblasts by TNF-alpha-induced secretion of MMP-2 in an active form. In support of this result, TNF-alpha stimulation-induced membrane-type matrix metalloproteinase (MT-MMP), a newly identified MMP-2-specific activator on synovial fibroblasts. Cycloheximide analysis demonstrated that protein synthesis may be required for TNF-alpha-mediated MT-MMP expression on synovial fibroblasts. Our results suggest that TNF-alpha induces MMP-2 activation in part by up-regulating MT-MMP expression, thus representing a new mechanism for cytokine-mediated articular destruction in rheumatoid arthritis (RA).
Migita
K
K
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Eguchi
K
K
Kawabe
Y
Y
Ichinose
Y
Y
Tsukada
T
T
Aoyagi
T
T
Nakamura
H
H
Nagataki
S
S
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D013268:Stimulation, Chemical; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2