Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes.
We recently reported that nitric oxide (NO), which is produced by chondrocytes treated with interleukin-1beta (IL-1), releases basic fibroblast growth factor (bFGF) stored in the matrix of articular chondrocytes. To clarify the mechanism of the IL-1-induced bFGF release, we investigated the production and gene expression of bFGF, matrix metalloproteinases (MMPs), syndecan 3, and inducible NO synthase (iNOS) by IL-1-treated rabbit articular chondrocytes. IL-1 stimulated not only the release of bFGF but also the production of it. Gelatin and casein zymography revealed that IL-1 stimulated the production of not only MMP-9 but also MMP-3. The increase in the production of these MMPs preceded the IL-1-stimulated bFGF release. An MMP inhibitor partially suppressed the release of bFGF, indicating that matrix degradation is at least partially involved in the IL-1-stimulated bFGF release even if increased production of bFGF is related to the release. IL-1 sequentially stimulated mRNA expression of iNOS, membrane type 1-MMP, MMP-9 and -3, and bFGF, in that order. NG-Monomethyl-L-arginine, an inhibitor of NO production, inhibited gene expression of MMP-9 and bFGF. These findings suggest that elevation of the NO level via iNOS mRNA expression stimulated by IL-1 mediates gene expression and production of MMPs and bFGF, resulting in the release of bFGF, and also reveal molecular mechanisms implicating the degradation of articular cartilage followed by angiogenesis in the synovium in arthritic joints.
Sasaki
K
K
Department of Biochemistry and Molecular Dentistry, Okayama University Dental School, Okayama 700-8525, Japan.
Hattori
T
T
Fujisawa
T
T
Takahashi
K
K
Inoue
H
H
Takigawa
M
M
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017364:Collagenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000235:genetics* / Q000494:pharmacology; D018093:Gelatinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D053504:Matrix Metalloproteinases, Membrane-Associated; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011480:Protease Inhibitors / Q000494:pharmacology; D011509:Proteoglycans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D053670:Syndecan-3; D019323:omega-N-Methylarginine / Q000494:pharmacology
D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011509:Proteoglycans; D053670:Syndecan-3; D016222:Fibroblast Growth Factor 2; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017364:Collagenases; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9