Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin fragment in rheumatoid synovial cells.
Fibronectin with IIICS region is present in rheumatoid synovium, and fibronectin fragments are increased in rheumatoid joints. We investigated the ability of COOH-terminal heparin-binding fibronectin fragment (COOH-HBFN-f) containing IIICS to induce matrix metalloproteinase (MMP) production and the role of mitogen-activated protein kinase (MAPK) pathway and CS-1 sequence that can bind alpha4beta1 integrin in MMP induction by COOH-HBFN-f in rheumatoid synovial fibroblasts (RSF). When RSF in monolayer culture were incubated with COOH-HBFN-f, COOH-HBFN-f stimulated the production of MMP-1, MMP-3, and MMP-13 by RSF in association with activation of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH(2)-terminal kinase. Immunoprecipitation of cell lysates demonstrated the presence of alpha4 integrin in cultured RSF. Similar to COOH-HBFN-f, treatment with CS-1 synthetic peptide derived from IIICS resulted in increased MMP production and activation of the kinases, although the MMP levels were low. Preincubation of RSF with anti-alpha4 integrin antibody resulted in partial suppression of the COOH-HBFN-f-stimulated MMP production. Inhibition studies using protein kinase inhibitors (PD98059 and SB203580) showed that those MAPK pathways contributed to MMP up-regulation by COOH-HBFN-f and CS-1. Thus, the present results have clearly shown that COOH-HBFN-f and CS-1 stimulate MMP production in association with activation of MAPK pathways in RSF. Integrin alpha4beta1 may be partially involved in the MMP induction by COOH-HBFN-f.
Yasuda
Tadashi
T
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Japan. tadyasu@kuhp.kyoto-u.ac.jp
Shimizu
Makoto
M
Nakagawa
Takefumi
T
Julovi
Sohel M
SM
Nakamura
Takashi
T
D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D039441:Integrin alpha4 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D005419:Flavonoids; D007093:Imidazoles; D009842:Oligopeptides; D010446:Peptide Fragments; D011725:Pyridines; C094697:glutamyl-isoleucyl-leucyl-aspartyl-valine; D039441:Integrin alpha4; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one