title: Hyaluronan inhibits p38 mitogen-activated protein kinase via the receptors in rheumatoid arthritis chondrocytes stimulated with fibronectin fragment.
abstract: This study was aimed to examine the inhibitory mechanism of high molecular weight hyaluronan (HA) on nitric oxide (NO) production by NH2-terminal heparin-binding fibronectin fragment (FN-f) in rheumatoid arthritis (RA) chondrocytes. When the RA cartilage explants or the isolated RA chondrocytes in monolayer were incubated with FN-f, the fragment stimulated NO production with induction of inducible nitric oxide synthase (iNOS) and activation of p38 mitogen-activated protein kinase. Pretreatment with 2,700 kDa HA resulted in significant suppression of FN-f-stimulated NO production in RA cartilage as well as in chondrocyte monolayer cultures in association with iNOS down-regulation. Inhibition studies with p38 inhibitor indicated the requirement of p38 for FN-f-induced NO production. HA suppressed p38 activation by the FN-f, leading to a decrease in NO production. Immunofluorescence cytochemistry revealed HA association with intercellular adhesion molecule-1 (ICAM-1) and CD44. While the individual antibody to ICAM-1 or CD44 partially reversed HA effect on the FN-f action, both antibodies in combination completely blocked the HA effect. The present study clearly demonstrated that the high molecular weight of HA suppressed the FN-f-activated p38 via ICAM-1 and the CD44 in RA chondrocytes. HA could down-regulate the catabolic action of FN-f in RA joints through the mechanism demonstrated in this study.
authors.affiliation: Department of Sports Medicine, Faculty of Budo and Sport Studies, Tenri University, 80 Tainosho-cho, Tenri, Nara, 632-0071, Japan. tadyasu@sta.tenri-u.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yasuda
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002358:Cartilage, Articular / Q000166:cytology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005353:Fibronectins / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000737:chemistry; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D009569:Nitric Oxide / Q000737:chemistry; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D018960:Hyaluronan Receptors; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D006820:Hyaluronic Acid; D006493:Heparin; D048051:p38 Mitogen-Activated Protein Kinases