Hyaluronan inhibits matrix metalloproteinase-1 production by rheumatoid synovial fibroblasts stimulated by proinflammatory cytokines

• Published in: Journal of rheumatology 2003-06, Vol.30 (6), p.1164-1172
• Main Authors: SHIMIZU, Makoto, YASUDA, Tadashi, NAKAGAWA, Takefumi, YAMASHITA, Eizaburo, JULOVI, Sohel M, HIRAMITSU, Teruko, NAKAMURA, Takashi
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Adjuvants, Immunologic - secretion; Aged; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Binding, Competitive - immunology; Biological and medical sciences; Cells, Cultured; Diseases of the osteoarticular system; Female; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - secretion; Humans; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Hyaluronic Acid - pharmacology; Hyaluronic Acid - secretion; Inflammatory joint diseases; Interleukin-1 - pharmacology; Male; Matrix Metalloproteinase Inhibitors; Medical sciences; Middle Aged; Stimulation, Chemical; Synovial Membrane - cytology; Synovial Membrane - immunology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0315-162X; 1499-2752

OBJECTIVE: To study the inhibitory effects of hyaluronan (HA) on the production of matrix metalloproteinase-1 (MMP-1) by rheumatoid synovial fibroblasts (RSF) stimulated by proinflammatory cytokines, tumor necrosis factor-a (TNF-a), and interleukin-1beta (IL-1beta). METHODS: HA of various sizes at various concentrations was added to monolayer cultures of RSF in the presence of TNF-a or IL-1beta, with or without pretreatment with a monoclonal antibody against CD44, OS/37. Concentrations of MMP-1 in cell lysates and conditioned media and of CD44 on RSF were assayed by immunoblotting. MMP-1 expression was analyzed by reverse transcriptase-polymerase chain reaction. Binding of HA to RSF was evaluated by confocal microscopy using fluorescein-conjugated HA and OS/37. RESULTS: Treatment with HA (0.3 approximately 3.0 mg/ml) resulted in a significant decrease in the production of MMP-1 induced by TNF-a and IL-1beta, in a dose-dependent manner. HA of 250 approximately 2300 kDa at 3 mg/ml was found to suppress the induction of MMP-1 by TNF-a. HA decreased the cytokine-induced MMP-1 synthesis in RSF at mRNA and protein levels. The monoclonal antibody, which showed abundant expression of CD44 on RSF by immunofluorescein cytochemistry, partially blocked the binding of fluorescein-conjugated HA to RSF. Pretreatment with OS/37 reversed the inhibition of MMP-1 production in TNF-a or IL-1beta-stimulated RSF caused by HA. CONCLUSION: HA suppresses the production of MMP-1 by TNF-a or IL-1beta-stimulated RSF. Based on data from anti-CD44 treatment, HA binding to CD44 is directly involved in the suppression of MMP-1 production. Those results provide the rationale for a therapeutic role of HA in treatment of rheumatoid joints.