Open AccessSuppression of Hyaluronan Synthesis Alleviates Inflammatory Responses in Murine Arthritis and in Human Rheumatoid Synovial Fibroblasts
Author(s) -
Yoshioka Yutaka,
Kozawa Eiji,
Urakawa Hiroshi,
Arai Eisuke,
Futamura Naohisa,
Zhuo Lisheng,
Kimata Koji,
Ishiguro Naoki,
Nishida Yoshihiro
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.37861
Subject(s) - arthritis , rheumatoid arthritis , fibroblast , matrix metalloproteinase , tumor necrosis factor alpha , inflammation , osteoarthritis , in vitro , chemistry , immunology , medicine , in vivo , microbiology and biotechnology , pathology , biology , biochemistry , alternative medicine
Objective To clarify the roles of hyaluronan (HA) in joint inflammation and the process of joint destruction, using 4‐methylumbelliferone (4‐MU), an inhibitor of HA synthesis, in a mouse model of collagen‐induced arthritis (CIA) and in a monolayer culture of fibroblast‐like synoviocytes (FLS) derived from patients with rheumatoid arthritis. Methods DAB/1J mice were immunized with type II collagen. The effects of 4‐MU were evaluated by the physiologic arthritis score, paw swelling, the histologic arthritis score, and expression of matrix metalloproteinase 3 (MMP‐3) and MMP‐13 in chondrocytes and synovial tissue. In vitro, the effect of 4‐MU on messenger RNA and protein expression of MMP‐1 and MMP‐3 was determined. The effects of 4‐MU on HA deposition and on serum/medium concentrations of HA were analyzed using biotinylated HA binding protein staining and an HA binding assay, respectively. Results Treatment with 4‐MU in mice with CIA dramatically decreased the severity of arthritis (based on the arthritis score), paw thickness, and histopathologic changes. MMP‐3 and MMP‐13 expression in chondrocytes and synovial cells was significantly inhibited by 4‐MU in vivo. Treatment with 4‐MU also inhibited MMP‐1 and MMP‐3 expression in tumor necrosis factor α–stimulated FLS, in a dose‐dependent manner. The 4‐MU–induced decreases in the serum HA concentration in mice with CIA and in “medium” and “pericellular” HA concentrations in cultured FLS support the contention that the inhibitory mechanism of 4‐MU is mediated by HA suppression. Conclusion Reduced disease activity induced by 4‐MU in mice with CIA revealed HA to be a crucial regulator in the course of arthritis. Therefore, 4‐MU is a potential therapeutic agent in arthritis, and its inhibitory mechanism is possibly mediated by suppression of HA synthesis.