title: Suppression of hyaluronan synthesis alleviates inflammatory responses in murine arthritis and in human rheumatoid synovial fibroblasts.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Yutaka
authors: Y
authors: Yoshioka
authors: Eiji
authors: E
authors: Kozawa
authors: Hiroshi
authors: H
authors: Urakawa
authors: Eisuke
authors: E
authors: Arai
authors: Naohisa
authors: N
authors: Futamura
authors: Lisheng
authors: L
authors: Zhuo
authors: Koji
authors: K
authors: Kimata
authors: Naoki
authors: N
authors: Ishiguro
authors: Yoshihiro
authors: Y
authors: Nishida
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013264:Stifle / Q000187:drug effects / Q000473:pathology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D018501:Antirheumatic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D006923:Hymecromone; D006820:Hyaluronic Acid