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.

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.

• Authors: Yutaka Yoshioka, Eiji Kozawa, Hiroshi Urakawa, Eisuke Arai, Naohisa Futamura, Lisheng Zhuo, Koji Kimata, Naoki Ishiguro, Yoshihiro Nishida
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 65 Issue 5 Pg. 1160-70 (May 2013) ISSN: 1529-0131 [Electronic] United States
• PMID: 23335273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 by the American College of Rheumatology.

Chemical References

• Adjuvants, Immunologic
• Antirheumatic Agents
• RNA, Messenger
• RNA, Small Interfering
• Hymecromone
• Hyaluronic Acid

Topics

• Adjuvants, Immunologic (antagonists & inhibitors, biosynthesis, blood)
• Administration, Oral
• Animals
• Antirheumatic Agents (pharmacology)
• Arthritis, Experimental (drug therapy, metabolism, pathology)
• Arthritis, Rheumatoid (drug therapy, metabolism, pathology)
• Cells, Cultured
• Edema (chemically induced, drug therapy, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Knockdown Techniques
• Hindlimb (drug effects, pathology)
• Humans
• Hyaluronic Acid (antagonists & inhibitors, biosynthesis, blood)
• Hymecromone (analogs & derivatives, pharmacology)
• Mice
• Mice, Inbred DBA
• RNA, Messenger (antagonists & inhibitors, metabolism)
• RNA, Small Interfering (genetics)
• Stifle (drug effects, pathology)
• Synovial Membrane (drug effects, metabolism, pathology)