hymecromone and Edema

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.. 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.. 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.. 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.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Edema; Fibroblasts; Gene Knockdown Techniques; Hindlimb; Humans; Hyaluronic Acid; Hymecromone; Mice; Mice, Inbred DBA; RNA, Messenger; RNA, Small Interfering; Stifle; Synovial Membrane

4-Methylumbelliferyl beta-D-xyloside was administered to 9-day-old chick embryos, and the morphological and chemical changes in the embryo were followed daily. Increases in wet weight, Na and Cl content, and visible edema were detectable at 10 days and fully apparent at 11 days. Dry weight increased to the same extent in control and treated embryos for four days, but then diverged. The degree of sulfation of chondroitin sulfate was slightly less in treated than control embryos at 10 days, and reached a steady low value at 11 days. Analysis of glycosaminoglycans in skin, muscle, and aorta showed an increase in chondroitin and its sulfates in the two former tissues but not the latter. In muscle and aorta, the degree of sulfation of chondroitin sulfate was markedly reduced; but in skin the results suggested a more complex picture in which the normal metabolism of glycosaminoglycans was altered. A possible physiological role is suggested for chondroitin sulfate in embryonic soft tissues.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Chick Embryo; Chlorides; Chondroitin Sulfates; DNA; Edema; Glycosaminoglycans; Glycosides; Hymecromone; Kinetics; Sodium; Tissue Distribution; Umbelliferones