A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts

Objective. Flavonoids including nobiletin are known to exert many biologica l actions in vitro. We investigated the chondroprotective effect of citrus flavonoids, especially nobiletin, using cultured rabbit synovial fibroblast s and articular chondrocytes. Methods. We examined the effects of citrus flavonoids on the production and gene expression of matrix metalloproteinases (MMP) and prostaglandin E-2 ( PGE(2)) production in rabbit synovial fibroblasts. Results. Six flavonoids isolated from Citrus depressa Rutaceae including ta ngeretin, 6-demethoxy-tangeretin, nobiletin, 5-demethylnobiletin, 6-demetho xynobiletin, and sinensetin suppressed the interleukin 1 (IL-1) induced pro duction of proMMP-9/progelatinase B in rabbit synovial cells in a dose depe ndent manner (< 64 mu M); nobiletin most effectively suppressed proMMP-9 pr oduction along with the decrease in its mRNA. Nobiletin also reduced IL-1 i nduced production of PGE(2) in the synovial cells, but did not modi fy the synthesis of total protein. These suppressive effects of nobiletin were als o observed in rabbit articular chondrocytes. Nobiletin inhibited proliferat ion of rabbit synovial fibroblasts in the growth phase. Conclusion. These results suggest nobiletin is a novel antiinflammatory can didate that has the potential to inhibit PGE(2) production. matrix degradat ion of the articular cartilage, and pannus formation in osteoarthritis and rheumatoid arthritis.