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 biological actions in vitro. We investigated the chondroprotective effect of citrus flavonoids, especially nobiletin, using cultured rabbit synovial fibroblasts and articular chondrocytes.


METHODS
We examined the effects of citrus flavonoids on the production and gene expression of matrix metalloproteinases (MMP) and prostaglandin E2 (PGE2)production in rabbit synovial fibroblasts.


RESULTS
Six flavonoids isolated from Citrus depressa Rutaceae including tangeretin, 6-demethoxytangeretin, nobiletin, 5-demethylnobiletin, 6-demethoxynobiletin, and sinensetin suppressed the interleukin 1 (IL-1) induced production of proMMP-9/progelatinase B in rabbit synovial cells in a dose dependent manner (<64 microM); nobiletin most effectively suppressed proMMP-9 production along with the decrease in its mRNA. Nobiletin also reduced IL-1 induced production of PGE2 in the synovial cells, but did not modify the synthesis of total protein. These suppressive effects of nobiletin were also observed in rabbit articular chondrocytes. Nobiletin inhibited proliferation of rabbit synovial fibroblasts in the growth phase.


CONCLUSIONS
These results suggest nobiletin is a novel antiinflammatory candidate that has the potential to inhibit PGE2 production, matrix degradation of the articular cartilage, and pannus formation in osteoarthritis and rheumatoid arthritis.
Ishiwa
J
J
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
Sato
T
T
Mimaki
Y
Y
Sashida
Y
Y
Yano
M
M
Ito
A
A
D000818:Animals; D002455:Cell Division; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology
D047309:Flavones; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; C000595792:6-demethoxytangeretin; C008661:nobiletin; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone