Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice.
Aggrecanase-1/a disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS)-4 and aggrecanase-2/ADAMTS-5 have been shown to play crucial roles in cartilage destruction in arthritic diseases, including rheumatoid arthritis and osteoarthritis. In this study, we examined the effects of nobiletin, a citrus polymethoxy flavone, on the expression and production of ADAMTS-4 and -5 in vitro and in vivo. Nobiletin (16-64muM) interfered with the interleukin (IL)-1beta-mediated ADAMTS-4 and -5 mRNA expression in cultured human synovial fibroblasts. Furthermore, intraperitoneal administration of nobiletin (15, 30, and 60mg/kg) also suppressed ADAMTS-4 and -5 mRNA expression in the joint tissues of collagen-induced arthritic (CIA) mice. Immunohistochemical analysis using an antibody against aggrecan neoepitope (NVTEGE(373)) revealed that aggrecanase-mediated degradation of aggrecan in cartilage was effectively inhibited by nobiletin. These results provide novel evidence that nobiletin effectively interferes with gene expression of ADAMTS-4 and -5, and thereby prevents cartilage destruction in CIA mice.
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392, Japan. imadak@ps.toyaku.ac.jp <imadak@ps.toyaku.ac.jp>
Keisuke
K
Imada
Na
N
Lin
Chunfang
C
Liu
Aiping
A
Lu
Weiheng
W
Chen
Masamichi
M
Yano
Takashi
T
Sato
Akira
A
Ito
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D002957:Citrus; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007596:Joints / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013582:Synovial Fluid
D053674:Aggrecans; D047309:Flavones; D012333:RNA, Messenger; C008661:nobiletin; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse