Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice

• Published in: Biochemical and biophysical research communications Vol. 373; no. 2; pp. 181 - 185
• Main Authors: Imada, Keisuke, Lin, Na, Liu, Chunfang, Lu, Aiping, Chen, Weiheng, Yano, Masamichi, Sato, Takashi, Ito, Akira
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2008
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - biosynthesis; ADAM Proteins - genetics; ADAMTS4 Protein; ADAMTS5 Protein; Aggrecanase; Aggrecans - analysis; Aggrecans - metabolism; Animals; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Experimental - pathology; Cartilage; Cartilage - drug effects; Cartilage - enzymology; Cartilage - pathology; Cells, Cultured; Citrus; Collagen-induced arthritis; Extracellular matrix; Fibroblasts - drug effects; Fibroblasts - metabolism; Flavones - pharmacology; Flavones - therapeutic use; Gene Expression - drug effects; Humans; Inflammation; Joints - drug effects; Joints - enzymology; Joints - pathology; Male; Matrix metalloproteinase; Mice; Mice, Inbred Strains; Nobiletin; Osteoarthritis; Polymethoxy flavonoid; Procollagen N-Endopeptidase - antagonists & inhibitors; Procollagen N-Endopeptidase - biosynthesis; Procollagen N-Endopeptidase - genetics; Rheumatoid arthritis; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; Synovial Fluid; RT; Collagen-induced arthritis; ADAMTS; Aggrecanase; Matrix metalloproteinase; TNF; Cartilage; OA; FBS; Extracellular matrix; CIA; PBS; IL; IGD; Inflammation; COX; RA; MMP; MEK; Polymethoxy flavonoid; Nobiletin; Rheumatoid arthritis; PG; GAPDH; Osteoarthritis; PCR; TIMP
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.05.171

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 (16–64 μM) interfered with the interleukin (IL)-1β-mediated ADAMTS-4 and -5 mRNA expression in cultured human synovial fibroblasts. Furthermore, intraperitoneal administration of nobiletin (15, 30, and 60 mg/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.