Aggrecanase-1/a disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS)-4 and aggfecanase-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 mu M) interfered with the interleukin (IL)-1 beta-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. (C) 2008 Elsevier Inc. All rights reserved.