title: Aurothiomalate inhibits COX-2 expression in chondrocytes and in human cartilage possibly through its effects on COX-2 mRNA stability.
abstract: Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with aurothiomalate. The results show that aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for aurothiomalate which may be important in the treatment of arthritis.
authors.affiliation: The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Nieminen
authors.forename: Katriina
authors.initials: K
authors.lastname: Vuolteenaho
authors.forename: Asko
authors.initials: A
authors.lastname: Riutta
authors.forename: Hannu
authors.initials: H
authors.lastname: Kankaanranta
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
authors.forename: Teemu
authors.initials: T
authors.lastname: Moilanen
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts
chemical_list: D018501:Antirheumatic Agents; D052246:Cyclooxygenase 2 Inhibitors; D012333:RNA, Messenger; D013778:Tetrazolium Salts; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; D006052:Gold Sodium Thiomalate; D051546:Cyclooxygenase 2; D015232:Dinoprostone