Thiol antioxidant, N-acetylcysteine, activates extracellular signal-regulated kinase signaling pathway in articular chondrocytes.
Reactive oxygen species (ROS) generated during inflammation and aging contribute to the resorption of articular cartilage. Low antioxidant levels are a risk factor for arthritis because they protect cartilage from ROS. N-Acetylcysteine (NAC) is a ROS scavenger and, depending upon the concentration, an anti-inflammatory or prooxidant agent. Mechanisms of action for NAC were studied in primary human and bovine chondrocytes. NAC dose-dependently activated phosphorylation of extracellular signal-regulated kinases-mitogen-acivated protein kinases (ERK-MAPK). ERK activation peaked within 15 min and declined afterward up to 180 min. This activation was inhibited by the MAPKK inhibitor, PD098059. The induction was mimicked by other thiols, l-cysteine, reduced glutathione, and pyrrolidine dithiocarbamate (PDTC) but not by a nonthiol, N-acetylalanine. The total nonphosphorylated ERKs levels remained unaffected by these treatments. Activation of the ERK-MAPK pathway provides a mechanism for the reported promotion of chondrocyte survival by thiol antioxidants.
Li
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WQ
Department of Medicine, Orthopaedic Surgery and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Notre-Dame Hospital of CHUM, 1560 Sherbrooke East, Montreal, Quebec, H2L 4M1, Canada.
Dehnade
F
F
Zafarullah
M
M
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D005419:Flavonoids; D016166:Free Radical Scavengers; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione; D003545:Cysteine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine