title: Inhibition of inducible nitric oxide synthase prevents lipid peroxidation in osteoarthritic chondrocytes.
abstract: Nitric oxide (NO) and the lipid peroxidation (LPO) product 4-hydroxynonenal (HNE) are considered to be key mediators of cartilage destruction in osteoarthritis (OA). NO is also known to be an important intermediary in LPO initiation through peroxynitrite formation. The aim of the present study was to assess the ability of the inducible NO synthase (iNOS) inhibitor N-iminoethyl-L-lysine (L-NIL) to prevent HNE generation via NO suppression in human OA chondrocytes and cartilage explants. Human OA chondrocytes and cartilage explants were treated with L-NIL and thereafter with or without interleukin-1beta (IL-1β) or HNE at cytotoxic or non-cytotoxic concentrations. Parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated. L-NIL stifled IL-1β-induced NO release, iNOS activity, nitrated proteins, and HNE generation in a dose-dependent manner. It also blocked IL-1β-induced inactivation of the HNE-metabolizing glutathione-s-transferase (GST). L-NIL restored both HNE and GSTA4-4 levels in OA cartilage explants. Interestingly, it also abolished IL-1β-evoked reactive oxygen species (ROS) generation and p47 NADPH oxidase activation. Furthermore, L-NIL significantly attenuated cell death and markers of apoptosis elicited by exposure to a cytotoxic dose of HNE as well as the release of prostaglandin E(2) and metalloproteinase-13 induced by a non-cytotoxic dose of HNE. Altogether, our findings support a beneficial effect of L-NIL in OA by (i) preventing the LPO process and ROS production via NO-dependent and/or independent mechanisms and (ii) attenuating HNE-induced cell death and different mediators of cartilage damage.
authors.affiliation: Orthopaedic Research Laboratory, Hôpital du Sacré-Cœur de Montréal and Department of Surgery, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Bentz
authors.forename: Charlotte
authors.initials: C
authors.lastname: Zaouter
authors.forename: Qin
authors.initials: Q
authors.lastname: Shi
authors.forename: Hassan
authors.initials: H
authors.lastname: Fahmi
authors.forename: Florina
authors.initials: F
authors.lastname: Moldovan
authors.forename: Julio C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benderdour
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D053583:Interleukin-1beta; C090663:N(6)-(1-iminoethyl)lysine; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D005982:Glutathione Transferase; D053509:Matrix Metalloproteinase 13; C027576:4-hydroxy-2-nonenal; D008239:Lysine; D015232:Dinoprostone