ReviewReactive oxygen species and superoxide dismutases: Role in joint diseases
Introduction
Reactive oxygen species (ROS) are normal by-products of cellular metabolism. Overproduction of ROS and their derivatives occurs in a number of diseases [1]. Among ROS, the superoxide anion (O2−) plays a pivotal role in inflammation, particularly in patients with inflammatory joint disease [2]. The enzyme superoxide dismutase (SOD) neutralizes O2− by transforming it into hydrogen peroxide (H2O2), thereby preventing the formation of highly aggressive compounds such as peroxynitrite (ONOO−) and hydroxyl radical (HO).
In many joint diseases, proinflammatory factors such as cytokines and prostaglandins are released at sites of inflammation, together with ROS [3] and nitric oxide (NO) [4]. These factors are associated with very low SOD concentrations in joint fluid [5]. Studies involving assays of nitrotyrosine residues in synovial tissues from patients with rheumatoid arthritis (RA) [6] or exposure of chondrocytes to synthetic peroxynitrite in vitro [7] have established that the combination of the superoxide anion to NO causes cartilage damage. Further evidence of the deleterious effects of O2− comes from a study in which intraarticular injections of native SOD (bovine orgotein) produced greater clinical improvements than did intraarticular aspirin in patients with RA involving the knee [8]. Experiments involving SOD knockout and overexpression in mouse models of arthritis have confirmed the ability of SOD to protect against the harmful effects of O2− [9], [10]. Several SOD mimetics have been developed as therapeutic tools for reducing inflammation while minimizing side effects [11].
SOD activity is a key component of the cellular antioxidant armamentarium that protects cells and the extracellular matrix (ECM) from the harmful effects of O2− and its derivatives. In this review, we discuss new insights into the roles for ROS and SOD in joint disease, as well as the potential therapeutic usefulness of SOD mimetics.
Section snippets
Reactive oxygen species
ROS are atoms or small molecules that have unpaired valence shell electrons. They readily accept another electron or transfer their unpaired electron to another molecule. ROS are normal by-products of cellular metabolism (Fig. 1). However, alterations in the amount and nature of released ROS occur in various disease states [12]. Reactivity varies widely from one ROS to the next. Among ROS produced by living cells, O2− is a proinflammatory compound that damages cells and the ECM. For instance, O2
The superoxide dismutases
SOD catalyses the dismutation of O2− to dioxygen (O2) and H2O2:O2− + O2− + 2H+ → H2O2 + O2
H2O2 is eliminated by glutathione peroxidase or catalase. Glutathione peroxidase also metabolizes the hydroperoxides generated by peroxidation of polyunsaturated fatty acids (linoleic acid, linolenic acid, arachidonic acid). Alterations in the activity of these enzymes may lead to oxidative stress. The biochemistry and molecular structure of three SOD isoforms found in different body compartments have been
Oxidative stress and osteoarthritis
The cartilage matrix undergoes considerable alterations in structure, molecular composition, and mechanical properties during aging. Surface fibrillation, proteoglycan structure and composition changes, and increased collagen breakdown are examples of these alterations. The cartilage loses tensile resistance and stiffness. IL-1β, one of the most active factors involved in osteoarthritis [34], diminishes the expression of type 2 collagen and aggrecan, and increases the expression of
SOD in joint disease
SODs exert protective effects in animal models of ischemia and inflammation [22]. In mice that are genetically deficient in SOD3, both the severity of collagen-induced arthritis and the production of proinflammatory cytokines are increased [9]. SOD3 gene transfer via the subcutaneous route [10] or into the knee decreased the severity of experimental arthritis in rodents [44].
In humans, serum SOD3 levels correlated negatively with disease activity [45]. Studies of orgotein in RA and
Conclusion
The body of available data points to several conclusions. First, joint diseases are associated with large increases in the production of ROS including O2−, NO, and their derivates. Second, TNF-α overproduction in joint disease substantially diminishes the activity of SODs and other antioxidant enzymes. SOD mimetics exert beneficial effects in various conditions including joint disease. O2− elimination via the administration of SOD mimetics may attenuate the inflammatory process via three main
Acknowledgments
We are grateful to the French Society for Rheumatology (research grant 2004 awarded to R Champy) and to the nonprofit organization Association Rhumatisme et Travail (research grant 2005) for their financial support.
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