Elsevier

Joint Bone Spine

Volume 74, Issue 4, July 2007, Pages 324-329
Joint Bone Spine

Review
Reactive oxygen species and superoxide dismutases: Role in joint diseases

https://doi.org/10.1016/j.jbspin.2007.02.002Get rights and content

Abstract

Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, aging, and cancer. The superoxide anion O2radical dot is the main ROS. Increased ROS production leads to tissue damage associated with inflammation. Superoxide dismutases (SODs) convert superoxide to hydrogen peroxide, which is then removed by glutathione peroxidase or catalase. Thus, SODs prevent the formation of highly aggressive ROS, such as peroxynitrite or the hydroxyl radical. Experimental models involving SOD knockout or overexpression are beginning to shed light on the pathophysiological role of SOD in humans. Although the antiinflammatory effects of exogenous native SOD (orgotein) are modest, synthetic SOD mimetics hold considerable promise for modulating the inflammatory response. In this review, we discuss new knowledge about the role of the superoxide anion and its derivates as mediators of inflammation and the role of SODs and SOD mimetics as antioxidant treatments in joint diseases such as rheumatoid arthritis, osteoarthritis, and crystal-induced arthropathies.

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 (O2radical dot) plays a pivotal role in inflammation, particularly in patients with inflammatory joint disease [2]. The enzyme superoxide dismutase (SOD) neutralizes O2radical dot by transforming it into hydrogen peroxide (H2O2), thereby preventing the formation of highly aggressive compounds such as peroxynitrite (ONOO) and hydroxyl radical (HOradical dot).

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 O2radical dot 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 O2radical dot [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 O2radical dot 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, O2radical dot is a proinflammatory compound that damages cells and the ECM. For instance, O2

The superoxide dismutases

SOD catalyses the dismutation of O2radical dot to dioxygen (O2) and H2O2:O2radical dot + O2radical dot + 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 O2radical dot, 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. O2radical dot 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.

References (50)

  • T.T. Huang et al.

    Superoxide-mediated cytotoxicity in superoxide dismutase-deficient fetal fibroblasts

    Arch Biochem Biophys

    (1997)
  • V. Afonso et al.

    TNF-α down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway

    Free Radic Biol Med

    (2006)
  • K.J. Morten et al.

    Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2: attenuation via antioxidant treatment

    J Biol Chem

    (2006)
  • M.D. Wheeler et al.

    Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat

    J Biol Chem

    (2001)
  • C.L. Fattman et al.

    Extracellular superoxide dismutase in biology and medicine

    Free Radic Biol Med

    (2003)
  • J.J. Enghild et al.

    The heparin-binding domain of extracellular superoxide dismutase is proteolytically processed intracellularly during biosynthesis

    J Biol Chem

    (1999)
  • P. Stralin et al.

    Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells

    Atherosclerosis

    (2000)
  • R. Liu-Bryan et al.

    Monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals, inflammation, and cellular signaling

    Joint Bone Spine

    (2005)
  • P.M. Reuben et al.

    Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals. Role of calcium-dependent protein kinase C alpha

    J Biol Chem

    (2002)
  • B. Halliwell et al.

    Free radicals, antioxidants and human disease. Where are we now?

    J Lab Clin Med

    (1992)
  • H. Sakurai et al.

    Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides

    J Clin Invest

    (1995)
  • S.L. Marklund et al.

    Superoxide dismutase isoenzymes of the synovial fluid in rheumatoid arthritis and in reactive arthritides

    Ann Rheum Dis

    (1986)
  • J.K. Sandhu et al.

    Distribution of protein nitrotyrosine in synovial tissues of patients with rheumatoid arthritis and osteoarthritis

    J Rheumatol

    (2003)
  • M. Mathy-Hartert et al.

    Reactive oxygen species downregulate the expression of pro-inflammatory genes by human chondrocytes

    Inflamm Res

    (2003)
  • A.D. Ross et al.

    Enhancement of collagen-induced arthritis in mice genetically deficient in extracellular superoxide dismutase

    Arthritis Rheum

    (2004)
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