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 O(2)(-) 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.
Subject(s)
Oxidative Stress/physiology , Reactive Oxygen Species/metabolism , Rheumatic Diseases/enzymology , Rheumatic Diseases/physiopathology , Superoxide Dismutase/metabolism , Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/physiopathology , Biomarkers/analysis , Cytokines/metabolism , Female , Humans , Male , Nitric Oxide/metabolism , Osteoarthritis/enzymology , Osteoarthritis/physiopathology , Pain Measurement , Predictive Value of Tests , Prognosis , Risk Assessment , Severity of Illness IndexABSTRACT
Rheumatoid arthritis (RA) is characterized by fibroblast-like synoviocyte (FLS) hyperplasia, which is partly ascribable to decreased apoptosis. In this study, we show that adrenomedullin (ADM), an antiapoptotic peptide, is constitutively secreted in larger amounts by FLS from joints with RA (RA-FLS) than with osteoarthritis (OA-FLS). ADM secretion was regulated by TNF-alpha. Peptidylglycine alpha-amidating monooxygenase, the ADM-processing enzyme, was expressed at the mRNA level by both RA-FLS and OA-FLS. Constituents of the ADM heterodimeric receptor calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP)-2 were up-regulated at the mRNA and protein levels in cultured RA-FLS compared with OA-FLS. ADM induced rapid intracellular cAMP production in FLS and reduced caspase-3 activity, DNA fragmentation, and chromatin condensation in RA-FLS exposed to apoptotic conditions, indicating that CRLR/RAMP-2 was fully functional. ADM-induced cAMP production was less marked in OA-FLS than in RA-FLS, suggesting differences in receptor regulation and expression. ADM dose-dependently inhibited RA-FLS apoptosis, and this effect was reversed by the 22-52 ADM antagonist peptide. ADM inhibited RA-FLS apoptosis triggered by extrinsic and intrinsic pathways. Our data suggest that ADM may prevent or reduce RA-FLS apoptosis, via up-regulation of its functional receptor CRLR/RAMP-2. Regulation of ADM secretion and/or CRLR/RAMP-2 activation may constitute new treatment strategies for RA.
Subject(s)
Apoptosis , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Peptides/metabolism , Receptors, Calcitonin/metabolism , Synovial Membrane/metabolism , Synovial Membrane/pathology , Adenylyl Cyclases/metabolism , Adrenomedullin , Apoptosis/drug effects , Arthritis, Rheumatoid/genetics , Calcitonin Receptor-Like Protein , Cell Separation , Cells, Cultured , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Fibroblasts , Gene Expression Regulation , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Peptide Fragments/pharmacology , Peptides/genetics , Receptor Activity-Modifying Proteins , Receptors, Adrenomedullin , Receptors, Calcitonin/genetics , Receptors, Peptide/antagonists & inhibitors , Receptors, Peptide/metabolism , Signal Transduction , Synovial Membrane/drug effects , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
OBJECTIVES: We recovered an IgG1-kappa cryocrystalglobulin in synovial fluid and membrane specimens from a patient with destructive arthropathy. In the present study, we investigated its proinflammatory properties by measuring its effects on TNF-alpha production by normal human monocytes. MATERIALS AND METHODS: Normal human monocytes isolated by plastic adhesion were cultured in microtiter plates. Adherent monocytes were cultured for 6, 8, and 24 hours with sterile cryocrystalglobulin (150 microg/mL and 2 mg/mL), type I noncrystallised cryoglobulin (same concentrations), monosodium urate (MSU) crystals (2 mg/mL), LPS (10 microg/mL), or medium alone. Supernatant TNF-a concentrations were assayed using an ELISA. RESULTS: Cryocrystalglobulin had no effect on TNF-alpha production by normal human monocytes. Noncrystallised cryoglobulin increased TNF-alpha levels in supernatants in a time-dependent and concentration-dependent fashion. This increase was significantly less marked than the increases achieved with MSU crystals or LPS. CONCLUSION: IgG1kappa cryocrystalglobulin has no effect on TNF-alpha production by normal human monocytes. Fc region changes within the cryocrystalglobulin molecule may explain this finding.
