Abstract
Poly(ADPR) polymerase (PARP; EC 2.4.2.30) is a nuclear enzyme, which, when activated by oxygen- and nitrogen-radical-induced DNA strand breaks, transfers ADP ribose units to nuclear proteins and initiates apoptosis by depletion of cellular NAD and ATP pools. The present study investigates whether the oxidative stressdependent activation of PARP plays a role in the etiopathogenesis of arthritis. The antiarthritic reactivity of the biogenic PARP inhibitor nicotinamide was tested in DBA/1 × B10A(4R) mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 4 mmol/kg of NA suppressed the arthritis by 35% and inhibited the phagocytic generation of reactive oxygen species, which increases sixfold during the development of arthritis. The onset, progression, and remission of arthritis correlated positively to the phorbolester-activated respiratory burst of neutrophils and monocytes, and a dose-dependent inhibition of NADPH oxidase activity was determined with human phagocytes. Our data support the hypothesis that oxidative stressinduced alterations in cellular signal transduction pathways play a pivotal role in the development of arthritis, which can be suppressed by the simultaneous inhibition of poly(ADPR) polymerase and NADPH oxidase.
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Althaus, F. R., S. D. Lawrence, Y. Z. He, G. L. Sattler, Y. Tsukada, andH. C. Pitot. 1982. Effects of altered (ADP-ribose)n metabolism on expression of fetal functions by adult hepatocytes.Nature 300:366–368.
Zhang, J., V. L. Dawson, T. M. Dawson, andS. H. Snyder. 1994. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity.Science 263:687–689.
Hoshino, J., G. Beckman, andH. Kröger. 1993. 3-Aminobenzamide protects the mouse thymocytes in vitro from dexamethasone-mediated apoptotic cell death and cytolysis without changing DNA strand breakage.J. Steroid Mol. Biol. 44:113–119.
Cerutti, P. A. 1985. Prooxidant states and tumor promotion.Science 227:375–381.
Miesel, R., H. Kröger, M. Zuber, R. Grätz, andJ. Neth. 1994. Elevated levels of oxygenand nitrogen-centered radicals in patients with rheumatic diseases.Z. Rheumatol. 53:6.
Miesel, R., andM. Zuber, 1993. Reactive nitrogen intermediates, antinuclear antibodies and copper-thionein in serum of patients with rheumatic diseases.Rheumatol. Int. 13:95–102.
Okolie, E. E., andS. Shall. 1979. The significance of antibodies to poly(adenosine diphosphate ribose) in systemic lupus erythematosus.Clin. Exp. Immunol. 36:151–164.
Altmann, H. 1983. Poly-(ADP-ribose-)Synthese und Regulationsstörungen bei Erkrankungen [Poly-(ADP-Ribose)-synthesis and defects in the regulation of DNA metabolism connected to human diseases].Wiener Klin. Wochenschr. 24:861–864.
Kanai, Y., Y. Kawamini, M. Miwa, T. Matsushima, T. Sugimura, Y. Moroi, andR. Yokohari. 1977. Naturally occurring antibodies to poly(ADP-ribose) in patients with systemic lupus erythematosus.Nature 265:175–177.
Miesel, R., M. Zuber, D. Sanocka, R. Grätz, andH. Kröger. 1994. The effects of allopurinol on thein vivo suppression of arthritis in mice and theex vivo modulation of the phagocytic production of oxygen radicals in whole human blood.Inflammation 18:597–611.
Miesel, R., andR. Haas. 1993. Reactivity of an active center analogue of Cu2Zn2 Superoxide dismutase in a murine model of acute and chronic inflammation.Inflammation 17:595–611.
Miesel, R., H. Kröger, N. Ulbrich, andM. Kurpisz. 1994. Arthritogenic reactivity of chromium(V).Z. Rheumatol. 53:59.
Miesel, R., D. Sanocka, M. Kurpisz, andH. Kröger. 1995. Anti-arthritic reactivity of NADPH oxidase inhibitors.Inflammation 19:347–362.
Miesel, R., A. Dietrich, B. Brandl, N. Ulbrich, M. Kurpisz, andH. Kröger. 1994. Suppression of arthritis by an active center analogue of Cu2Zn2 Superoxide dismutase.Rheumatol. Int. 14:119–126.
Marcus, R., andA. M. Coulston. 1985. The vitamins.In The Pharmacological Basis of Therapeutics, 7th ed. A. Goodman Gilman, L. S. Goodman, T. W. Rall, and R. Murad, editor.) Macmillan New York. 1557–1559.
Miesel, R., N.Ulbrich, H.Kröger, and A.Mitchison. 1995. Assessment of collagen type II induced arthritis in mice by whole blood chemiluminescence.Autoimmunity (in press).
Miesel, R., andU. Weser. 1988. Reactivity of active centre analogues of Cu2Zn2 Superoxide dismutase during the aqueous decay of K3CrO8.Inorg. Chim. Acta 160:119–121.
Wooley, P. H., H. S. Luthra, J. M. Stuart, andC. S. David. 1981. Type II collageninduced arthritis in mice. Major histocompatibility complex (I region) linkage and antibody response.J. Exp. Med. 154:688–700.
Agarwal, S., andN. P. Piesco. 1994. Poly ADP-ribosylation of a 90-kDa protein is involved in TNF-alpha-mediated cytotoxicity.J. Immunol. 153:473–481.
Elliott, M. J., R. M. Maini, M. Feldmann, A. Long-Fox, P. Charles, andF. M. Breman. 1993. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNFα. Safety, clinical efficacy and regulation of the acute phase response.Br. J. Rheumatol. 32:209–216.
Aloe, L., L. Probert, G. Kollias, L. Bracci-Laudieri, M. G. Spillantini, andR. Levi-Montalcini. 1993. The synovium of transgenic arthritic mice expressing human tumor necrosis factor contains a high level of nerve growth factor.Growth Factors 9:149–155.
Pellat-Deceunynck, C., J. Wietzerbin, andJ. C. Drapier. 1994. Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages.Biochem. J. 297:53–58.
Stockett, P., andJ. Stavnezer. 1994. Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching.J. Immunol. 151:6962–6976.
Ayer, L. M., S. M. Edworthy, andM. J. Fritzler. 1994. Effect of procainamide and hydralazine on poly(ADP-ribosylation) in cell lines.Lupus 2:167–172.
Halldorsson, H., T. Bodvarsdottir, M. Kjeld, andG. Thorgeirsson. 1992. Role of ADP-ribosylation in endothelial signal transduction and prostacyclin production.FEBS Lett. 314:322–326.
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Miesel, R., Kurpisz, M. & Kröger, H. Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase. Inflammation 19, 379–387 (1995). https://doi.org/10.1007/BF01534394
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DOI: https://doi.org/10.1007/BF01534394