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Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase

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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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Authors and Affiliations

  1. Department of Biochemistry, Deutsches RheumaForschungsZentrum, Berlin, Germany

    Ralf Miesel & Hans Kröger

  2. Department of Biochemistry, University of Otago, Box 56, Dunedin, New Zealand

    Ralf Miesel

  3. Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland

    Maciej Kurpisz

Authors
  1. Ralf Miesel
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  2. Maciej Kurpisz
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  3. Hans Kröger
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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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