MODULATION OF INFLAMMATORY ARTHRITIS BY INHIBITION OF POLY(ADP RIBOSE) POLYMERASE

Poly(ADPR) polymerase (PARP; EC 2.4.2.30) is a nuclear enzyme, which, when activated by oxygen- and nitrogen-radical-induced DNA strand brea ks, transfers ADP ribose units to nuclear proteins and initiates apopt osis by depletion of cellular NAD and ATP pools. The present study inv estigates whether the oxidative stress-dependent activation of PARP pl ays a role in the etiopathogenesis of arthritis. The antiarthritic rea ctivity of the biogenic PARP inhibitor nicotinamide was tested in DBA/ 1 x B10A(4R) mice suffering from potassium peroxochromate-induced arth ritis. Daily doses of 4 mmol/kg of NA suppressed the arthritis by 35% and inhibited the phagocytic generation of reactive oxygen species, wh ich increases sixfold during the development of arthritis. The onset, progression, and remission of arthritis correlated positively to the p horbolester-activated respiratory burst of neutrophils and monocytes, and a dose-dependent inhibition of NADPH oxidase activity was determin ed with human phagocytes. Our data support the hypothesis that oxidati ve stress-induced alterations in cellular signal transduction pathways play a pivotal role in the development of arthritis, which can be sup pressed by the simultaneous inhibition of poly(ADPR) polymerase and NA DPH oxidase.