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(American Journal of Pathology. 2003;163:1525-1537.)
© 2003 American Society for Investigative Pathology

Deficiency of NADPH Oxidase Components p47phox and gp91phox Caused Granulomatous Synovitis and Increased Connective Tissue Destruction in Experimental Arthritis Models

Fons A. J. van de Loo*, Miranda B. Bennink*, Onno J. Arntz*, Ruben L. Smeets*, Erik Lubberts*, Leo A. B. Joosten*, Peter L. E. M. van Lent*, Christina J. J. Coenen-de Roo{dagger}, Salvatore Cuzzocrea{ddagger}, Brahm H. Segal§, Steven M. Holland§ and Wim B. van den Berg*

From the Department of Rheumatology,* University Medical Center Nijmegen, Nijmegen, The Netherlands; N.V. Organon,{dagger} Oss, The Netherlands; the Institute of Pharmacology,{ddagger} School of Medicine, University of Messina, Messina, Italy; and the Laboratory of Host Defenses,§ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox-/- and gp91-/- mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-{alpha}, interleukin-1{alpha}, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-{kappa}B ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.




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