REDUCED CARTILAGE PROTEOGLYCAN LOSS DURING ZYMOSAN-INDUCED GONARTHRITIS IN NOS2-DEFICIENT MICE AND IN ANTI-INTERLEUKIN-1-TREATED WILD-TYPE MICE WITH UNABATED JOINT INFLAMMATION

Objective. To investigate the role of nitric oxide (NO) and interleuki n-l in (IL-1) joint inflammation and cartilage destruction during zymo san-induced gonarthritis (ZIA). Methods. Monarticular arthritis was el icited by intraarticular injection of zymosan. The effect of NO defici ency on arthritis was studied in mice with genetically disrupted NOS2, The role of IL-1 nas examined by treating wild-type mice with neutral izing anti-murine IL-1(alpha+beta) antibodies, Joint swelling was meas ured externally by the increased uptake of circulating (99m)technetium pertechnetate. Proteoglycan (PG) synthesis was assessed using S-35-su lfate incorporation into patellae ex vivo, Histology evaluated exudati on and infiltration of leukocytes and the extent of cartilage destruct ion, Results. The proinflammatory mediators NO, IL-1, and IL-6 were re leased by the articular tissues during the first hours of inflammation , Interestingly, anti-IL-l treatment moderately reduced, and NOS2 defi ciency moderately enhanced, joint swelling, However, the influx of neu trophils into the joint occurred independently of IL-1 and NOS2 activi ties, In the first week of inflammation, chondrocyte PG synthesis was significantly suppressed and chondrocytes became unresponsive to their essential anabolic factor, insulin-like growth factor I (IGF-I), Anti -IL-1 treatment or NOS2 deficiency prevented the inhibition of PG synt hesis, and the chondrocytes remained IGF-1 responsive, Intraarticular injections of IL-1 alpha into NOS2-deficient mice did not affect PG sy nthesis, thus proving that NO mediated this IL-1 effect in vivo, Furth ermore, histology showed that cartilage PG loss was markedly ameliorat ed in NOS2-deficient and anti-IL-1-treated mice, Intermediate cartilag e pathology was found in mice that were heterozygous for disrupted NOS 2. Conclusion. IL-1 and NO play a minor role in edema and neutrophil i nflux, but a major role in cartilage destruction of ZIA. In this model of murine arthritis, cartilage destruction was, for the most part, ca used by pronounced suppression of PG synthesis and IGF-1 unresponsiven ess of the chondrocytes, which were induced by de novo-synthesized IL- 1 and were mediated by NOS2 activation.