Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody‐driven K/BxN serum–transfer arthritis

Objective Prostaglandins (PGs) are found in high levels in the synovial fluid of patients with rheumatoid arthritis, and nonsteroidal blockade of these bioactive lipids plays a role in patient care. The aim of this study was to explore the relative contribution of cyclooxygenase (COX) isoforms and PG species in the autoantibody-driven K/BxN serum–transfer arthritis. Methods The prostanoid content of arthritic ankles was assessed in ankle homogenates, and the importance of this pathway was confirmed with pharmacologic blockade. The presence of COX isoforms was assessed by Western blotting and their functional contribution was compared using COX-1−/− and COX-2−/− mice as well as isoform-specific inhibitors. The relative importance of PGE2 and PGI2 (prostacyclin) was determined using mice deficient in microsomal PGE synthase 1 (mPGES-1) and in the receptors for PGI2. Results High levels of PGE2 and 6-keto-PGF1α (a stable metabolite of PGI2) were detected in arthritic joint tissues, correlating strongly with the intensity of synovitis. Pharmacologic inhibition of PG synthesis prevented arthritis and ameliorated active disease. While both COX isoforms were found in inflamed joint tissues, only COX-1 contributed substantially to clinical disease; COX-1−/− mice were fully resistant to disease, whereas COX-2−/− mice remained susceptible. These findings were confirmed by isoform-specific pharmacologic inhibition. Mice lacking mPGES-1 (and therefore PGE2) developed arthritis normally, whereas mice incapable of responding to PGI2 exhibited a significantly attenuated arthritis course, confirming a role of PGI2 in this arthritis model. Conclusion These findings challenge previous paradigms of distinct “housekeeping” versus inflammatory functions of the COX isoforms and highlight the potential pathogenic contribution of prostanoids synthesized via COX-1, in particular PGI2, to inflammatory arthritis.