Faculty Bibliography

Targeted tumor necrosis factor-alpha antagonists, first approved by the FDA in 1998, have had a significant impact on the treatment of patients with rheumatoid arthritis. In general, the benefit/ risk ratio for these agents and the IL-1 receptor antagonist, anakinra, has been quite favorable. However, infrequent adverse events can be serious and require continued pharmacovigilance. Infections, particularly tuberculosis and less commonly fungal infections, are among the most serious adverse events, especially given delays in diagnosis due to subtle or atypical presentations. Questions have also arisen regarding whether anti-TNF-alpha agents increase the risk of lymphoma, a complicated issue confounded by the multiple risk factors for lymphoma in patients with rheumatoid arthritis and low observed incidence rates of lymphoma, requiring prolonged monitoring. Additional rare reported complications include systemic lupus erythematosus-like syndromes, congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy). Ongoing post-marketing surveillance of these and other serious adverse events is necessary to determine the true incidence rates, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required

OBJECTIVE: In the current studies we have examined the effects of nitric oxide, and its redox derivatives peroxynitrite and S-nitrosothiol, S-nitrosocysteine, on nuclear factor kappaB (NF-kappaB) activation in cytokine-stimulated bovine chondrocytes. METHODS: The kinetics of NF-kappaB activation (p65 nuclear translocation) were assessed by immunofluorescence and immunoblot assays. RESULTS: We observed that the two nitric oxide redox species, peroxynitrite and S-nitrosocysteine, exert opposing effects on NF-kappaB activation. However, in lipopolysaccharide (LPS)/cytokine-stimulated chondrocytes (LPS, IL-1beta and TNF-alpha (LIT)) in the presence or absence of the NOS inhibitor L-NG-monomethyl arginine citrate (L-NMMA), the results indicate that nitric oxide causes persistent activation of NF-kappaB, most likely via generation of the free radical derivative peroxynitrite. CONCLUSION: The studies indicate that while nitric oxide is not required for immediate NF-kappaB activation in cytokine-stimulated chondrocytes, its effect is to sustain nuclear translocation of p65 and thereby provide a persistent 'on signal' to NF-kappaB dependent gene transcription. Persistent activation of NF-kappaB may represent a mechanism by which nitric oxide sustains catabolic processes and promotes cartilage degeneration in osteoarthritis

1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated