Influence of hypoxia and reoxygenation on cytokine‐induced production of proinflammatory mediators in articular cartilage

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Abstract
Objective: Articular cartilage is an avascular tissue that functions at a lower oxygen tension than do most tissues. With mobilization, arthritic joints may undergo cycles of hypoxia and reoxygenation. The goal of this study was to determine the effects of hypoxia and reoxygenation on cytokine‐induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in articular cartilage.Methods: Porcine cartilage explants were incubated at 37°C for 72 hours in either 1% O2 (hypoxia) or 20% O2 (normoxia) in media supplemented with interleukin‐1α (IL‐1α) or tumor necrosis factor α (TNFα), with or without the NO synthase 2 (NOS2) selective inhibitor 1400W. Culture media were then removed and replaced with freshly prepared media and incubated for a further 24 hours in normoxia.Results: NO levels were significantly higher in explants supplemented with IL‐1α and TNFα compared with controls, in both hypoxia and normoxia. Compared with normoxia, hypoxia decreased IL‐1α– and TNFα‐induced NO production significantly. Reoxygenation of hypoxic explants resulted in sustained significant NO production in response to either cytokine. However, comparably high levels of NO production were not sustained in explants cultured continuously in normoxia. Although IL‐1α alone did not significantly increase PGE2 production, significant PGE2 superinduction occurred in cartilage stimulated with IL‐1α and the NOS2 inhibitor 1400W compared with stimulation with IL‐1α alone in hypoxia, but not in normoxia.Conclusion: Oxygen tension significantly affects cytokine‐induced proinflammatory mediator production in articular cartilage. Furthermore, hypoxia alters NO mediation of PGE2 production. Hypoxia and reoxygenation can affect cytokine‐induced proinflammatory mediator production, suggesting that oxygen tension may influence inflammation associated with cartilage injury and disease.