Influence of oxygen tension on interleukin 1-induced peroxynitrite formation and matrix turnover in articular cartilage.
OBJECTIVE: Osteoarthritis is characterized by the degradation of articular cartilage. The catabolic activity of chondrocytes is partly regulated by nitric oxide (NO), which with superoxide (O2-) leads to the formation of peroxynitrite (OONO-), a potentially damaging reactive species. Cartilage is avascular and functions at reduced oxygen tension. We investigated whether oxygen tension influences the effects of interleukin 1 (IL-1) on peroxynitrite formation and cartilage matrix metabolism. METHODS: Porcine cartilage explants were incubated at either 1% O2 or 20% O2 with either 1 ng/ml IL-1alpha, 25 microM MnTE-2-PyP5+ [Mn porphyrin-based catalytic antioxidant, Mn(III) tetrakis(N-ethylpyridinium-2-yl)porphyrin], or 1 ng/ml IL-1 + 25 microM MnTE-2-PyP5+ to decrease peroxynitrite formation. Nitrotyrosine, formed by nitration of tyrosine by peroxynitrite, was measured by immunoblot. Proteoglycan and collagen synthesis and proteoglycan degradation were also determined. RESULTS: IL-1-induced peroxynitrite formation was decreased in 1% O2 as compared to 20% O2. MnTE-2-PyP5+ inhibited IL-1-induced peroxynitrite formation in either 1% O2 or 20% O2. In 1% O2 (but not in 20% O2), Mn porphyrin significantly inhibited IL-1-induced proteoglycan degradation. IL-1 decreased both proteoglycan and collagen II synthesis in cartilage explants in 1% O2 or 20% O2, but MnTE-2-PyP5+ did not prevent these anti-anabolic effects. MnTE-2-PyP5+ alone caused a significant decrease in collagen synthesis at 20% O2 but not at 1% O2. CONCLUSION: Our findings show that oxygen tension alters IL-1-induced peroxynitrite formation, which can influence proteoglycan degradation. Oxygen tension may influence the effects of reactive oxygen and nitrogen species on matrix homeostasis.
Cernanec, JM; Weinberg, JB; Batinic-Haberle, I; Guilak, F; Fermor, B
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