Effects of cobalt and chromium ions on glycolytic flux and the stabilization of hypoxia-inducible factor-1α in macrophages in vitro.

Implant wear and corrosion have been associated with adverse tissue reactions that can lead to implant failure. Wear and corrosion products are therefore of great clinical concern. For example, Co and Cr originating from CoCrMo-based implants have been shown to induce a proinflammatory response in macrophages in vitro. Previous studies have also shown that the polarization of macrophages by some proinflammatory stimuli is associated with a hypoxia-inducible factor-1α (HIF-1α)-dependent metabolic shift from oxidative phosphorylation (OXPHOS) towards glycolysis. However, the potential of Co and Cr to induce this metabolic shift, which plays a determining role in the proinflammatory response of macrophages, remains largely unexplored. We recently demonstrated that Co , but not Cr , increased oxidative stress and decreased OXPHOS in RAW 264.7 murine macrophages. In the present study, we analyzed the effects of Co and Cr on glycolytic flux and HIF-1α stabilization in the same experimental model. Cells were exposed to 6 to 24 ppm Co or 50 to 250 ppm Cr . Glycolytic flux was determined by analyzing extracellular flux and lactate production, while HIF-1α stabilization was analyzed by immunoblotting. Results showed that Co , and to a lesser extent Cr , increased glycolytic flux; however, only Co acted through HIF-1α stabilization. Overall, these results, together with our previous results showing that Co increases oxidative stress and decreases OXPHOS, suggest that Co (but not Cr ) can induce a HIF-1α-dependent metabolic shift from OXPHOS towards glycolysis in macrophages. This metabolic shift may play an early and pivotal role in the inflammatory response induced by Co in the periprosthetic environment.