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Effects of cobalt and chromium ions on glycolytic flux and the stabilization of hypoxia-inducible factor-1alpha in macrophages in vitro #MMPMID32462687
Salloum Z; Lehoux EA; Harper ME; Catelas I
J Orthop Res 2021[Jan]; 39 (1): 112-120 PMID32462687show ga
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(2+) and Cr(3+) 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-1alpha (HIF-1alpha)-dependent metabolic shift from oxidative phosphorylation (OXPHOS) towards glycolysis. However, the potential of Co(2+) and Cr(3+) to induce this metabolic shift, which plays a determining role in the proinflammatory response of macrophages, remains largely unexplored. We recently demonstrated that Co(2+) , but not Cr(3+) , increased oxidative stress and decreased OXPHOS in RAW 264.7 murine macrophages. In the present study, we analyzed the effects of Co(2+) and Cr(3+) on glycolytic flux and HIF-1alpha stabilization in the same experimental model. Cells were exposed to 6 to 24 ppm Co(2+) or 50 to 250 ppm Cr(3+) . Glycolytic flux was determined by analyzing extracellular flux and lactate production, while HIF-1alpha stabilization was analyzed by immunoblotting. Results showed that Co(2+) , and to a lesser extent Cr(3+) , increased glycolytic flux; however, only Co(2+) acted through HIF-1alpha stabilization. Overall, these results, together with our previous results showing that Co(2+) increases oxidative stress and decreases OXPHOS, suggest that Co(2+) (but not Cr(3+) ) can induce a HIF-1alpha-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(2+) in the periprosthetic environment.
J+Orthop+Res 2021 ; 39 (1): 112-120
