title: Differential regulation of HIF-mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts.
abstract: Inappropriate osteoclast activity instigates pathological bone loss in rheumatoid arthritis. We have investigated how osteoclasts generate sufficient ATP for the energy-intensive process of bone resorption in the hypoxic microenvironment associated with this rheumatic condition. We show that in human osteoclasts differentiated from CD14(+) monocytes, hypoxia (24 h, 2% O2 ): (a) increases ATP production and mitochondrial electron transport chain activity (Alamar blue, O2 consumption); (b) increases glycolytic flux (glucose consumption, lactate production); and (c) increases glutamine consumption. We demonstrate that glucose, rather than glutamine, is necessary for the hypoxic increase in ATP production and also for cell survival in hypoxia. Using siRNA targeting specific isoforms of the hypoxia-inducible transcription factor HIF (HIF-1α, HIF-2α), we show that employment of selected components of the HIF-1α-mediated metabolic switch to anaerobic respiration enables osteoclasts to rapidly increase ATP production in hypoxia, while at the same time compromising long-term survival. We propose this atypical HIF-driven metabolic pathway to be an adaptive mechanism to permit rapid bone resorption in the short term while ensuring curtailment of the process in the absence of re-oxygenation.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, The Womens Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Morten
authors.forename: Luned
authors.initials: L
authors.lastname: Badder
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Knowles
mesh_terms: D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D045222:Electron Transport Chain Complex Proteins; D005947:Glucose; D005973:Glutamine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D011768:Pyruvate Dehydrogenase Complex; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human