How do osteoclasts generate energy to maintain bone resorption within a hypoxic environment?
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1
University of Oxford, Botnar Research Centre, NDORMS, United Kingdom
Bone resorption is an energy-intensive process mediated by osteoclasts, the activity of which increases in a hypoxic environment (Knowles & Athanasou, J Pathol 218:256; 2009). Osteoclasts exhibit increased citric acid cycle and mitochondrial respiration rates in order to generate ATP for the energy-intensive resorption process (Kim et al, Cell Physiol Biochem 20:935, 2007). We have investigated whether osteoclasts are able to meet their hypoxic energy requirements by switching to anaerobic glycolysis, as is the case for monocytes / macrophages and other cells of the haematopoietic lineage (Cramer et al, Cell 112:645; 2003). {BR}Osteoclasts were differentiated from CD14+ PBMC with M-CSF (25 ng/ml) and RANKL (50 ng/ml) for 16 days. An Illumina HumanWG-6 v3.0 48k array performed on 6 paired samples of normoxic versus hypoxic (2% O2, 24 h) osteoclasts identified hypoxic induction of a range of glycolytic enzymes (e.g. LDHA, PGK1, PFKFB3, ENO2), subsequently confirmed by real-time PCR. Hypoxic over-expression of the glucose transporter, Glut-1, was also evident at both the mRNA and protein level. Hypoxia resulted in a 2.1-fold increase in glucose consumption (p<0.05), a 2.3-fold increase in lactate production (p<0.001) and a 2.1-fold increase in complex I activity (p<0.05). Exposure of mature osteoclasts to the glycolytic inhibitor 2-deoxy-d-glucose resulted in significant cell death after 24h (22% reduction, 10mM 2DG, p<0.01), whereas the same concentration of glucose increased osteoclast numbers 2-fold (p<0.001). Compared with either their monocytic precursors or osteoblastic cells (no change in cell number), osteoclasts exhibited extreme sensitivity to hypoxia-induced cell death (68% reduction in cell number after 72h at 2% O2, p<0.001).{BR}The lack of hypoxic effect on the 'lactate production':'glucose consumption' ratio and increased activity within the mitochondrial electron transport chain suggests that osteoclasts do not switch to anaerobic glycolysis, but that hypoxia instead initiates an increase in activity throughout the respiratory chain. Increased glucose utilisation within a low energy environment will rapidly deplete local substrate stores, possibly explaining osteoclast sensitivity to hypoxia-induced cell death. These results suggest a potential mechanism whereby osteoclasts are able to generate sufficient energy, in the short term, to mediate pathological levels of bone resorption within a hypoxic environment.
Keywords:
Bones,
Bone Research
Conference:
2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society, Cambridge, United Kingdom, 27 Jun - 29 Jun, 2011.
Presentation Type:
Oral
Topic:
Abstracts
Citation:
Knowles
H and
Athanasou
N
(2011). How do osteoclasts generate energy to maintain bone resorption within a hypoxic environment?.
Front. Endocrinol.
Conference Abstract:
2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society.
doi: 10.3389/conf.fendo.2011.02.00036
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Received:
30 Sep 2011;
Published Online:
30 Sep 2011.
*
Correspondence:
Dr. HJ Knowles, University of Oxford, Botnar Research Centre, NDORMS, Oxford, United Kingdom, helen.knowles@ndorms.ox.ac.uk