Glucose is a key metabolic regulator of osteoclasts; glucose stimulated increases in ATP/ADP ratio and calmodulin kinase II activity.
Glucose-stimulated increases in osteoclast activity are mediated, at least in part, by transcriptional regulation of H+-ATPase expression through a mechanism involving p38 mitogen-activated protein kinase. We hypothesized that early events in the glucose-dependent signaling pathway would be similar to those identified in other glucose-sensitive cells, such as islet beta-cells, including rapid changes in the cellular ATP/ADP ratio and mobilization of intracellular Ca2+. We demonstrate that glucose stimulates a prolonged 50% increase in the ATP/ADP ratio that was maximal 30 s after glucose concentrations were increased. Glucose stimulated a transient 30% increase in calcium/calmodulin-dependent kinase II (CaMK II) activity that was maximal 3 min after the glucose concentration was increased. CaMK II was activated maximally by 3 mmol D-glucose/L in 3-min assays. Activation of CaMK II in the presence of the nonmetabolizable glucose analog 2-deoxyglucose was 2-fold greater than with D-glucose but was unchanged by glucosamine. Pretreatment of osteoclasts with the intracellular Ca2+ chelator BAPTA-AM inhibited glucose transport by 75%. BAPTA-AM treatment also prevented glucose-dependent stimulation of CaMK II. The data indicate that osteoclasts utilize a glucose-sensing mechanism similar to that of beta-cells and that glucose-stimulated signaling in osteoclasts involves changes in the ATP/ADP ratio and mobilization of intracellular Ca2+, resulting in activation of CaMK II.
Larsen
Kirsten I
KI
Department of Pathology, University of Alabama, Birmingham, 918 University Blvd., AL 35294, USA.
Falany
Marina
M
Wang
Wei
W
Williams
John P
JP
D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002645:Chickens; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005947:Glucose