title: Glucose-dependent regulation of osteoclast H(+)-ATPase expression: potential role of p38 MAP-kinase.
abstract: Bone resorption is glucose concentration dependent. Mechanisms regulating glucose-dependent increases in bone resorption have not been identified. Glucose activates p38 MAP-kinase in other cells and since MAP kinases activate transcription factors, we hypothesized that glucose-stimulated bone resorption may be modulated by increased expression of the vacuolar H(+)-ATPase. Glucose activates osteoclast p38 MAP-kinase in a time and concentration-dependent manner as determined by Western analysis with phospho-specific p38 antibody while total p38 levels are unchanged. The K0.5 for glucose-dependent activation of p38 MAP-kinase is approximately 7 mM, activation is maximal at 30 min and is elevated but returning to basal levels by 60 min. The concentration-dependent increase in H(+)-ATPase expression was confirmed by Northern analysis. The specific inhibitor of p38 MAP-kinase, SB203580, inhibited glucose transport in osteoclasts, as well as glucose concentration-dependent increases in bone resorption and expression of H(+)-ATPase A and B subunits. Glucose had no effect on calmodulin expression levels that are regulated in response to other environmental changes. The glucose-stimulated increase in H(+)-ATPase mRNA expression is a specific response to glucose since glucose has little effect on G3PDH mRNA levels. We conclude that glucose regulates osteoclast H(+)-ATPase expression by a mechanism likely to involve p38 MAP-kinase.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Kirsten I
authors.initials: KI
authors.lastname: Larsen
authors.forename: Marina L
authors.initials: ML
authors.lastname: Falany
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Ponomareva
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
mesh_terms: D000818:Animals; D001692:Biological Transport; D001717:Birds; D015152:Blotting, Northern; D015153:Blotting, Western; D001862:Bone Resorption; D002147:Calmodulin / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010010:Osteoclasts / Q000201:enzymology* / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002147:Calmodulin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006180:Proton-Translocating ATPases; D005947:Glucose; C093642:SB 203580