RT Journal Article
SR Electronic
T1 A Molecular Mechanism of Pyruvate Protection against Cytotoxicity of Reactive Oxygen Species in Osteoblasts
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 925
OP 935
DO 10.1124/mol.106.024398
VO 70
IS 3
A1 Eiichi Hinoi
A1 Takeshi Takarada
A1 Yuriko Tsuchihashi
A1 Sayumi Fujimori
A1 Nobuaki Moriguchi
A1 Liyang Wang
A1 Kyosuke Uno
A1 Yukio Yoneda
YR 2006
UL http://molpharm.aspetjournals.org/content/70/3/925.abstract
AB We demonstrated previously that exogenous pyruvate has a protective action against cell death by hydrogen peroxide in cultured osteoblasts through a mechanism associated with its antioxidative property. In the present study, we have evaluated possible participation of monocarboxylate transporters (MCTs) responsible for the bidirectional membrane transport of pyruvate in the cytoprotective property in osteoblasts. Expression of the MCT2 isoform was found in cultured rat calvarial osteoblasts and in osteoblasts located on mouse tibia at both mRNA and protein levels. The accumulation of [14C]pyruvate occurred in a temperature- and pH-dependent manner in osteoblasts cultured for 7 days with high sensitivity to a specific MCT inhibitor, whereas pyruvate was released into extracellular spaces from cultured osteoblasts in a fashion sensitive to the MCT inhibitor. Transient overexpression of the MCT2 isoform led to reduced vulnerability to the cytotoxicity of hydrogen peroxide with an increased activity of [14C]pyruvate accumulation in murine osteoblastic MC3T3-E1 cells. Ovariectomy significantly decreased the content of pyruvate in femoral bone marrows in mice in vivo, whereas daily i.p. administration of pyruvate at 0.25 g/kg significantly prevented alterations of several histomorphometric parameters as well as cancellous bone loss in femurs by ovariectomy on 28 days after the operation. These results suggest that MCTs may be functionally expressed by osteoblasts to play a pivotal role in mechanisms related to the cytoprotective property of pyruvate. The American Society for Pharmacology and Experimental Therapeutics