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First published on June 9, 2006; DOI: 10.1124/mol.106.024398

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Received for publication March 14, 2006.
Revised June 6, 2006.
Accepted for publication June 9, 2006.

A Molecular Mechanism of Pyruvate Protection against Cytotoxicity of Reactive Oxygen Species in Osteoblasts

Eiichi Hinoi 1, Takeshi Takarada 1, Yuriko Tsuchihashi 1, Sayumi Fujimori 1, Nobuaki Moriguchi 1, Liyang Wang 1, Kyosuke Uno 1, Yukio Yoneda 1*

1 Kanazawa University Graduate School of Natural Science and Technology

* Address correspondence to: E-mail: yyoneda{at}p.kanazawa-u.ac.jp

Abstract

We previously demonstrated that exogenous pyruvate has a protective action against cell death by hydrogen peroxide in cultured osteoblasts through a mechanism associated with its anti-oxidative property. In the present study, we have evaluated possible participation of monocaroboxylate transporters (MCTs) responsible for the bi-directional membrane transport of pyruvate in the cytoprotective property in osteoblasts. Expression of 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, while pyruvate was released into extracellular spaces from cultured osteoblasts in a fashion sensitive to the MCT inhibitor. Transient overexpression of 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, while daily intraperitoneal 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.


Key words: Organic anion, Immunocytochemistry, In situ hybridization, Oxidative stress/antioxidants, Overexpression


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