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J. Biol. Chem., Vol. 280, Issue 52, 42952-42959, December 30, 2005

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The P2X₇ Nucleotide Receptor Mediates Skeletal Mechanotransduction^*

Jiliang Li1, Dawei Liu1, Hua Zhu Ke¶, Randall L. Duncan, and Charles H. Turner||2

From the Department of Anatomy and Cell Biology and Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, the ^¶Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, and the ^||Biomechanics and Biomaterials Research Center, Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202

The P2X₇ nucleotide receptor (P2X₇R) is an ATP-gated ion channel expressed in many cell types including osteoblasts and osteocytes. Mice with a null mutation of P2X₇R have osteopenia in load bearing bones, suggesting that the P2X₇R may be involved in the skeletal response to mechanical loading. We found the skeletal sensitivity to mechanical loading was reduced by up to 73% in P2X₇R null (knock-out (KO)) mice. Release of ATP in the primary calvarial osteoblasts occurred within 1 min of onset of fluid shear stress (FSS). After 30 min of FSS, P2X₇R-mediated pore formation was observed in wild type (WT) cells but not in KO cells. FSS increased prostaglandin (PG) E₂ release in WT cells but did not alter PGE₂ release in KO cells. Studies using MC3T3-E1 osteoblasts and MLO-Y4 osteocytes confirmed that PGE₂ release was suppressed by P2X₇R blockade, whereas the P2X₇R agonist BzATP enhanced PGE₂ release. We conclude that ATP signaling through P2X₇R is necessary for mechanically induced release of prostaglandins by bone cells and subsequent osteogenesis.

Received for publication, June 13, 2005 , and in revised form, September 29, 2005.

^* This work was supported by National Institutes of Health Grants R01AR046530 (to C. H. T.), RO1AR43222 (to R. L. D.), and P01AR045218 (to R. L. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both of these authors contributed equally.

² To whom correspondence should be addressed. Tel.: 317-274-3226; Fax: 317-274-3702; E-mail: turnerch{at}iupui.edu.

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