The P2X7 Nucleotide Receptor Mediates Skeletal Mechanotransduction

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 f...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-12, Vol.280 (52), p.42952-42959
Main Authors: Li, Jiliang, Liu, Dawei, Ke, Hua Zhu, Duncan, Randall L., Turner, Charles H.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Apoptosis
Blotting, Western
Bone and Bones - metabolism
Bone Diseases, Metabolic - pathology
Bone Regeneration
Caspase 3
Caspases - metabolism
Dinoprostone - metabolism
Ion Channels - chemistry
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Models, Biological
Osteoblasts - metabolism
Osteocytes - metabolism
Radius - metabolism
Receptors, Prostaglandin E - metabolism
Receptors, Purinergic P2 - metabolism
Receptors, Purinergic P2 - physiology
Receptors, Purinergic P2X7
Signal Transduction
Stress, Mechanical
Time Factors
Ulna - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M506415200