The P2X7 nucleotide receptor mediates skeletal mechanotransduction

The P2X(7) nucleotide receptor (P2X(7)R) is an ATP-gated ion channel expressed in many cell types including osteoblasts and osteocytes. Mice with a null mutation of P2X(7)R have osteopenia in load bearing bones, suggesting that the P2X(7)R 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 P2X(7)R 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, P2X(7)R-mediated pore formation was observed in wild type (WT) cells but not in KO cells. FSS increased prostaglandin ( PG) E-2 release in WT cells but did not alter PGE(2) release in KO cells. Studies using MC3T3-E1 osteoblasts and MLO-Y4 osteocytes confirmed that PGE2 release was suppressed by P2X(7)R blockade, whereas the P2X(7)R agonist BzATP enhanced PGE(2) release. We conclude that ATP signaling through P2X(7)R is necessary for mechanically induced release of prostaglandins by bone cells and subsequent osteogenesis.