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Bone Abstracts (2014) 3 OC3.2 | DOI: 10.1530/boneabs.3.OC3.2

Osteoclasts, gastric hormones and HIF

Activation of the P2Y2 receptor enhances osteoclast function by stimulating the release of ATP, a pro-resorptive extracellular nucleotide

Isabel Orriss1, Mark Hajjawi2 & Timothy Arnett2


1The Royal Veterinary College, London, UK; 2University College London, London, UK.

Extracellular nucleotides, signalling through P2 receptors, play a significant role in bone biology. ATP and ADP act via the P2Y1 or P2Y12 receptors to promote osteoclast formation and activity. Bone cells express the P2Y2 receptor and, in osteoblasts, it plays a role in regulating bone mineralisation. This investigation examined the role of the P2Y2 receptor in osteoclasts. Primary osteoclasts were isolated from the bone marrow of 8-week WT or P2Y2 receptor knockout mice (P2Y2R−/−) and cultured on dentine discs for 9 days in the presence of 150 ng/ml M-CSF and 2 ng/ml RANKL. UTP (≧0.1 μM), the principal P2Y2 receptor agonist, increased bone resorption by 40% (P≤0.05). P2Y2R-/- osteoclasts displayed a 65% reduction in resorptive activity (P≤0.001); osteoclast number was unchanged. Osteoclasts constitutively release ATP into the extracellular environment where it acts locally to stimulate resorption. We found that ATP release was reduced 60% in P2Y2R−/− osteoclasts (P≤0.001). To investigate whether decreased levels of extracellular ATP were causing the reduction in osteoclast function, P2Y2R−/− cells were cultured with exogenous ATP (1–10 μM). Addition of ATP to the culture medium fully rescued the bone resorption defect in P2Y2R-/- osteoclasts. We found that UTP, (≧10 μM), stimulated ATP release from osteoclasts by up to fourfold (P≤0.001). The enhanced ATP release was evident from 10 min after UTP treatment and was sustained for up to 90 min. The stimulatory action of UTP on ATP release was mediated via the P2Y2 receptor, since UTP failed to induce ATP release in P2Y2R−/− osteoclasts. MicroCT analysis of P2Y2R−/− mice demonstrated an increased trabecular bone volume (20%, P<0.001) and trabecular number (25%, P<0.01) in the long bones. Taken together, these data suggest the P2Y2 receptor regulates osteoclast function indirectly by promoting ATP release. Once released, ATP and its breakdown product, ADP, can act via other P2Y receptors to increase bone resorption.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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