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Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

Orriss, I R; Gueneri, D; Hajjawai, M O; Shaw, K; Patel, J J; Arnett, T R


I R Orriss

D Gueneri

M O Hajjawai

K Shaw

J J Patel

T R Arnett


Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y2 receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y2 receptor knockout (P2Y2R−/−) mouse model to investigate the role of this receptor in bone. MicroCT analysis of P2Y2R−/− mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%). In vitro P2Y2R−/− osteoblasts displayed a 3-fold increase in bone formation and alkaline phosphatase activity, whilst P2Y2R−/− osteoclasts exhibited a 65% reduction in resorptive activity. Serum cross-linked C-telopeptide levels (CTX, resorption marker) were also decreased (≤35%). The resorption defect in P2Y2R−/− osteoclasts was rescued by the addition of exogenous ATP, suggesting that an ATP deficit could be a key factor in the reduced function of these cells. In agreement, we found that basal ATP release was reduced up to 53% in P2Y2R−/− osteoclasts. The P2Y2 receptor agonists, UTP and 2-thioUTP, increased osteoclast activity and ATP release in wild-type but not in P2Y2R−/− cells. This indicates that the P2Y2 receptor may regulate osteoclast function indirectly by promoting ATP release. UTP and 2-thioUTP also stimulate ATP release from osteoblasts suggesting that the P2Y2 receptor exerts a similar function in these cells. Taken together, our findings are consistent with the notion that the primary action of P2Y2 receptor signalling in bone is to regulate extracellular ATP levels.


Orriss, I. R., Gueneri, D., Hajjawai, M. O., Shaw, K., Patel, J. J., & Arnett, T. R. (2017). Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release. Journal of Endocrinology, 233, 341-356.

Journal Article Type Article
Acceptance Date Apr 18, 2017
Publication Date Jun 1, 2017
Deposit Date Apr 20, 2017
Publicly Available Date May 1, 2018
Print ISSN 0022-0795
Publisher BioScientifica
Peer Reviewed Peer Reviewed
Volume 233
Pages 341-356
Public URL


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