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Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y₁ receptor on bone cells

ASTRID HOEBERTZ^*,, SAJEDA MEGHJI, GEOFFREY BURNSTOCK^*, and TIMOTHY R. ARNETT^*1

^* Department of Anatomy and Developmental Biology,
Cellular Microbiology Research Group, Eastman Dental Institute, and
Autonomic Neuroscience Institute, University College London, London WC1E 6BT, U.K.

¹Correspondence: Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, U.K. E-mail: t.arnett{at}ucl.ac.uk

There is increasing evidence that extracellular nucleotides act on bone cells via P2 receptors. This study investigated the action of ADP and 2-methylthioADP, a potent ADP analog with selectivity for the P2Y₁ receptor, on osteoclasts, the bone-resorbing multinuclear cells. Using three different assays, we show that ADP and 2-methylthioADP at nanomolar to submicromolar levels caused up to fourfold to sixfold increases in osteoclastic bone resorption. On mature rat osteoclasts, cultured for 1 day on polished dentine disks, peak effects on resorption pit formation were observed between 20 nM and 2 µM of ADP. The same concentrations of ADP also stimulated osteoclast and resorption pit formation in 10-day mouse marrow cultures on dentine disks. In 3-day explant cultures of mouse calvarial bones, the stimulatory effect of ADP on osteoclast-mediated Ca²⁺ release was greatest at 5–50 µM and equivalent to the maximal effects of prostaglandin E₂. The ADP effects were blocked in a nontoxic manner by MRS 2179, a P2Y₁ receptor antagonist. Using in situ hybridization and immunocytochemistry, we found evidence for P2Y₁ receptor expression on both osteoclasts and osteoblasts; thus, ADP could exert its actions both directly on osteoclasts and indirectly via P2Y₁ receptors on osteoblasts. As a major ATP degradation product, ADP is a novel stimulator of bone resorption that could help mediate inflammatory bone loss in vivo.—Hoebertz, A., Meghji, S., Burnstock, G., Arnett, T. Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y₁ receptor on bone cells.

Key Words: P2 receptors • ADP • ATP • osteoclast • bone resorption • P2Y₁

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