Figure 2.

Schematic diagram illustrating the potential functions of extracellular nucleotides and P2 receptors in modulating bone cell function. ATP released from osteoclasts (e.g. through shear stress or constitutively) or from other sources can be degraded to adenosine 5′-diphosphate (ADP) or converted into uridine 5′-triphosphate (UTP) through ecto-nucleotidases. All three nucleotides can function separately on specific P2 receptor subtypes, as indicated by the colour coding. ATP is a universal agonist, whereas UTP is only active at the P2Y₂ receptor and ADP is only active at the P2Y₁ receptor. ADP acting on P2Y₁ receptors seems to stimulate both the formation (i.e. fusion) of osteoclasts from haematopoietic precursors and the resorptive activity of mature osteoclasts. For the latter, a synergistic action of ATP and protons by the P2X₂ receptor has been proposed. ADP could also stimulate resorption indirectly through actions on osteoclasts, which in turn release pro-resorptive factors (e.g. receptor activator of nuclear factor κB ligand, RANKL). ATP at high concentrations might facilitate fusion of osteoclast progenitors through P2X₇ receptor pore formation or induce cell death of mature osteoclasts through P2X₇ receptors. In osteoblasts, ATP, through P2X₅ receptors, might enhance proliferation and/or differentiation. By contrast, UTP, through P2Y₂ receptors, is a strong inhibitor of bone formation by osteoblasts. For some receptors (e.g. P2X₄ and P2Y₂ receptors on osteoclasts or P2X₂ receptors on osteoblasts), evidence for expression has been found but their role is still unclear. (Reproduced from [68], with permission.)