The P2X7 Receptor: A Key Player in Immune-Mediated Bone Loss?

Figure 2

The theoretical involvement of the P2X7 receptor in inflammatory-induced bone loss. The inflammatory process involves release of large amounts of ATP that activates P2X7 receptors on immune cells and possibly also P2X7 receptors on bone cells. (1) P2X7 receptors on bone cells are activated by ATP released from tissue/cell injury at the site of inflammation. (2) P2X7 receptors on monocytes (Mo), macrophages (Ma), and dendritic cells (DC) at the site of inflammation are activated by ATP released from cell/tissue injury. P2X7 receptor activation on these cells induces K⁺ efflux and activation of the NALP3 inflammasome leading to processing and release of proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). (3) TNF-α inhibits osteoblastic function (reduces bone formation and cell growth). (4) Both IL-1β and TNF-α converge to nuclear factor κB (NF-κB) and subsequently stimulating osteoclastic bone resorption. (5) TNF-α is directly proresorptive. In addition (not shown on figure), expression of receptor activator of nuclear factor ligand (RANKL) on inflammatory cells is increased and upon binding to receptor activator of nuclear factor (RANK) on mononuclear osteoclast precursors stimulating formation of multinucleated osteoclasts and activation of osteoclastic bone resorption.