N-arylpiperazine modified analogues of the P2X(7) receptor KN-62 antagonist are potent inducers of apoptosis of human primary osteoclasts

The P2X7 nucleotide receptor is an ATP-gated ion channel that plays an important role in bone cell function. Here, we investigated the effects of L-tyrosine derivs. 1-3 as potent P2X7 antagonists on human primary osteoclasts. We found that the level of expression of P2X7 receptor increased after treatment with the derivs. 1-3, together with the induction of high levels of apoptosis. This effect is assocd. with activation of caspase-3 and inhibition of expression of IL-6. Interestingly, no pro-apoptotic effect of compds. 1-3 was found on human osteoblasts. Our results suggest that the development of specific P2X7 receptor antagonists may be considered a useful tool to modulate apoptosis of human osteoclasts. Since bone loss due to osteoclast-mediated resorption represents one of the major unsolved problem in osteogenic disorders, the identification of mols. able to induce apoptosis of osteoclasts is of great interest for the development of novel therapeutic strategies.