N-Arylpiperazine modified analogues of the P2X7 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 derivatives 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 derivatives 1-3, together with the induction of high levels of apoptosis. This effect is associated with activation of caspase-3 and inhibition of expression of IL-6. Interestingly, no pro-apoptotic effect of compounds 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 osteopenic disorders, the identification of molecules able to induce apoptosis of osteoclasts is of great interest for the development of novel therapeutic strategies.
Penolazzi
Letizia
L
Department of Biochemistry and Molecular Biology, Molecular Biology section, University of Ferrara, 44100, Ferrara, Italy.
Bianchini
Ercolina
E
Lambertini
Elisabetta
E
Baraldi
Pier Giovanni
PG
Romagnoli
Romeo
R
Piva
Roberta
R
Gambari
Roberto
R
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000135:Acid Phosphatase / Q000494:pharmacology; D017209:Apoptosis; D001851:Bone Diseases, Metabolic / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000494:pharmacology; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000737:chemistry*; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D000071681:Tartrate-Resistant Acid Phosphatase; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D007527:Isoenzymes; D016328:NF-kappa B; C546468:P2RX7 protein, human; D010879:Piperazines; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D013778:Tetrazolium Salts; D013844:Thiazoles; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue