The development of a new drug TNFα antagonistic peptide that inhibits bone destruction by cancer cells

在以前的研究中，我们已经报道了肿瘤坏死因子α拮抗肽(W9肽)能抑制RANKL和M-CSF在KO小鼠骨髓细胞培养中诱导的破骨细胞形成。此外，W9肽还可阻断RANKL诱导的RANK下游信号传导。由于这些结果，W9肽不仅干扰了肿瘤坏死因子α-肿瘤坏死因子受体的相互作用，而且还干扰了RANKL/RANK的相互作用。观察W9肽对胶原诱导性关节炎(CIA)小鼠炎性骨吸收的影响。W9肽对CIA小鼠炎症和骨吸收均有抑制作用。提示W9肽对炎症性骨吸收有抑制作用。此外，我们还研究了W9肽是否能抑制小鼠牙周病原体感染时的骨破坏。输液泵Preve…治疗W9多肽牙周病原体感染小鼠的跟骨诱导更多的骨吸收。W9肽对牙周病原体的骨吸收有抑制作用。这些结果表明，W9肽在体内是RANKL/RANK相互作用的拮抗剂。最近，有报道称，具有骨转移能力的癌细胞，如乳腺癌、前列腺癌和肺癌，在体外可以促进破骨细胞的形成和分化。另有报道称，OPG和双膦酸类药物可防止小鼠骨转移所致的骨破坏。这些结果提示，破骨细胞在肿瘤转移所致的骨破坏中起着关键作用。因此，我们认为W9肽可能作为RANKL/RANK相互作用的拮抗剂，抑制癌细胞的骨破坏。综上所述，W9肽在体内抑制了RANKL诱导的炎症骨吸收，在体外抑制了RANKL诱导的RANK下游信号传导，提示W9肽可能用于治疗癌细胞的骨破坏。较少

In previous studies, we have reported that TNFα antagonistic peptide (W9 peptide) inhibit in vitro osteoclast formation induced by RANKL and M-CSF in bone marrow cell culture derived from the TNF receptor KO mice. Furthermore, W9 peptide blocked RANKL induced signaling downstream of RANK. Because of these results, W9 peptide interfered with not only TNFα-TNF receptor interaction but also RANKL/RANK interaction.In this study, we confirmed the effects of W9 peptide on the various model mice in vivo. We investigated the effects of W9 peptide on the Collagen-Induced Arthritis (CIA) mice induced inflammatory bone resorption. W9 peptide injections inhibited both inflammation and bone resorption induced in the CIA mice. These results indicated that W9 peptide had an inhibitory effect on the inflammatory bone resorption. In addition, we also investigated whether W9 peptide inhibited bone destruction in periodontal pathogens infection in mice or not. W9 peptide treatment by infusion pumps preve … More nted bone resorption induced in the calvalia of periodontal pathogens infection mice. W9 peptide could inhibit the bone resorption by periodontal pathogens. These results suggested that W9 peptide acted as antagonist of the RANKL/RANK interaction in vivo.Recently, it is reported that cancer cells capable of the metastasis to the bone, such as breast, prostate, and lung cancer, accelerate osteoclast formation and differentiation in vitro. It is also reported that OPG and bisphosphonates treatments prevent bone destruction induced by the metastasis to the bone in mice. These results is suggested that osteoclasts have a pivotal role in bone destruction induced by the metastasis. Therefore, we suggest the possibility that W9 peptide, acted as the antagonist of the RANKL/RANK interaction, inhibits bone destruction by cancer cells.In conclusion, W9 peptide inhibited the inflammatory bone resorption in vivo and RANKL-induced signaling downstream of RANK in vitro, suggesting that W9 peptide is possibly useful for the treatment of bone destruction by the cancer cells. Less