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

在之前的研究中，我们报道了TNFα拮抗肽（W9肽）在TNF受体KO小鼠骨髓细胞培养中抑制RANKL和M-CSF诱导的体外破骨细胞形成。此外，W9肽阻断RANKL诱导的RANK下游信号通路。由于这些结果，W9肽不仅干扰tnf - α- tnf受体的相互作用，还干扰RANKL/RANK的相互作用。在本研究中，我们在体内证实了W9肽对多种模型小鼠的作用。我们研究了W9肽对胶原诱导关节炎（CIA）小鼠炎性骨吸收的影响。W9肽注射对CIA小鼠炎症和骨吸收均有抑制作用。提示W9肽对炎性骨吸收具有抑制作用。此外，我们还研究了W9肽是否抑制小鼠牙周病原体感染时的骨破坏。灌注泵处理W9肽对牙周病原菌感染小鼠足部骨吸收有明显的抑制作用。W9肽能抑制牙周病原菌的骨吸收。这些结果表明W9肽在体内具有RANKL/RANK相互作用的拮抗剂作用。最近，据报道，能够转移到骨的癌细胞，如乳腺癌、前列腺癌和肺癌，在体外加速破骨细胞的形成和分化。也有报道称，OPG和双膦酸盐治疗可防止小鼠骨转移引起的骨破坏。这些结果提示破骨细胞在骨转移引起的骨破坏中起关键作用。因此，我们认为W9肽可能作为RANKL/RANK相互作用的拮抗剂，抑制癌细胞对骨的破坏。综上所述，W9肽在体内抑制炎症性骨吸收，并在体外抑制rankl诱导的RANK下游信号，提示W9肽可能对癌细胞的骨破坏有一定的治疗作用。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