A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis
A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis
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DOI：
10.1002/art.22495
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发表时间：
2007-04-01
影响因子：
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通讯作者：
Aoki, Kazuhiro
中科院分区：
文献类型：
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作者：
Saito, Hiroaki;Kojima, Takefumi;Aoki, Kazuhiro
客观的。环肽 WP9QY (YCWSQYLCY) 旨在模拟 TNF 受体 1 上最关键的肿瘤坏死因子 α (TNF α) 识别环，并防止 TNFa 与其受体相互作用。我们进行这项研究是为了比较 WP9QY 肽与抗 TNF α 单克隆抗体对小鼠胶原诱导性关节炎 (CIA) 的影响。方法。 CIA是通过初次和二次免疫诱导的。在加强注射当天（第21天）将渗透微型泵植入所有小鼠的背部，并连续输注媒介物、抗TNF抗体（4mg/kg/天）或WP9QY肽（2mg/kg/天或4mg/kg/天）直至处死小鼠（第40天）。此后，进行临床、放射学和组织学评估。结果。 WP9QY 治疗抑制了 CIA 诱导的关节炎评分增加，但该肽并没有延迟疾病的发作。 WP9QY对炎症的抑制作用明显弱于抗TNF抗体。然而，微焦计算机断层扫描分析表明，WP9QY 可以阻止 CIA 诱导的膝关节骨质破坏，其程度与抗 TNF 抗体相同。此外，WP9QY 抑制滑膜血管翳浸润并减少破骨细胞数量。此外，WP9QY对CIA诱导的全身性骨丢失的抑制作用比抗TNF抗体更明显。结论。 TNF α 拮抗剂 WP9QY 将成为开发小分子抑制剂的有用模板，以预防类风湿性关节炎中的炎症性骨破坏和全身性骨丢失。
Objective. The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor alpha (TNF alpha) recognition loop on TNF receptor 1, and it prevents interactions of TNFa with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNF alpha monoclonal antibody.Methods. CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed.Results. WP9QY treatment inhibited CIA-induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody.Conclusion. The TNF alpha antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.