Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss.
Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss.
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DOI：
10.1002/jbmr.2125
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发表时间：
2014
影响因子：
6.2
通讯作者：
Ueki, Yasuyoshi
中科院分区：
文献类型：
--
作者：
Yoshitaka, Teruhito;Ishida, Shu;Mukai, Tomoyuki;Kittaka, Mizuho;Reichenberger, Ernst J.;Ueki, Yasuyoshi
切尔鲁贝氏症是一种由信号适配器蛋白SH3BP2(SH3BP2)功能获得突变引起的头面部骨骼遗传性疾病。在嵌合型小鼠模型中，我们先前证明纯合子突变小鼠发展T/B细胞非依赖性全身性巨噬细胞炎症，导致骨侵蚀和关节破坏。纯合子小鼠会出现多发性骨质疏松症，而人类的长臂骨症病变仅限于颌骨。我们通过创建纯合子的肿瘤坏死因子-α缺陷的长寿突变体来确定肿瘤坏死因子-α在自体炎症发展中的关键作用，在这些突变体中，全身炎症和骨破坏被挽救。在目前的研究中，我们检查了出生后给予抗肿瘤坏死因子-α拮抗剂是否可以预防或改善小鼠的疾病进展。对于尚未出现活动性炎症的纯合子突变新生儿，用大剂量依那西普(25 mg/kg，每周两次)治疗7周。依那西普治疗的新生小鼠表现出强烈的面部肿胀和颌骨和颅骨骨质丢失的恢复。高剂量组关节破坏完全恢复。此外，高剂量治疗组大鼠肺和肝脏的炎性病变明显减轻。然而，曾被依那西普成功治疗的炎症和骨丢失在依那西普停药后复发。低剂量组(0.5 mg/kg，2次/周)和赋形剂治疗组未见明显作用。相比之下，当10周龄的完全活动性炎症的小鼠接受依那西普治疗7周时，即使是高剂量给药也没有减少骨丢失、肺或肝脏的炎症。综上所述，这些结果表明，如果在炎症期或骨吸收发生之前进行治疗，抗肿瘤坏死因子-α治疗对年轻的天使症患者可能是有效的。因此，早期的基因诊断和抗肿瘤坏死因子-α拮抗剂的早期治疗可能能够预防或改善畸形症，特别是在SH3BP2突变的患者。
Cherubism is a genetic disorder of the craniofacial skeleton caused by gain-of-function mutations in the signaling adaptor protein, SH3-domain binding protein 2 (SH3BP2). In a knock-in mouse model for cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell-independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions while cherubism lesions in humans are limited to jawbones. We identified a critical role of TNF-α in the development of autoinflammation by creating homozygous TNF-α-deficient cherubism mutants, where systemic inflammation and bone destruction were rescued. In the current study, we examined whether postnatal administration of an anti-TNF-α antagonist can prevent or ameliorate the disease progression in cherubism mice. Neonatal homozygous mutants, where active inflammation has not yet developed, were treated with a high dose of etanercept (25 mg/kg, twice/week) for 7 weeks. Etanercept-treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high dose group. Moreover, the high dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration recurred after etanercept discontinuation. No significant effect was observed in low dose- (0.5 mg/kg, twice/week) and vehicle-treated groups. In contrast, when 10-week-old cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high dose administration did not decrease bone loss, lung or liver inflammation. Taken together, the results suggest that anti-TNF-α therapy may be effective in young cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti-TNF-α antagonists may be able to prevent or ameliorate cherubism, especially in patients with a mutation in SH3BP2.
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