High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice
High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice
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DOI：
10.1038/pr.2012.118
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发表时间：
2012-11-01
影响因子：
3.6
通讯作者：
Pleshko, Nancy
中科院分区：
文献类型：
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作者：
Bargman, Renee;Poshann, Ram;Pleshko, Nancy
背景：核因子-κ B 配体受体激活剂 (RANKL) 抑制剂正在考虑用于治疗成骨不全症 (OI) 儿童。我们试图评估两种剂量的 RANKL 抑制剂骨保护素免疫球蛋白 Fc 片段复合物 (OPG-Fc) 在生长动物模型 01、colla2 缺陷型小鼠 (oim/oim) 及其野生型对照 (+/+) 中的疗效。方法：接受高剂量（20 mg/kg，每周两次）或低剂量（1毫克/公斤/周）OPG-Fc。由于这一不良事件，OPG-Fc 治疗停止，小鼠被处死或通过每月 X 光照片监测恢复情况，并评估血清破骨细胞活性（抗酒石酸酸性磷酸酶 5b、TRACP-5b），直至 25 周龄。 结果：12 周的 OPG-Fc 治疗导致放射学和组织学骨石症，无骨模型证据，且抗酒石酸酸性磷酸酶染色阴性，牙根牙本质异常和 TRACP-5b 活性抑制。治疗后 4-8 周出现恢复迹象。 结论：高剂量和低剂量 OPG-Fc 治疗都会导致幼年小鼠发生骨质疏松变化，这一结果在 RANKL 抑制剂 RANK 免疫球蛋白 Fc 片段复合物 (RANK-Fc) 的研究或老年动物的研究中未见。在考虑将 RANKL 抑制剂用于儿童之前，有必要对其进行进一步研究。
BACKGROUND: Receptor activator of nuclear factor-kappa B ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of 01, the colla2-deficient mouse (oim/oim) and its wild-type controls (+/+).METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b,TRACP-5b) until 25 wk of age.RESULTS:Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment.CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.