Exogenous C-type natriuretic peptide therapy for impaired skeletal growth in a murine model of glucocorticoid treatment
Exogenous C-type natriuretic peptide therapy for impaired skeletal growth in a murine model of glucocorticoid treatment
复制标题
DOI：
10.1038/s41598-019-44975-w
复制
发表时间：
2019-06
影响因子：
4.6
通讯作者：
Y. Ueda;A. Yasoda;Keisho Hirota;I. Yamauchi;T. Yamashita;Y. Kanai;Yoriko Sakane;T. Fujii;N. Inagaki
中科院分区：
文献类型：
--
作者：
Y. Ueda;A. Yasoda;Keisho Hirota;I. Yamauchi;T. Yamashita;Y. Kanai;Yoriko Sakane;T. Fujii;N. Inagaki
生长迟缓是糖皮质激素类药物的一个重要副作用，糖皮质激素类药物被广泛应用于各种儿科疾病的治疗。我们研究了外源性CNP-53（一种稳定的内源性CNP分子形式）对GC诱导的生长迟缓小鼠模型的治疗作用。我们发现，当从4至8周龄注射地塞米松（DEX）和CNP-53时，CNP-53成功地恢复了GC诱导的生长迟缓。值得注意的是，CNP-53在第一周内无效。从4 - 5周龄开始，CNP-53在DEX之前或高剂量CNP-53都没有改善CNP的效果。相反，当在5周龄时开始CNP-53给药时，8周龄时的最终体长与4周龄时开始CNP-53给药时的体长相当。至于对CNP效应的抵抗机制，DEX不损害CNP诱导的cGMP产生。即使在DEX处理下，CNP也可降低Erk磷酸化，而CNP未改变p38或GSK 3 β的磷酸化。总之，CNP-53对GC诱导的生长迟缓的影响取决于小鼠模型中的年龄，表明在临床环境中适当和谨慎使用CNP可有效治疗GC诱导的生长迟缓。
Growth retardation is an important side effect of glucocorticoid (GC)-based drugs, which are widely used in various preparations to treat many pediatric diseases. We investigated the therapeutic effect of exogenous CNP-53, a stable molecular form of intrinsic CNP, on a mouse model of GC-induced growth retardation. We found that CNP-53 successfully restored GC-induced growth retardation when both dexamethasone (DEX) and CNP-53 were injected from 4 to 8 weeks old. Notably, CNP-53 was not effective during the first week. From 4 to 5 weeks old, neither CNP-53 in advance of DEX, nor high-dose CNP-53 improved the effect of CNP. Conversely, when CNP-53 was started at 5 weeks old, final body length at 8 weeks old was comparable to that when CNP-53 was started at 4 weeks old. As for the mechanism of resistance to the CNP effect, DEX did not impair the production of cGMP induced by CNP. CNP reduced Erk phosphorylation even under treatment with DEX, while CNP did not changed that of p38 or GSK3β. Collectively, the effect of CNP-53 on GC-induced growth retardation is dependent on age in a mouse model, suggesting adequate and deliberate use of CNP would be effective for GC-induced growth retardation in clinical settings.