Systemic Administration of C-Type Natriuretic Peptide as a Novel Therapeutic Strategy for Skeletal Dysplasias
Systemic Administration of C-Type Natriuretic Peptide as a Novel Therapeutic Strategy for Skeletal Dysplasias
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DOI：
10.1210/en.2008-1676
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发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Yasoda, Akihiro;Kitamura, Hidetomo;Nakao, Kazuwa
骨骼发育不良是一组以骨生长严重受损为特征的遗传性疾病。它们的各种形式增加了显著的发病率和死亡率，但迄今为止还没有开发出有效的药物治疗。我们以前证明，C型利钠肽（CNP），利钠肽家族的一员，是一个强大的刺激软骨内骨生长。此外，我们展示了生长板中CNP转基因的靶向过表达挽救了软骨发育不全（Ach）小鼠模型中观察到的受损骨生长，这是人类骨骼发育不良的最常见形式，这使我们提出CNP可能被证明是这种疾病的有效治疗方法。在本研究中，为了阐明CNP全身给药是否是骨骼发育不良的新型药物治疗，我们研究了血浆CNP对Ach小鼠（在人血清淀粉样蛋白P组分启动子控制下，肝脏中特异性过表达CNP）或连续CNP输注系统治疗的Ach小鼠中骨生长受损的影响。我们的结果表明，增加血浆CNP从肝脏或通过静脉注射合成CNP-22拯救受损的骨生长表型的乙酰胆碱小鼠没有显着的不良反应。这些结果表明，全身CNP治疗是人类骨骼发育不良（包括Ach）的潜在治疗策略。（内分泌学150：3138-3144，2009）
Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Furthermore, we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in a mouse model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, to elucidate whether or not the systemic administration of CNP is a novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by iv administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans. (Endocrinology 150: 3138-3144, 2009)