Circulating C-Type Natriuretic Peptide (CNP) Rescues Chondrodysplastic CNP Knockout Mice from Their Impaired Skeletal Growth and Early Death
Circulating C-Type Natriuretic Peptide (CNP) Rescues Chondrodysplastic CNP Knockout Mice from Their Impaired Skeletal Growth and Early Death
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DOI：
10.1210/en.2010-0078
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发表时间：
2010-09-01
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：
Fujii, Toshihito;Komatsu, Yasato;Nakao, Kazuwa
C型利钠肽（CNP）是一种通过膜鸟苷酸环化酶受体（GC-B）亚型促进软骨内骨生长的强效刺激剂。尽管其两种同源利钠肽ANP和BNP是由心脏产生的心脏激素，但CNP被认为是自分泌/旁分泌调节剂。为了阐明CNP的全身给药是否是软骨发育不良的一种新型药物治疗方法（尚未开发药物治疗），我们通过使用在人血清淀粉样蛋白P组分启动子控制下循环CNP增加的CNP转基因小鼠（SAP-Nppc-Tg小鼠）研究了循环CNP的影响。SAP-Nppc-Tg小鼠通过软骨内骨化形成明显的骨过度生长。在器官培养实验中，SAP-Nppc-Tg小鼠的胫骨外植体的生长与其野生型同窝小鼠的胫骨外植体的生长相比没有变化，表明在SAP-Nppc-Tg小鼠中观察到的对软骨内骨生长的刺激作用是体液性的。然后，我们将软骨发育不良CNP缺失小鼠与SAP-Nppc-Tg小鼠杂交。CNP敲除小鼠中受损的软骨内骨生长通过增加循环CNP而显著恢复，随后不仅其纵向生长而且其体重也得到改善。此外，CNP敲除小鼠的死亡率大大降低循环CNP。CNP全身给药可能不仅对骨骼生长受损具有治疗潜力，而且对软骨发育不良患者生长受损的其他方面（包括体重增加受损）也具有治疗潜力，并可能因此保护其免于过早死亡。（内分泌学151：4381-4388，2010）
C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death. (Endocrinology 151: 4381-4388, 2010)