Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification
Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification
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DOI：
10.1210/en.2002-220307
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发表时间：
2002-09-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Miyazawa, T;Ogawa, Y;Nakao, K
纵向骨生长由生长板处的软骨内骨化决定，生长板位于长骨和椎骨的两端，涉及许多全身激素和局部调节因子。 C 型利钠肽 (CNP) 是利钠肽家族的第三个成员，存在于生长板，通过细胞内环化 GMP (cGMP) 的积累，在局部发挥软骨内骨化的正调节作用。众所周知，cGMP 浓度的增加会激活不同的信号传导介质，例如环核苷酸磷酸二酯酶、cGMP 调节的离子通道和 cGMP 依赖性蛋白激酶 (cGK)。 II型cGK (cGKII)缺陷小鼠(Prkg2(-/-)小鼠)由于软骨内骨化受损而出现侏儒症，这表明cGKII对于CNP介导的软骨内骨化很重要。然而，鉴于Prkg2(-/-)小鼠与CNP缺陷小鼠(Nppc(-/-)小鼠)在生长板组织学上存在差异，cGMP下游介质在该过程中发挥关键作用仍然是一个谜。在这里，我们发现生长板软骨细胞中 CNP 的靶向表达无法挽救 Prkg2(-/-) 小鼠的骨骼缺陷。使用培养的胎儿小鼠胫骨（软骨内骨化的体外模型系统），我们还证明CNP不能增加Prkg2（-/-）小鼠的纵向骨生长、软骨细胞增殖和肥大以及软骨基质合成。这项研究提供了体内和体外遗传证据，表明 cGKII 在 CNP 介导的软骨内骨化中发挥着关键作用。
Longitudinal bone growth is determined by endochondral ossification at the growth plate, which is located at both ends of long bones and vertebrae, and involves many systemic hormones and local regulators. C-type natriuretic peptide (CNP), a third member of the natriuretic peptide family, occurs at the growth plate and acts locally as a positive regulator of endochondral ossification through the intracellular accumulation of cyclic GMP (cGMP). The increase in cGMP concentrations is known to activate different signaling mediators, such as cyclic nucleotide phosphodiesterases, cGMP-regulated ion channels, and cGMP-dependent protein kinases (cGKs). The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral ossification, suggesting that cGKII is important for the CNP-mediated endochondral ossification. However, given that Prkg2(-/-) mice differ from CNP-deficient mice (Nppc(-/-) mice) in the growth plate histology, which downstream mediator(s) of cGMP play key roles in the process is still an enigma. Here we show that targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice. Using cultured fetal mouse tibias, an in vitro model system of endochondral ossification, we also demonstrated that CNP cannot increase the longitudinal bone growth, and chondrocytic proliferation and hypertrophy, and cartilage matrix synthesis in Prkg2(-/-) mice. This study provides in vivo and in vitro genetic evidence that cGKII plays a critical role in CNP-mediated endochondral ossification.