8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage
8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage
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DOI：
10.1016/j.freeradbiomed.2017.05.022
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发表时间：
2017-09-01
影响因子：
7.4
通讯作者：
Kamijo, Ryutaro
中科院分区：
文献类型：
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作者：
Hoshino, Marie;Kaneko, Kotaro;Kamijo, Ryutaro
在软骨内骨化中，骨的生长发生在其生长板软骨处。虽然已知一氧化氮（NO）脱氢酶是生长板软骨中软骨细胞增殖和骨生长所必需的，但NO促进这些过程的确切机制尚未阐明。C型利钠肽（CNP）也通过生长板软骨的扩张积极调节骨的伸长。已知NO和CNP都使用cGMP作为第二信使。最近，8-硝基-cGMP被鉴定为在各种类型的细胞中存在NO时产生的信号分子。在这里，我们发现8-硝基-cGMP产生于生长板中增殖的软骨细胞中，其在离体培养的骨中被CNP增强。此外，8-硝基-cGMP促进骨生长，增殖区扩大以及生长板中增殖细胞数量增加。8-Nitro-cGMP对体外培养的软骨细胞增殖也有促进作用。另一方面，8-bromo-cGMP促进骨的生长，并扩大生长板的肥大区，而不影响增殖区的宽度或软骨细胞的增殖。这些结果表明，生长板软骨中形成的8-硝基-cGMP作为NO的下游分子促进软骨细胞增殖和骨生长。
In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C-type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8-nitro-cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8-nitro-cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8-nitro-cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8-Nitro-cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8-bromo-cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8-nitro-cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO.