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Free Radic Biol Med. 2017 Sep;110:63-71. doi: 10.1016/j.freeradbiomed.2017.05.022. Epub 2017 May 27.

8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage.

Author information

1
Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Prosthodontics, Showa University School of Dentistry, Tokyo, Japan.
2
Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo, Japan.
3
Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan. Electronic address: yoichim@dent.showa-u.ac.jp.
4
Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan.
5
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.
6
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
7
Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Japan.
8
Division of Pathology, Department of Oral Diagnostic Sciences, Showa University School of Dentistry, Tokyo, Japan.
9
Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo, Japan.
10
Department of Prosthodontics, Showa University School of Dentistry, Tokyo, Japan.

Abstract

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.

KEYWORDS:

8-Nitro-cGMP; C-type natriuretic peptide; Chondrocytes; Growth plate cartilage; Nitric oxide

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