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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Development / drug effects*
  • Cartilage / cytology
  • Cartilage / drug effects*
  • Cartilage / growth & development
  • Cartilage / metabolism
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Chondrocytes / cytology
  • Chondrocytes / drug effects*
  • Chondrocytes / metabolism
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / pharmacology
  • Fetus
  • Growth Plate / cytology
  • Growth Plate / drug effects*
  • Growth Plate / growth & development
  • Growth Plate / metabolism
  • Mice
  • Mice, Inbred ICR
  • Natriuretic Peptide, C-Type / pharmacology
  • Nitric Oxide / metabolism
  • Primary Cell Culture
  • Tibia / cytology
  • Tibia / drug effects*
  • Tibia / growth & development
  • Tibia / metabolism
  • Tissue Culture Techniques


  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Natriuretic Peptide, C-Type
  • Nitric Oxide
  • Cyclic GMP