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Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance
Yugo Kanai, … , Naoki Mochizuki, Nobuya Inagaki
Yugo Kanai, … , Naoki Mochizuki, Nobuya Inagaki
Published October 9, 2017
Citation Information: J Clin Invest. 2017;127(11):4136-4147. https://doi.org/10.1172/JCI94912.
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Research Article Bone Biology Endocrinology

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

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Abstract

Although peptides are safe and useful as therapeutics, they are often easily degraded or metabolized. Dampening the clearance system for peptide ligands is a promising strategy for increasing the efficacy of peptide therapies. Natriuretic peptide receptor B (NPR-B) and its naturally occurring ligand, C-type natriuretic peptide (CNP), are potent stimulators of endochondral bone growth, and activating the CNP/NPR-B system is expected to be a powerful strategy for treating impaired skeletal growth. CNP is cleared by natriuretic peptide clearance receptor (NPR-C); therefore, we investigated the effect of reducing the rate of CNP clearance on skeletal growth by limiting the interaction between CNP and NPR-C. Specifically, we generated transgenic mice with increased circulating levels of osteocrin (OSTN) protein, a natural NPR-C ligand without natriuretic activity, and observed a dose-dependent skeletal overgrowth phenotype in these animals. Skeletal overgrowth in OSTN-transgenic mice was diminished in either CNP- or NPR-C–depleted backgrounds, confirming that CNP and NPR-C are indispensable for the bone growth–stimulating effect of OSTN. Interestingly, double-transgenic mice of CNP and OSTN had even higher levels of circulating CNP and additional increases in bone length, as compared with mice with elevated CNP alone. Together, these results support OSTN administration as an adjuvant agent for CNP therapy and provide a potential therapeutic approach for diseases with impaired skeletal growth.

Authors

Yugo Kanai, Akihiro Yasoda, Keita P. Mori, Haruko Watanabe-Takano, Chiaki Nagai-Okatani, Yui Yamashita, Keisho Hirota, Yohei Ueda, Ichiro Yamauchi, Eri Kondo, Shigeki Yamanaka, Yoriko Sakane, Kazumasa Nakao, Toshihito Fujii, Hideki Yokoi, Naoto Minamino, Masashi Mukoyama, Naoki Mochizuki, Nobuya Inagaki

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Figure 6

Additive effect of CNP and OSTN on the skeletal growth in double-transgenic mice.

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Additive effect of CNP and OSTN on the skeletal growth in double-transge...
(A) Gross appearance of 10-week-old WT, SAP-Nppc-Tg, SAP-Ostn-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice. SAP-Nppc-Tg/SAP-Ostn-Tg mice were longer than SAP-Nppc-Tg and SAP-Ostn-Tg mice. (B and C) Growth curves based on naso-anal (B) and naso-tail length (C) of WT (open triangles), SAP-Nppc-Tg (filled triangles), SAP-Ostn-Tg (open squares), and SAP-Nppc-Tg/SAP-Ostn-Tg (filled squares) mice measured every week from the ages of 3 to 10 weeks. n = 6, 6, 6, and 7 in WT, SAP-Nppc-Tg, SAP-Ostn-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice, respectively. †P < 0.05, ††P < 0.01 vs. SAP-Ostn-Tg mice; ‡P < 0.05, ‡‡P < 0.01 vs. SAP-Nppc-Tg mice; §P < 0.05, §§P < 0.01 vs. WT mice. One-way ANOVA followed by Tukey-Kramer test was used for statistical analysis. (D) Bone lengths of 10-week-old WT, SAP-Nppc-Tg, SAP-Ostn-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice. n = 6, 6, 6, and 7 in WT, SAP-Nppc-Tg, SAP-Ostn-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice, respectively. Statistical differences between genotypes are summarized in Table 1. (E and F) Histological pictures of the growth plates of 10-week-old mice. Alcian blue and H&E staining (E) and immunohistochemical staining for type X collagen (F) are shown. Arrows indicate the widths of growth plates (E) and hypertrophic chondrocyte layers (F). Scale bars in E and F: 100 μm. (G and H) Widths of growth plates (G) and hypertrophic zone (H) of 10-week-old mice. n = 6, 6, 6, and 7 in WT, SAP-Nppc-Tg, SAP-Ostn-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice, respectively. (I) Plasma CNP concentrations in 6-week-old SAP-Ostn-Tg, SAP-Nppc-Tg, and SAP-Nppc-Tg/SAP-Ostn-Tg mice. There was no significant difference in plasma CNP levels between SAP-Ostn-Tg and SAP-Nppc-Tg mice. SAP-Nppc-Tg/SAP-Ostn-Tg mice had significantly higher blood CNP levels than SAP-Ostn-Tg and SAP-Nppc-Tg mice. n = 4 each. **P < 0.01, by 1-way ANOVA followed by Tukey-Kramer test.
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