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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 1

Generation of serum amyloid P–OSTN-transgenic (SAP-Ostn-Tg) mice.

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Generation of serum amyloid P–OSTN-transgenic (SAP-Ostn-Tg) mice.
(A) St...
(A) Structure of the SAP-Ostn transgene. Arrowheads indicate the recognition sites of restriction endonucleases. SAP, human SAP promoter. (B) Expression of the transgene in tissues of WT and line 51 SAP-Ostn-Tg mice analyzed by RT-PCR. Transgene expression was detected only in the liver of SAP-Ostn-Tg mice. (C) Gross appearance of WT and SAP-Ostn-Tg male mice at the age of 10 weeks observed from the left side (top panel) and above (bottom panel). SAP-Ostn-Tg mice showed longer bodies, limbs, and tails than WT mice. (D–F) Growth curves based on naso-anal length (D), naso-tail length (E), and body weight (F) of WT (open squares), line 33 SAP-Ostn-Tg (filled triangles), and line 51 SAP-Ostn-Tg (filled squares) male mice measured every week from the ages of 3 to 10 weeks. Body lengths of SAP-Ostn-Tg mice became significantly larger than those of WT mice, and the body elongation of SAP-Ostn-Tg mice increased in accordance with blood OSTN levels. There was no significant difference in body weight between the 3 groups throughout the observation period. n = 10 each. *P < 0.05, **P < 0.01 vs. WT mice, by 1-way ANOVA followed by Tukey-Kramer test. Data are representative of 2 independent experiments (B).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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