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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 4

Mechanistic analyses of skeletal overgrowth in SAP-Ostn-Tg mice.

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Mechanistic analyses of skeletal overgrowth in SAP-Ostn-Tg mice.
(A) Gro...
(A) Gross appearance of Nppc–/– and Nppc–/–/SAP-Ostn-Tg mice. Top panel shows 9-week-old WT and Nppc–/– mice, and bottom panel shows 9-week-old WT and Nppc–/–/SAP-Ostn-Tg mice. (B) Growth curves of naso-anal length of Nppc–/– (filled squares) and Nppc–/–/SAP-Ostn-Tg (open squares) mice measured every week from the ages of 3 to 9 weeks. n = 3 each. (C) Bone lengths of 9-week-old Nppc–/– and Nppc–/–/SAP-Ostn-Tg mice. n = 3 each, for each bone length in Nppc–/– and Nppc–/–/SAP-Ostn-Tg mice. (D) Histological photographs of the tibial growth plates of Alcian blue and H&E staining of 9-week-old Nppc–/– and Nppc–/–/SAP-Ostn-Tg mice. Arrows indicate the widths of growth plates. Scale bar: 100 μm. (E) The widths of the tibial growth plates of 9-week-old Nppc–/– and Nppc–/–/SAP-Ostn-Tg mice. n = 3 each. (F) Growth curves of naso-anal length of Npr3–/– (filled triangles) and Npr3–/–/SAP-Ostn-Tg (open triangles) mice measured every week from the ages of 3 to 10 weeks. n = 7 each. (G) Bone lengths of 10-week-old Npr3–/– and Npr3–/–/SAP-Ostn-Tg mice. n = 6 each, for each bone length in Npr3–/– and Npr3–/–/SAP-Ostn-Tg mice. (H) Histological images of the tibial growth plates of Alcian blue and H&E staining of 10-week-old Npr3–/– and Npr3–/–/SAP-Ostn-Tg mice. Arrows indicate the widths of growth plates. Scale bar: 100 μm. (I) Widths of the tibial growth plates of 10-week-old Npr3–/– and Npr3–/–/SAP-Ostn-Tg mice. n = 3 each. (J) Plasma CNP concentrations of 6-week-old WT and SAP-Ostn-Tg mice. n = 4 each. **P < 0.01, by Student’s t test.
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