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

Authors :
Kanai Y
Yasoda A
Mori KP
Watanabe-Takano H
Nagai-Okatani C
Yamashita Y
Hirota K
Ueda Y
Yamauchi I
Kondo E
Yamanaka S
Sakane Y
Nakao K
Fujii T
Yokoi H
Minamino N
Mukoyama M
Mochizuki N
Inagaki N
Source :
The Journal of clinical investigation [J Clin Invest] 2017 Nov 01; Vol. 127 (11), pp. 4136-4147. Date of Electronic Publication: 2017 Oct 09.
Publication Year :
2017

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.

Details

Language :
English
ISSN :
1558-8238
Volume :
127
Issue :
11
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
28990933
Full Text :
https://doi.org/10.1172/JCI94912