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J Clin Invest. 2017 Nov 1;127(11):4136-4147. doi: 10.1172/JCI94912. Epub 2017 Oct 9.

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

Author information

1
Department of Diabetes, Endocrinology and Nutrition, and.
2
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
Department of Cell Biology and.
4
Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
5
Department of Oral and Maxillofacial Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
6
Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
7
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

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.

PMID:
28990933
PMCID:
PMC5663354
DOI:
10.1172/JCI94912
[Indexed for MEDLINE]
Free PMC Article

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