期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 11, 页码 4136-4147出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI94912
关键词
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资金
- Japan Society for the Promotion of Science KAKENHI [26461381]
- Japan Agency for Medical Research and Development Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST) [15652238, 13414779]
- Grants-in-Aid for Scientific Research [26461381, 16H05326, 17K18414, 17K16079, 17K09881, 17K09706] Funding Source: KAKEN
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.
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