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

Area of Science:

• Endocrinology
• Skeletal Biology
• Molecular Biology

Background:

• Peptide therapeutics face challenges with degradation and rapid metabolism.
• Activating the C-type natriuretic peptide (CNP) and natriuretic peptide receptor B (NPR-B) system is a promising strategy for promoting skeletal growth.
• CNP clearance by natriuretic peptide clearance receptor (NPR-C) limits its therapeutic efficacy.

Purpose of the Study:

• To investigate the effect of reduced CNP clearance on skeletal growth.
• To explore osteocrin (OSTN) as a modulator of the CNP/NPR-C interaction for therapeutic benefit.

Main Methods:

• Generation of transgenic mice with elevated circulating osteocrin (OSTN) levels.
• Assessment of skeletal growth phenotypes in OSTN-transgenic mice.
• Analysis of OSTN-transgenic mice on CNP- or NPR-C-depleted backgrounds.
• Evaluation of combined CNP and OSTN overexpression in double-transgenic mice.

Main Results:

• OSTN administration led to a dose-dependent skeletal overgrowth phenotype in mice.
• Skeletal overgrowth was dependent on the presence of both CNP and NPR-C.
• Elevated OSTN levels resulted in increased circulating CNP and enhanced bone length.
• Combined OSTN and CNP overexpression produced greater bone growth than CNP overexpression alone.

Conclusions:

• Osteocrin (OSTN) administration can enhance skeletal growth by inhibiting CNP clearance.
• The CNP/NPR-C pathway is crucial for OSTN-mediated bone growth.
• OSTN shows potential as an adjuvant therapy to augment CNP treatment for impaired skeletal growth disorders.