Translational Research of the Activation of the C-Type Natriuretic Peptide (CNP)-Guanylyl Cyclase-B Pathway for Skeletal Dysplasia

Abstract

The natriuretic peptide family consists of three endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They exert their biological actions through two subtypes of particulate guanylyl cyclase (GC): GC-A for ANP and BNP, and GC-B for CNP. Among the natriuretic peptide family members, ANP and BNP are cardiac hormones that are produced and released from the atrium and ventricle of the heart, respectively, and play important roles in the regulation of the cardiovascular system. On the other hand, although CNP and its receptor, GC-B, exist ubiquitously in the body, we elucidated that the CNP/GC-B system is a crucial stimulator of endochondral bone growth, using CNP or GC-B knockout or transgenic mice. We planned to utilize the activation of the CNP/GC-B pathway as a novel therapeutic strategy for skeletal dysplasia, which consists of multiple skeletal diseases including those with impaired bone growth. We tried to investigate this effect on impaired skeletal growth in a mouse model of achondroplasia, the most common form of skeletal dysplasias, and successfully recovered the skeletal phenotype by using transgenic technology or by administration of synthetic CNP. In the future, the activation of the CNP/GC-B system may constitute a novel therapeutic strategy for the treatment of skeletal dysplasias.