A novel therapeutic strategy for midfacial hypoplasia using the CNP/GC-B system

Abstract

ObjectiveC-type natriuretic peptide (CNP), a potent stimulator of endochondral ossification, acts through guanylyl cyclase B (GC-B), a subtype of membranous guanylyl cyclase. In previous studies, we revealed that CNP stimulates the longitudinal growth of vertebrae and long bones formed through endochondral ossification in mice. Furthermore, we showed that CNP stimulates endochondral ossification in the craniofacial region and is crucial for midfacial skeletogenesis using cartilage-specific CNP transgenic mice and systemic CNP knockout mice. In the present report, we investigated the effect of increased circulating CNP on craniofacial skeletogenesis in a murine model. MethodsWe analyzed the craniofacial morphology of transgenic mice in which CNP is expressed under the control of the human serum amyloid P component promoter (SAP-Nppc-Tg mice), resulting in elevated levels of circulating CNP. Next we crossed these SAP-Nppc-Tg mice with CNP knockout mice to clarify whether midfacial hypoplasia in CNP knockout mice will be rescued or not. ResultsSAP-Nppc-Tg mice exhibited longitudinal overgrowth along the cranial length through endochondral ossification. The midfacial hypoplasia in CNP knockout mice was significantly rescued by increasing circulating CNP level. In addition, the foramen magnum stenosis of CNP knockout mice was significantly ameliorated in the rescued mice. ConclusionsCirculating CNP affects cartilage and promotes endochondral ossification in craniofacial region. Systemic administration of CNP might have therapeutic potential not only against midfacial hypoplasia, but also against other aspects of impaired craniofacial skeletal growth, including foramen magnum stenosis, in patients suffering from skeletal dysplasias.