C-type natriuretic peptide (CNP) and postnatal linear growth

Abstract

C-type natriuretic peptide (CNP) is a member of a family of structurally related peptides, including atrial (ANP) and B-type (BNP) natriuretic peptides, best known for their cardiovascular actions. Surprisingly, recent evidence from rodents shows that CNP is essential for endochondral bone growth - blocking the CNP signaling pathway yields a dwarfed phenotype whereas overexpression leads to skeletal overgrowth. In humans, loss of function mutations in the CNP receptor gene (NPR-B) cause the profoundly dwarfed phenotype of acromesomelic dysplasia Maroteaux type. By contrast, overexpression of CNP, arising from balanced translocations involving chromosome 2, results in severe skeletal overgrowth as reported recently in three patients with marfanoid habitus. CNP is expressed in a broad range of tissues including bone, but the circulating concentration of CNP in blood is low, close to assay detection limits, due in part to its rapid degradation by clearance receptors and enzyme hydrolysis. However, a stable product of the CNP gene, amino-terminal proCNP (NTproCNP), is readily measurable in plasma and has been used to study the regulation of CNP secretion in vivo. Plasma NTproCNP is strongly correlated with skeletal growth and markers of bone formation in lambs and children throughout the growing period. In addition plasma levels of NTproCNP are rapidly suppressed by glucocorticoid treatment or caloric restriction (which reduce growth) and stimulated by anabolic hormones including GH, thyroid hormones, and estrogens. These and other recent findings support the view that the plasma concentration of NTproCNP, in reflecting growth plate cartilage activity, is a unique marker of linear growth which may assist in the diagnosis of growth disorders in humans.