Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.