The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A

Proteolytic cleavage of the six known insulin-like growth factor binding pr oteins (IGFBPs) is a powerful means of rapid structure and function modific ation of these important growth-regulatory proteins. Intact IGFBP-4 is a po tent inhibitor of IGF action in vitro, and cleavage of IGFBP-4 has been sho wn to abolish its ability to inhibit IGF stimulatory effects in a variety o f systems, suggesting that IGFBP-4 proteolysis acts as a positive regulator of IGF bioavailability. Here we report the isolation of an IGF-dependent I GFBP-4-specific protease from human fibroblast-conditioned media and its id entification bg mass spectrometry microsequencing as pregnancy-associated p lasma protein-A (PAPP-A), a protein of unknown function found in high conce ntrations in the maternal circulation during pregnancy. Antibodies raised a gainst PAPP-A both inhibited and immunodepleted IGFBP-4 protease activity i n human fibroblast-conditioned media. Moreover, PAPP-A purified from pregna ncy sera had IGF-dependent IGFBP-4 protease activity. PAPP-A mRNA was expre ssed by the human fibroblasts and osteoblasts, and PAPP-A protein was secre ted into the culture medium. In conclusion, we have identified an IGF-depen dent IGFBP protease and at the same time assigned a function to PAPP-A, Thi s represents an unanticipated union of two areas of research that were not linked in any way before this report.