title: IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts.
abstract: Insulin-like growth factor (IGF) signaling is critical for osteoblast development and IGF binding protein (IGFBP)-4 is one of the principle IGFBPs expressed by osteoblasts. Release of bound IGF via proteolytic degradation of IGFBP-4 is likely to be critical for osteoblast development. We have investigated whether IGF-sensitive, IGFBP-4 degradation in mouse MC3T3-E1 osteoblasts is due to the metzincin pregnancy-associated plasma protein (PAPP)-A. Degradation of IGFBP-4 by PAPP-A or MC3T3-E1 conditioned medium was enhanced by IGF-II but inhibited by mutation of basic residues at or near the PAPP-A cleavage site in IGFBP-4. Furthermore, immunodepletion of PAPP-A from MC3T3-E1 conditioned medium abolished IGFBP-4 degradation. We also found that PAPP-A messenger RNA was expressed throughout differentiation of MC3T3-E1 cells. These results demonstrate for the first time that PAPP-A is the IGFBP-4 protease in MC3T3-E1 cells, a widely used model for osteoblast development, and that PAPP-A may regulate IGF release throughout osteoblast differentiation.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. bunnrobertc@uams.edu
authors.forename: R Clay
authors.initials: RC
authors.lastname: Bunn
authors.forename: Latonya D
authors.initials: LD
authors.lastname: Green
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.forename: John L
authors.initials: JL
authors.lastname: Fowlkes
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001673:Biodegradation, Environmental; D002460:Cell Line; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D018974:Insulin-Like Growth Factor Binding Protein 4; D011994:Recombinant Proteins; D013002:Somatomedins; D011266:Pregnancy-Associated Plasma Protein-A