TY - JOUR
T1 - IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts
AU - Bunn, R Clay
AU - Green, Latonya D
AU - Overgaard, Michael Toft
AU - Oxvig, Claus
AU - Fowlkes, John L
PY - 2004/12/17
Y1 - 2004/12/17
N2 - 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.
AB - 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.
U2 - 10.1016/j.bbrc.2004.10.092
DO - 10.1016/j.bbrc.2004.10.092
M3 - Journal article
C2 - 15541345
SN - 0006-291X
VL - 325
SP - 698
EP - 706
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -