IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts

R. Clay Bunn, La Tonya D. Green, Michael T. Overgaard, Claus Oxvig, John L. Fowlkes

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)698-706
Number of pages9
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - Dec 17 2004

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant R01DK055653 (J.L.F.), National Institutes of Health Grant C06 RR16517 to Arkansas Children’s Hospital Research Institute and the Arkansas Biosciences Institute (R.C.B. and J.L.F.).


  • Growth factor
  • IGF
  • Osteoblast
  • Protease

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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