Matrix metalloprotease-3 and -9 proteolyze insulin-like growth factor-binding protein-1.
Growth in utero depends on adequate development and function of the fetal/maternal interface. During pregnancy, the insulin-like growth factors (IGFs), which are known to be critically involved in placental development, are controlled by a binding protein-IGFBP-1-produced by maternal decidualized endometrium. We have previously found that decidua also produces a protease that cleaves IGFBP-1; because proteolysis of IGFBP-1 may represent a mechanism for increasing IGF bioavailability, the present study aimed to identify the protease and its regulators to understand the control of IGF activity at the maternal/fetal interface. Immunochemical methods were used to show that decidualized endometrial cells from first-trimester pregnancy produced matrix metalloprotease (MMP)-3; incubation of IGFBP-1 with either this enzyme or MMP-9, which is produced by the trophoblast, produced a series of fragments that were unable to bind IGF-I. Western immunoblot analysis and immunocytochemistry demonstrated that decidual cells also produce tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, and alpha(2)-macroglobulin, and all three inhibitors attenuated the proteolysis of IGFBP-1 by MMPs. The N-terminal sequence analysis of the fragments revealed that the enzymes cleave IGFBP-1 at (145)Lys/Lys(146), resulting in a small (9-kDa) C-terminal peptide of IGFBP-1. These findings suggest cleavage of IGFBP-1 as a novel mechanism in the control of placental development by matrix metalloproteases.
Coppock
Hedley A
HA
Endocrine Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK.
White
Anne
A
Aplin
John D
JD
Westwood
Melissa
M
D000595:Amino Acid Sequence; D002465:Cell Movement / Q000502:physiology; D003656:Decidua / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism* / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology
D018970:Insulin-Like Growth Factor Binding Protein 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9