Matrix Metalloprotease-3 and -9 Proteolyze Insulin-Like Growth Factor-Binding Protein-1

• Published in: Biology of reproduction Vol. 71; no. 2; pp. 438 - 443
• Main Authors: COPPOCK, Hedley A, WHITE, Anne, APLIN, John D, WESTWOOD, Melissa
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction 01.08.2004
• Subjects: Amino Acid Sequence; Biological and medical sciences; Cell Movement - physiology; Decidua - cytology; Decidua - enzymology; Female; Fundamental and applied biological sciences. Psychology; Humans; Insulin-Like Growth Factor Binding Protein 1 - chemistry; Insulin-Like Growth Factor Binding Protein 1 - metabolism; Mammalian male genital system; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase 3 - pharmacology; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase 9 - pharmacology; Molecular Sequence Data; Morphology. Physiology; Pregnancy; Pregnancy Trimester, First; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tissue Inhibitor of Metalloproteinase-3 - metabolism; Trophoblasts - cytology; Trophoblasts - enzymology; Vertebrates: reproduction; Insulin like growth factor binding protein; Reproduction
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.103.023101

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 α 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.