Pregnancy

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

Abstract
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 decidualised endometrium. We have previously found that decidua also produces a protease which cleaves IGFBP-1; since proteolysis of IGFBP-1 may represent a mechanism for increasing IGF bioavailability, this study aimed to identify the protease and its regulators in order to understand the control of IGF activity at the maternal/fetal interface. Immunochemical methods were used to show that decidualised endometrial cells from first trimester pregnancy produced MMP-3; incubation of IGFBP-1 with either this enzyme or MMP-9, which is known to be produced by trophoblast, produced a series of fragments that were unable to bind IGF-I. Western immunoblotting and immunocytochemistry demonstrated that decidual cells also produce TIMP-1, TIMP-2 and ₂-macroglobulin and all three inhibitors attenuated the proteolysis of IGFBP-1 by MMPs. N-terminal sequence analysis of the fragments revealed that the enzymes cleave IGFBP-1 at ¹⁴⁵Lys / Lys¹⁴⁶ resulting in a small (9kDa) 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.

Key words: Decidua • Growth factors • Placenta • Trophoblast

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