Tissue inhibitor of metalloproteinases-3 is the major metalloproteinase inhibitor in the decidualizing murine uterus.

Embryo implantation in the mouse is a highly orchestrated process, a key aspect of which is the invasion of trophoblast cells of the blastocyst into the maternal uterine endometrium. Invasion is facilitated via proteinases expressed by trophoblast cells and balanced by expression of inhibitors of proteinases in the maternal decidua. The predominant proteinase expressed by trophectodermal derivatives of the implanting mouse embryo is matrix metalloproteinase-9 (MMP-9; gelatinase B). Using in situ hybridization, transcripts for MMP-9 were detected in trophoblast cells of the embryo from the earliest stage of decidual formation (day 6.0) examined. MMP-9 transcripts were localized to trophoblast giant cells at the periphery of the embryo at the egg cylinder stage (day 7.0). By the neural-fold stage (day 8.5), expression was restricted to giant cells adjacent to the maternal side of the developing placenta, and by day 9.5 few MMP-9-positive cells remained. The major tissue inhibitor of metalloproteinases (TIMP) produced during this period was TIMP-3. Transcripts encoding TIMP-3 were detected from day 6.0-7.0 in the maternal decidua immediately adjacent to embryonic cells expressing MMP-9. The intensity of TIMP-3 expression in later-stage embryos declined in parallel with MMP-9 expression. Maternal TIMP-3 expression also occurred in the absence of embryonic MMP-9 expression in decidual reactions induced by parthenogenetic embryos (where MMP-9 positive cells were not detected) or in oil-induced deciduomas. These results support the hypothesis that MMP-9 is an important mediator of cellular invasiveness during embryo implantation, and that TIMP-3 serves as a regulator within the uterus to restrict invasion to the site of implantation.