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During the course of human pregnancy, there is a marked increase in insulin-like growth factor (IGF) binding protein (IGFBP)-3 pro- tease activity in maternal serum that is first evident at 6 weeks of gestation, persists through term, and returns to nonpregnancy levels by day 5 postpartum. This protease activity cleaves IGFBP-3 into smaller fragments that have markedly reduced affinity for the IGFs. To date, the precise identity and cellular origin of the pregnancy- associated serum IGFBP-3 protease have not been established. To investigate whether placental and/or decidual tissues, which uniquely develop during pregnancy, may be sources of the pregnancy- associated serum IGFBP protease, we examined the secretion of IGFBP-3 protease in vitro by isolated human cytotrophoblasts or fibroblasts from second trimester placentae and by in vitro decidu- alized human endometrial stromal cells. Cytotrophoblasts were ei- ther cultured alone, which favors aggregation and fusion, or cocul- tured with decidualized endometrial stromal cells, which favors differentiation to an invasive phenotype. IGFBP-3 protease activity was detected in trophoblast, but not in placental fibroblast or decidu- alized endometrial cultures, and was also present in trophoblast- endometrial cocultures. Western ligand blot and Western immuno- blot analyses showed that most of the endogenous IGFBP-3 in trophoblast cultures was in the form of low molecular weight frag- ments with reduced IGF binding affinity. The substrate specificity of the trophoblast-derived protease was identical to that in pregnancy serum, showing activity against IGFBP-2, -3, and -4, but being in- active against IGFBP-1. IGFBP-3 proteolysis by both pregnancy se- rum and trophoblast conditioned medium showed a major peak of activity at neutral pH. The trophoblast-derived activity caused time- and temperature-dependent proteolysis of IGFBP-3 into fragments of identical size as those produced by pregnancy serum, and also shared its sensitivity to protease inhibitors: highly sensitive to EDTA and o-phenanthroline, partially sensitive to the serine protease inhibitors AEBSF and aprotinin, and insensitive to a2-antiplasmin, and to as- partic and cysteine protease inhibitors. IGFBP-3 proteolysis by both pregnancy serum and trophoblast conditioned medium was also in- sensitive to tissue inhibitor of metalloproteinase-1, precluding the involvement of the matrix metalloproteinases. In contrast, both the pregnancy serum- and trophoblast-derived proteases were preferen- tially inhibited by a hydroxamic acid derivative with selective activity against the disintegrin-metalloproteinase tumor necrosis factor-a converting enzyme. This study shows that placental trophoblasts produce an IGFBP-3 protease with characteristics very similar to the activity found in pregnancy serum and indicates these cells at the maternal-fetal interface are a potential source of the pregnancy-as- sociated serum IGFBP-3 protease. The findings further suggest that the main IGFBP-3 protease activity in both pregnancy serum and trophoblast conditioned medium may correspond to a disintegrin- metalloproteinase type enzyme. (Endocrinology 141: 666 - 674, 2000)

endocrinology

Human Placental Trophoblasts Secrete a Disintegrin Metalloproteinase Very Similar to the Insulin-Like Growth Factor Binding Protein-3 Protease in Human Pregnancy Serum