Expression of Matrix Metalloproteinase-2, -9, and -14, Tissue Inhibitors of Metalloproteinase-1, and Matrix Proteins in Human Placenta During the First Trimester1

Abstract

Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix; they play important roles in the invasion of the trophoblast cell into the maternal endometrium during placentation. Previous studies have concentrated on comparison of MMP expression in trophoblast cells between the first and third trimester. But the dynamic expression of MMPs during the first trimester has not been reported. In the present study, the expression of MMP-2, -9, and -14 (membrane-type MMP-1) and the production of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) by cultured human cytotrophoblast cells from 6 to 11 wk of gestation were investigated. The cells were cultured under serum-free conditions. There was no MMP-9 secretion by the cells at Week 6, but from Week 7 to 11 the MMP-9 secretion increased gradually. Week 11 cells secreted more than 10-fold as much MMP-9 (167.7 +/- 18.8 ng/ml) as Week 7 (14.7 +/- 3.9 ng/ml) cultures. However, MMP-2 production declined from Week 6 to Week 11, and the production at Week 11 (32.3 +/- 8.1 ng/ml) was about one sixth that at Week 6 (205.7 +/- 27.2 ng/ml). The expression of mRNA transcripts for MMP-2 and MMP-9 correlated with enzyme secretion; we did not detect any MMP-9 mRNA signal in 20 microg total RNA extracted from cultured cells at Weeks 6, 7, and 8 of pregnancy, but a signal was apparent in Weeks 9 and 11. MMP-2 mRNA was expressed throughout the 6- to 11-wk period and exhibited a remarkable decline during this period. MMP-14 mRNA transcripts remained relatively stable from 6 to 11 wk. Significantly more TIMP-1 (P < 0.01) was detected in Week 9 (87.5 +/- 15.0 ng/ml) and Week 11 (169.1 +/- 30.2 ng/ml) media compared to Week 6 media (23.5 +/- 4.8 ng/ml), but we did not detect any TIMP-2 in the media of the tested cells. This study demonstrated that first-trimester human cytotrophoblast cells were able to produce abundant laminin, fibronectin, and vitronectin. However, we did not observe detectable secretion of collagen I and collagen IV. These data indicated that human trophoblast-derived MMPs and their inhibitors are intrinsically and developmentally regulated. The same cytotrophoblast cells that produced MMPs could also secrete various substrates for these enzymes.

Testosterone inhibits matrix metalloproteinase-1 production in human endometrial stromal cells in vitro

“…In fact, MMPs play a pivotal role in embryo implantation (Xu et al 2000) and the initiation of menstruation (Hampton & Salamonsen 1994, Marbaix et al 1995. MMPs are grouped according to their domain structure into collagenases, gelatinases, stromelysins, and matrilysin (Sternlicht & Werb 2001).…”

Detection of MMP-9 and TIMP-3 mRNA expression in the villi of patients undergoing early spontaneous abortion: A report of 30 cases

“…MMP-9 is richly expressed in the post-ovulation implantation window, suggesting that it is conducive to blastocyst implantation. Xu et al (12) performed in vitro culture of human cytotrophoblast cells for 6-11 weeks. At the end of week 6, no MMP-9 secretion was detected, while secretion started and gradually increased from weeks 7-11, and reached a level in week 11 that was 10-fold greater than that in week 7.…”

Thrombophilia in Assisted Reproductive Technology — Place and Needs of Thromboprophylaxis

“…The gene knockout studies in mice suggest that MMP-9 is critical for implantation [108]. MMP-9 is known to degrade collagen IV, the main component of the basement membrane, and in conjunction with MMP-2 may enable the invasion of trophoblast cells through the decidua and into the maternal vasculature [109]. Although divergent effects of heparin on MMPs have been observed, LMWH in therapeutic doses has been shown to induce trophoblast MMP-2 and MMP-9 transcription and protein expression.…”