EXPRESSION OF GELATINASE-B BY TROPHOBLAST CELLS - DOWN-REGULATION BY PROGESTERONE

OBJECTIVE: It is now accepted that gelatinase B (92 kd type IV collage nase) is involved in blastocyst implantation and trophoblast invasion. However, little is known about the regulation of this enzyme at the f etomaternal interface. Progesterone has been demonstrated to inhibit g elatinase B secretion from endometrial cells, myometrium, and cervical fibroblasts. Interestingly, the promotor of gelatinase B contains a p rogesterone-responsive element that may explain transcriptional activa tion of this metalloproteinase by progesterone. It may be hypothesized that progesterone secreted from trophoblast cells, representing the f etal part of the fetomaternal interface, may have a role in the regula tion of gelatinase secretion and blastocyst implantation. STUDY DESIGN : To this end, use was made of first-trimester trophoblast cells obtai ned from first-trimester pregnancy terminations. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gr adients. Metalloproteinase activity was measured by zymography, and th e expression of the gelatinase B messenger ribonucleic acid was determ ined by the solution hybridization/ribonuclease protection assay. RESU LTS: Primary cell cultures of trophoblasts from first trimesters of pr egnancy constitutively elaborated two species of type IV collagenases (gelatinase A and B) as assessed on a gelatin matrix. Treatment with p rogesterone decreased the accumulation of a gelatinase B species in a dose-dependent fashion, Administration of a progesterone receptor anta gonist onapristone (ZK-98.299) neutralized the progesterone inhibitory effect on the gelatinase B in a dose-dependent fashion, thus supporti ng the presumption that the progesterone effect is receptor mediated. Progesterone significantly attenuated the expression of gelatinase B b y trophoblast cells, an effect that was neutralized by ZK-98.299. CONC LUSION: These observations provide strong indirect support for the par ticipation of progesterone in the regulation of gelatinase B in tropho blast cells. It may be an important regulator of gelatinase production at the fetomaternal interface.