INDUCTION OF TISSUE INHIBITOR OF METALLOPROTEINASE-3 GENE-EXPRESSION DURING IN-VITRO DECIDUALIZATION OF HUMAN ENDOMETRIAL STROMAL CELLS

Endometrial stromal differentiation (decidualization) is essential for implantation of the developing blastocyst, To investigate the process of progesterone (P)-induced decidualization of human endometrial stro mal cells (ESC), a complementary DNA library enriched with P-induced g enes was constructed from cultured human ESC by subtractive hybridizat ion and the polymerase chain reaction. One, of the isolated clones was the complementary DNA for the tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently identified member of the human TlMP family. When human ESC were cultured in the presence of P for 6 days, the inductio n of TIMP-3 messenger RNA (mRNA) expression was observed by Northern b lotting. In contrast, the marked induction of PRL mRNA expression and morphological changes were observed after 9 days of culture. P-induced TIMP-3 mRNA expression was dose dependent, and this induction was inh ibited by the antiprogestin RU486. Estrogen did not induce TIMP-3 mRNA expression under similar conditions. In situ hybridization analysis o f endometria from nonpregnant women revealed that the TIMP-3 mRNA expr ession was restricted to predecidualized stromal cells. At the fete-ma ternal interface, TIMP-3 expression was observed in fetal extravillous trophoblasts that had invaded the maternal decidual tissues as well a s in the maternal decidual cells. These findings suggest that TIMP-3 i s a sensitive indicator of ESC decidualization, and that the induction of TIMP-3 expression in decidual cells and trophoblasts may be import ant in the regulation of trophoblast invasion.