HUMAN ENDOMETRIAL MATRIX METALLOPROTEINASE-2, A PUTATIVE MENSTRUAL PROTEINASE - HORMONAL-REGULATION IN CULTURED STROMAL CELLS AND MESSENGER-RNA EXPRESSION DURING THE MENSTRUAL-CYCLE

Proteinases are likely effecters of endometrial menstrual breakdown. W e have investigated proteinase production by human endometrial stromal cells subjected in vitro to progesterone (P) withdrawal, the physiolo gic stimulus for menstruation. Culture media of cells exposed to estra diol, P, or estradiol plus P had low levels of proteolytic activity si milar to cultures maintained in the absence of steroids. P withdrawal, or addition of RU486 to P-treated cultures, stimulated proteinase sec retion. The stromal cell proteinase was characterized by gelatin zymog raphy, inhibitor profile, and organomercurial activation, as a metallo proteinase present mostly as a 66-kD proenzyme with lower levels of a 62-kD active form. The P withdrawal-induced metalloproteinase was iden tified as matrix metalloproteinase-2 (MMP-2) by Western blotting, The increase of MMP-2 induced by P withdrawal was associated with the meta lloproteinase-dependent breakdown of stromal cultures, involving disso lution of extracellular matrix and dissociation of stromal cells. Nort hern analysis showed the differential expression of MIMP-2 mRNA in lat e secretory phase endometrium. These findings are consistent with the involvement of stromal cell-derived MMP-2 in the proteolysis of extrac ellular matrix promoting cyclic endometrial breakdown and the onset of menstrual bleeding.