Regulation of matrix metalloproteinase-9/gelatinase B expression and activation by ovarian steroids and LEFTY-A/endometrial bleeding-associated factor in the human endometrium.
Various matrix metalloproteinases (MMPs) participate in the menstrual breakdown of the human endometrium. MMP-9/gelatinase B is proposed as a major factor because it degrades many extracellular matrix constituents, including in the vasculature. Although globally under ovarian steroids control, endometrial MMP-9 seems expressed differently than other MMPs, and conflicting publications prevent a clear understanding of its regulation. We therefore quantified MMP-9 expression in the cycling human endometrium, defined its localization, and analyzed its regulation by estradiol and progesterone and by LEFTY-A/endometrial bleeding-associated factor in explant cultures. In fresh tissues, a major increase in MMP-9 mRNA expression occurred at menstruation, after a larger increase in LEFTY-A mRNA. MMP-9 was immunodetected in all cell types throughout the cycle, especially in foci of stromal cells during menstruation. MMP-9 synthesis by these cells was confirmed in cultured explants. In proliferative explants, ovarian steroids slightly decreased MMP-9 mRNA. They had no consistent effect on MMP-9 release in culture medium but strongly inhibited proMMP-9 activation. Addition of recombinant LEFTY-A to explants induced MMP-9 in most samples, a response prevented by ovarian steroids. We propose that endometrial MMP-9 activity is overall controlled by the ovarian steroids and locally adjusted through a network of modulators, including LEFTY-A.
Cornet
Patricia B
PB
Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Galant
Christine
C
Eeckhout
Yves
Y
Courtoy
Pierre J
PJ
Marbaix
Etienne
E
Henriet
Patrick
P
D001483:Base Sequence; D001706:Biopsy; D002478:Cells, Cultured; D017931:DNA Primers; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D055458:Left-Right Determination Factors; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008597:Menstrual Cycle / Q000502:physiology; D010053:Ovary / Q000502:physiology; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
D017931:DNA Primers; C526161:LEFTY1 protein, human; D055458:Left-Right Determination Factors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D011374:Progesterone; D020780:Matrix Metalloproteinase 9