Response of matrix metalloproteinases and tissue inhibitors of metalloproteinases messenger ribonucleic acids to ovarian steroids in human endometrial explants mimics their gene- and phase-specific differential control in vivo.
BACKGROUND
Cyclic remodeling and breakdown of the extracellular matrix, a unique feature of the human endometrium, depends on matrix metalloproteinases (MMPs). These enzymes are globally controlled by estradiol and progesterone or their withdrawal, but various MMPs and their tissue inhibitors (TIMPs) show distinct responses.


OBJECTIVE
To clarify the role of ovarian steroids in the differential regulation of MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, TIMP-1, TIMP-2, and TIMP-3 mRNAs, we compared their variations in the cycling endometrium in vivo with their response to hormone addition or withdrawal in corresponding explants.


RESULTS
Different patterns were identified in vivo according to the time frame (secretory vs. perimenstrual increase), sharpness (peak vs. progressive increase or decrease), and magnitude of the changes. In vivo ratios between early/midsecretory and perimenstrual phases ranged from more than 1000 (MMP-1, MMP-3, and MMP-10) to less than 10 (TIMPs). Differential response to ovarian steroids of the various MMPs and TIMPs mRNAs tested in cultured explants matched the same ranking and varied according to the phase at sampling. Remarkably, ovarian steroids repressed MMPs and TIMP-1 and TIMP-2 but, in secretory explants, increased TIMP-3 mRNA. Finally, in situ hybridization evidenced the major contribution of fibroblasts to the increase in MMP-8 mRNA at menstruation or in explants cultured without hormones.


CONCLUSIONS
Both phase- and gene-specific modulators finely tune in space, time, and amplitude the global control of MMPs and TIMPs mRNAs by estradiol and progesterone in the cycling human endometrium.
Vassilev
Vassil
V
Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, avenue Hippocrate, 75, B-1200 Bruxelles, Belgium.
Pretto
Chrystel M
CM
Cornet
Patricia B
PB
Delvaux
Denis
D
Eeckhout
Yves
Y
Courtoy
Pierre J
PJ
Marbaix
Etienne
E
Henriet
Patrick
P
D000328:Adult; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D008597:Menstrual Cycle / Q000502:physiology; D008875:Middle Aged; D010053:Ovary / Q000187:drug effects / Q000502:physiology*; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*
D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D011374:Progesterone; D004958:Estradiol; D020782:Matrix Metalloproteinases