Matrix metalloproteinases (MMPs) are spatiotemporally expressed in the uterus across normal estrous and menstrual cycles and are known to participate in the extensive endometrial tissue remodeling. MMP‐9/gelatinase B is one of the major MMPs found in the uterus that modulates uterine biology during various reproductive processes. Although it seems that uterine MMP‐9 is under ovarian steroid hormonal control, there are conflicting reports regarding steroidal hormonal regulation of MMP‐9 expression, and there is little information on the effects of estrogen in vivo in this respect. We therefore examined the steroidal regulation of MMP‐9 within the mouse uterus. Female mice (2–3 months old) were ovariectomized and treated with estradiol‐l7β (E2) or E2 + progesterone (P4) and uterine gelatinase activity and expression were determined. Gelatin zymography revealed that E2 alone or in combination with P4 increased MMP‐9 activation, whereas Northern analysis showed that E2 decreased MMP‐9 steady state mRNA expression and an estrogen receptor antagonist ICI‐182, 780 blocked this effect. In contrast, uterine MMP‐2 expression and activity were not affected by steroidal treatments. Pretreatment with a transcription inhibitor actinomycin D or translation inhibitor cycloheximide indicates that E2 regulates uterine MMP‐9 at multiple points, involving transcriptional and posttranscriptional control as well as modulation of inhibitor activities. Collectively, these data suggest that E2 regulates uterine MMP‐9 expression and activity in vivo via a complex mechanism. This estrogen regulation of MMP‐9 activity may play an important role in uterine tissue remodeling. Mol. Reprod. Dev. © 2006 Wiley‐Liss, Inc.
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