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Steroidal Regulation of Uterine Edema and Tissue Inhibitors of Metalloproteinase (TIMP)-3 Messenger RNA Expression Is Altered in TIMP-1-Deficient Mice¹

Departments of Obstetrics and Gynecology, Division of Basic and Clinical Women's Research,³ Molecular and Integrative Physiology,⁴ University of Kansas Medical Center, Kansas City, Kansas 66160

Tissue inhibitors of metalloproteinases (TIMPs) are expressed within the uteri of virtually all species where they are postulated to control extracellular matrix turnover, cellular apoptosis, and proliferation. The objective of the current study was to examine the steroidal regulation of uterine TIMP expression and to determine the potential role of the TIMP-1 gene product in this regulation. To accomplish these goals, ovariectomized female TIMP-1 wild-type and null mice were treated with estradiol, progesterone, or estradiol and progesterone and killed at various times after steroid administration. Estradiol induced a significant reduction in uterine TIMP-3 expression in wild-type mice at 8 and 24 h post-steroid administration, but the ability of this steroid to decrease TIMP-3 expression was impaired in the uteri of TIMP-1 null mice. Further, estrogen-induced uterine wet-weight gain/edema was enhanced in the TIMP-1 null mice, and the antiestrogen compound ICI 182,780 or progesterone could only partially block this estrogenic effect. It is concluded from this study that steroidal modulation of uterine TIMP-3 expression and regulation of wet-weight gain/edema are altered in TIMP-1 null mice. These observations suggest that steroids induce uterine TIMP-1 expression and, in turn, that TIMP-1 influences TIMP-3 mRNA expression and uterine edema.

¹ This research was supported by NIH grant award HD39765 to W.B.N.

² Correspondence: Warren B. Nothnick, University of Kansas Medical Center, Department of Obstetrics and Gynecology, 3901 Rainbow Blvd., Kansas City, KS 66160. FAX: 913 588 6271; wnothnic{at}kumc.edu

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