Non-human primate models: artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts

Abstract

Rhesus monkeys are useful models in which to examine the hormonal regulation of endometrial matrix metalloproteinases (MMP) and to evaluate the role of MMP in uterine bleeding. Artificial 28 day menstrual cycles can be induced in ovariectomized monkeys by inserting an oestradiol implant for 2 weeks, then inserting a progesterone implant for 2 weeks, and then, with the oestradiol implant remaining in place, removing and reinserting the progesterone implant at 2 week intervals. To examine MMP during menses, we established such cycles and removed uteri by hysterectomy at closely spaced intervals before, during and after menses, as well as at later time points. Some samples were also obtained during menses induced by the withdrawal of both progesterone and oestradiol. We examined mRNA of the following MMP by Northern blotting: matrilysin, stromelysin-1, stromelysin-2, stromelysin-3 and the tissue inhibitor of MMP TIMP-1. The expression of these MMP mRNA increased substantially by 2-3 days after progesterone withdrawal, whether or not oestradiol was maintained. The expression of some of the MMP (stromelysins-1 and -2) returned very rapidly to baseline levels by 5 days after progesterone withdrawal, while the expression of others (matrilysin, stromelysin-3 and TIMP-1) declined more slowly, reaching a baseline level by 10 days after progesterone withdrawal, with little or no further decline after progesterone concentrations rose during the induced luteal phase. Immunocytochemical studies showed that matrilysin was expressed primarily in the glands of the upper functionalis. In other work with the rhesus monkey model, we used a s.c. endometrial autograft technique in which pieces of endometrium were autotransplanted to the abdominal skin. During menses in the grafts, matrilysin was expressed in the glands of the grafts similar to the glands in the eutopic endometrium. Endometrial autografts can serve as a useful model for the study of MMP in uterine bleeding.

Matrix Metalloproteinases and Their Tissue Inhibitors in the Developing Neonatal Mouse Uterus1

“…Although MMP-11-null mice are fertile, MMP-11 can contribute in a paracrine manner to epithelial malignancy [34]. In the cyclic human and primate uterus, MMP-10 is observed in the uterine stroma and regulated by ovarian steroid hor- mones [20,35]. In the present study, MMP-10 mRNA was detected predominantly in the uterine epithelium and decreased after PND 9.…”

“…Results of available studies strongly support the idea that MMPs and TIMPs are important regulators of uterine growth and remodeling in both humans and primates during the menstrual cycle and pregnancy [18][19][20]. Many MMP and TIMP knockout mice do not exhibit overt reproductive phenotypes, which may be attributed to compensation and redundancy because of the size of the MMP and TIMP family as well as their overlapping activities [18].…”

Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors

“…In this model, MMP-7, MMP-3, MMP-10, and MMP-11 increased in endometrial tissue at menstruation and returned to baseline levels 5-10 days later. The TIMP-1 mRNA level was elevated from days 1 -6 following progesterone withdrawal, with peak expression on day 1 associating with menstruation [82]. Unlike humans and primates, rodents do not have a menstrual phase, and their cycle is termed the estrous cycle.…”

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

“…All but TIMP-4 are expressed within the uterus of a variety of species that include mice [19], sheep [20], humans [21][22][23][24][25], and nonhuman primates [26,27]. TIMPs are known modulators of cell proliferation, differentiation, and apoptosis [8,17] and elicit these activities through processes that are either dependent on or independent of their ability to regulate MMP activity [17].…”

“…For example, in vivo studies in the cycling sheep uterus suggest that expression of TIMP-1 is down-regulated by estrogen, while that of TIMP-2 may be up-regulated by progesterone [20]. In contrast, in nonhuman primates, progesterone withdrawal [25,26] is associated with a rapid increase in uterine TIMP-1 expression followed by a reduction in expression. Results from in vitro studies that incorporated human endometrial stromal cells are conflicting.…”