The primate endometrium undergoes extensive steroid-dependent remodeling during the menstrual cycle (Slayden and Keator, 2007
). In the follicular phase of the cycle, estradiol (E2
) stimulates endometrial cell proliferation and growth. Following ovulation in the luteal phase of the cycle, E2
and progesterone stimulate endometrial secretory differentiation and the endometrium becomes receptive to embryo implantation. If pregnancy does not occur, the corpus luteum regresses and circulating levels of E2
and progesterone decline, which triggers degradation and shedding of the endometrial functionalis zone during menses. Tissue sloughing during menses is mediated by cycle-dependent expression of tissue degrading matrix metalloproteinase (MMP) enzymes (Goffin et al., 2003
). The MMPs are a family of 23 endopeptidases that degrade extracellular matrix (ECM) substrates and play roles in ECM homeostasis (Sternlicht and Werb, 2001
). Endometrial expression of MMP-1, -3, -7, -8, -9, -10, -11 and -12 is strikingly up-regulated following progesterone withdrawal in the menstrual phase of the cycle (Goffin et al., 2003
Matrix metalloproteinase-26 (MMP-26), also referred to as matrilysin-2 or endometase, displays a unique expression pattern compared with other endometrial MMPs. In women, MMP-26 is up-regulated during the early secretory phase of the cycle immediately preceding the period of embryo implantation (Li et al., 2002
; Pilka et al., 2003
; Pilka et al., 2004a
). Several reports indicate that estrogen, acting through estrogen receptor 1 (ESR-1), regulates MMP-26 expression and that MMP-26 levels are elevated in estrogen-dependent endometrial hyperplasia (Pilka et al., 2004a
). These authors suggest a complex web of regulation of the MMP-26 gene via indirect estrogen regulation of pathways including Ras and Jun families of proteins and/or by β–catenin via the Wnt signal transduction pathway. However, careful review of published data does not support a role for estrogens in stimulating MMP-26 expression because there appears to be no positive correlation between levels of MMP-26 and circulating levels of E2
or the expression of ESR1.
The regulation of MMP-26 is complicated in that both estrogen and progesterone are secretory products of the corpus luteum during the secretory phase. However, progesterone action typically opposes many of the effects of estrogen on the endometrium. A clear understanding of MMP-26 regulation is further confounded by reports that MMP-26 was elevated in subjectively staged samples of endometrial tissue collected from women during the late proliferative phase (Pilka et al., 2003
). However, the same report indicated that MMP-26 was undetectable in endometrial explants collected from the proliferative stage and then subsequently treated with high levels of E2
(Pilka et al., 2003
). In that same study, MMP-26 was detectable when similar explants were cultured in the presence of E2
plus progesterone (Pilka et al., 2003
) indicating that progesterone, not estrogen, regulates the expression of MMP-26. Moreover, in a recent study, levels of MMP-26 were examined in the secretory endometrium collected from women during the natural cycle or from women given supplemental E2
and progesterone, with the authors concluding that exogenous estrogen therapy stimulated MMP-26 despite elevated levels of progesterone (Pilka et al., 2006
). All of these studies reaffirm a possible role of progesterone in stimulating MMP-26 expression. Therefore, hormonal regulation of MMP-26 expression in the secretory phase is unclear, and the broad perception that MMP-26 is regulated by estrogen alone is a gross misinterpretation.
The regulation of MMP-26 is most likely a complex system and assessing hormonal regulation of the endometrium in women is complicated in and of itself. The staging of human endometrium following the Noyes criteria (Noyes et al., 1950
) is a subjective system that has been scrutinized in recent years because of its inaccuracies in properly dating the endometrial phase of the menstrual cycle (Murray et al., 2004
; Fadare and Zheng, 2005
). In addition, clinical studies on MMP-26 are limited by practical considerations, including unwanted effects resulting from manipulating the hormonal milieu in women.
In this study we assessed MMP-26 expression and localization in the endometrium from ovariectomized hormone-treated rhesus macaques, a model in which steroid hormone levels can be tightly regulated. We focused our experiments on the action of E2, E2 plus progesterone and progesterone alone following E2 priming. This study achieves what is not possible in women and lays an important foundation for future functional studies. We report that MMP-26 is minimal in the endometrium from hormone-deprived animals and maximal in macaques during the first 3–7 days of progesterone treatment, with or without E2 present, in the artificial secretory phase of the cycle. Thereafter, MMP-26 expression was refractory to progesterone stimulation. Reduced expression of MMP-26 in the secretory phase was closely associated with the loss of endometrial ESR1 and PGR in the glandular epithelium during the late secretory phase of the menstrual cycle.