Ovarian Membrane-Type Matrix Metalloproteinases: Induction of MMP14 and MMP16 During the Periovulatory Period in the Rat, Macaque, and Human1

Abstract

An intrafollicular increase in proteolytic activity drives ovulatory events. Surprisingly, the periovulatory expression profile of the membrane-type matrix metalloproteinases (MT-MMPs), unique proteases anchored to the cell surface, has not been extensively examined. Expression profiles of the MT-MMPs were investigated in ovarian tissue from well-characterized rat and macaque periovulatory models and naturally cycling women across the periovulatory period. Among the six known MT-MMPs, mRNA expression of Mmp14, Mmp16, and Mmp25 was increased after human chorionic gonadotropin (hCG) administration in rats. In human granulosa cells, mRNA expression of MMP14 and MMP16 increased following hCG treatment. In contrast, mRNA levels of MMP16 and MMP25 in human theca cells were unchanged before ovulation but declined by the postovulatory stage. In macaque granulosa cells, hCG increased mRNA for MMP16 but not MMP14. Immunoblotting showed that protein levels of MMP14 and MMP16 in rats increased, similar to their mRNA expression. In macaque granulosa cells, only the active form of the MMP14 protein increased after hCG, unlike its mRNA or the proprotein. By immunohistochemistry, both MMP14 and MMP16 localized to the different ovarian cell types in rats and humans. Treatment with hCG resulted in intense immunoreactivity of MMP14 and MMP16 proteins in the granulosa and theca cells. The present study shows that MMP14 and MMP16 are increased by hCG administration in the ovulating follicle, demonstrating that these MMPs are conserved among rats, macaques, and humans. These findings suggest that MT-MMPs could have an important role in promoting ovulation and remodeling of the ovulated follicle into the corpus luteum.

A novel regulatory pathway in granulosa cells, the LH/human chorionic gonadotropin-microRNA-125a-3p-Fyn pathway, is required for ovulation

“…Herein, we showed that during the peri-ovulatory period, mural granulosa cells retrieved from mice, administered PMSG followed by hCG injection, acquire migratory capacities, as opposed to cells retrieved from mice administered PMSG only. These results are in agreement with the increase in the level of protein expression and of the active forms of Mmp 14 and Mmp 16 (key members in extracellular matrix remodeling and cell migration), found in rat ovaries 8 h after the administration of hCG and in macaque and human granulosa cells during the peri-ovulatory period (34). This peri-ovulatory hCG-induced mural granulosa cell migration might participate in the events leading to follicular wall rupture, adding a new insight into the role of mural granulosa cells toward ovulation.…”

Ovarian cancer: involvement of the matrix metalloproteinases

“…In the normal ovary, we have observed an increase in MT6 around the time of ovulation (Puttabyatappa et al 2014). In ovarian cancer, the data that do exist have been performed in cell lines.…”

Follicle rupture during ovulation with an emphasis on recent progress in fish models

“…Further detailed studies of proteolytic events occurring at the apex of the periovulatory follicle in human ovulation will clarify the commonality and difference in follicle rupture mechanisms between humans and medaka. Nevertheless, reproductive biologists appear to assume that at least MMPs may have a significant function in the degradation of the collagenous connective tissue in the follicle wall across mammalian species (Espey & Richards 2006, Liu et al 2013, Puttabyatappa et al 2014, Rosewell et al 2015. This leads to a speculation that the functional role of the MMP system in the rupture may be conserved from teleosts to mammals.…”