Matrix metalloproteinases (MMPs) are Zn(2+)-binding endopeptidases that degrade various components of the extracellular matrix (ECM). The MMPs are enzymes implicated in normal and pathologic tissue remodeling processes, wound healing, angiogenesis, and tumor invasion. MMPs have different substrate specificities and are encoded by different genes. Sato et al. (1994) cloned a cDNA for the human gene from a placenta cDNA library (they called the gene MMP-X1 and the gene product membrane-type metalloproteinase).
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily; each member of this subfamily contains a potential transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. This protein activates MMP2 protein, and this activity may be involved in tumor invasion.
Enzyme, Hydrolase, Peptidase/Protease
In the ovary, extensive tissue remodeling is required during both follicular development and the break down of the follicular
wall at the time of ovulation. Extracellular proteases such as serine proteases and matrix metalloproteinases (MMPs) are
thought to play pivotal roles in these processes.
Extracellular Matrix, Plasma membrane
Liu et al used in situ hybridization to study the regulation and distribution of mRNA coding for MMP-2 (gelatinase A) and its cell surface activator membrane-type MMP1 (MT1-MMP)
during gonadotropin induced ovulation in the rat. In ovaries of untreated immature rats, the levels of MT1-MMP
and MMP-2 mRNA were low. MMP-2 mRNA was found in theca-interstitial cells while MT1-MMP mRNA was found in
both granulosa and theca-interstitial cells and both messages were induced after stimulation with PMSG. After an ovulatory
dose of hCG, the expression of MT1-MMP was dramatically down regulated in the granulosa cell layers of large
preovulatory follicles but the expression remained and appeared to be up regulated together with MMP-2 in the
theca-interstitial cells surrounding the large preovulatory follicles. The expression kinetics and tissue distribution supports
the notion that MT1-MMP may have dual functions in the ovary. Initially MT1-MMP may act as a matrix degrading protease
inside the follicle during follicular development and later, just prior to ovulation, as an activator of proMMP-2 in
theca-interstitial cells surrounding preovulatory follicles.
Expression regulated by
Ovarian Membrane Type Matrix Metalloproteinases: Induction of MMP14 and MMP16 During the Periovulatory Period in the Rat, Macaque, and Human. Puttabyatappa M 2014 et al.
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 hCG in the rat. 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 prior to ovulation but declined by the post-ovulatory stage. In macaque granulosa cells, hCG increased mRNA for MMP16 but not MMP14. Immunoblotting showed that protein levels of MMP14 and MMP16 in the rat 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 pro-protein. By immunohistochemistry both MMP14 and MMP16 localized to the different ovarian cell types in the rat and human. 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 rat, macaque and human. These findings suggest that MT-MMPs could have an important role to promote ovulation and remodeling of the ovulated follicle into the corpus luteum.
Membrane Type 1-Matrix Metalloproteinase (MMP)-Associated MMP-2 Activation Increases in the Rat Ovary in Response to an Ovulatory Dose of Human Chorionic Gonadotropin.
Jo M, et al .
Gonadotropins stimulate ovarian proteolytic enzyme activity that is believed to be important for the remodeling of the follicular extracellular matrix. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been identified in vitro as an activator of pro-MMP-2 by forming a complex with tissue inhibitors of metalloproteinase-2 (TIMP-2). In the present study, the expression pattern of MT1-MMP mRNA and the role of MT1-MMP were examined in the ovary using the gonadotropin-treated immature rat model. Ovaries were collected at selected times after eCG or hCG. RNase protection assays revealed a transient increase in MT1-MMP mRNA beginning 4 h after hCG. High expression of MT1-MMP mRNA was localized to the theca-interstitial layer of developing and preovulatory follicles, while low expression was observed in the granulosa cell layer of developing follicles by in situ hybridization. The localization pattern of MT1-MMP mRNA was compared with TIMP-2 mRNA. Both MMP-2 and TIMP-2 mRNA were expressed in the theca layer of preovulatory follicles, showing a similarity to MT1-MMP mRNA expression. To further determine whether MT1-MMP activates pro-MMP-2 in the ovary, crude plasma membrane fractions from preovulatory ovaries were analyzed by gelatin zymography. In plasma membrane fractions, pro-MMP-2 increased around the time of ovulation. Upon incubation, pro-MMP-2 was activated with the highest levels of activation at 12 h post-hCG. The addition of MT1-MMP antibody or excess TIMP-2 to membrane fractions inhibited pro-MMP-2 activation. The increase in MT1-MMP mRNA may be an important part of the mechanism necessary for the efficient generation of active MMP-2 during the ovulatory process.
Granulosa, Theca, Luteal cells
Immunohistochemical expression of MMP-14 and MMP-2, and MMP-2 activity during human ovarian follicular development. Vos MC 2014 et al.
The aim of this study was to investigate the presence of MMP-14 and MMP-2 during human ovarian follicular development using immunohistochemistry, and the activity of MMP-2 in follicular fluid using zymography.
Ovarian tissue collected from the archives of the Department of Pathology was examined and medical records and histopathology were reviewed. Follicular fluids were collected at the IVF-department and analyzed using zymography.
MMP-14 and MMP-2 were increasingly found in the growing follicles and MMP-2 was highly expressed in the corpus luteum. Pro-MMP-2 was present in follicular fluid of IVF-patients.
The presence of MMP-14 and MMP-2 during human ovarian follicular development from the primordial follicle to the tertiary follicle and corpus luteum is confirmed, as was indicated by earlier animal studies following stimulation with gonadotrophins.
Liu et al examined the physiological regulation pattern and cellular distribution of messenger RNAs coding for membrane type MMP 1 (MT1-MMP, MMP-14) in the CL of adult pseudopregnant (psp) rat. MT1-MMP, known to activate progelatinase A and procollagenase-3 in vitro, was constitutively expressed during the formation, function, and regression of the CL and may therefore be involved in the activation of these MMPs.
Preovulatory, Corpus luteum
Mutation name: None
type: null mutation fertility: unknown Comment:Holmbeck et al. (1999) generated mice deficient in the Mmp14 gene, which they called MT1-MMP.
MMP14 deficiency caused craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to
ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues.