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matrix metallopeptidase 9 OKDB#: 1154
 Symbols: MMP9 Species: human
 Synonyms: GELB, CLG4B, MMP-9, MANDP2  Locus: 20q13.12 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment The 72- and 92-kD type IV collagenases are members of a group of secreted zinc metalloproteases which, in mammals, degrade the collagens of the extracellular matrix.

NCBI Summary: 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. The enzyme encoded by this gene degrades type IV and V collagens. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. [provided by RefSeq, Jul 2008]
General function Hydrolase, Peptidase/Protease
Comment
Cellular localization Extracellular Matrix, Secreted
Comment
Ovarian function Ovulation, Luteinization
Comment Robker RL, et al 2000 reviewed the role of progesterone receptor in ovulation. The luteinizing hormone (LH) surge initiates a cascade of proteolytic events that control ovulation. One of the genes induced by LH is the progesterone receptor (PR). Because mice with a mutant PR gene (PRKO) fail to ovulate and are infertile, we have used them as a model in which to determine PR target genes that might mediate the ovulatory process. The matrix metalloproteinases (MMPs: MMP2, MMP9, and MMP13) appear to be expressed in ovaries of PRKO mice in a manner similar to that in their wild-type littermates. Young KA, Stouffer reported the gonadotropin and Steroid Regulation of Matrix Metalloproteinases and Their Endogenous Tissue Inhibitors in the Developed Corpus Luteum of the Rhesus Monkey During the Menstrual Cycle. The factors regulating the dynamic expression of matrix metalloproteinases (MMPs) and their inhibitors, TIMPs in the primate corpus luteum (CL) during the menstrual cycle are unknown. The authors hypothesized that luteinizing hormone (LH) or progesterone (P) regulate interstitial-collagenase (MMP-1), the gelatinases (MMP-2, MMP-9), TIMP-1 and TIMP-2 in the CL. Hormone ablation/replacement was performed in rhesus monkeys on luteal d9-11 in five treatment groups (n=4/group): control (no treatment); antide (A; GnRH antagonist); antide +LH; antide +LH +trilostane (TRL; 3betaHSD inhibitor); antide +LH+TRL+R5020 (nonmetabolizable progestin). On d12, the CL was removed with RNA and protein isolated for real-time PCR and immunoassays, respectively. MMP-1 mRNA increased 20-fold with A, whereas LH-replacement maintained MMP-1 mRNA at control levels. Likewise, TRL increased MMP-1 mRNA 54-fold and R5020 prevented this effect. Immunodetectable MMP-1 protein also increased with antide or TRL; these increases were abated with LH or R5020. Gelatinase mRNA and/or protein levels increased with antide (e.g., 3-fold, MMP-2 mRNA) and LH-replacement reduced protein levels (e.g., 11-fold, MMP-2). TRL increased MMP-9 but not MMP-2 expression; however R5020 replacement had no effect on mRNA or protein levels. LH treatment increased TIMP-1 and -2 mRNA and TIMP-1 protein expression compared to controls, and antide groups, whereas R5020 enhanced only immunodetectable TIMP-1. These data strongly suggest that LH suppresses MMP-1 in the primate CL via P. LH also suppresses gelatinases, whether at the mRNA (MMP-2) or protein (MMP-2, -9) levels, perhaps in part via steroids, including P. In contrast, LH promotes TIMP expression, perhaps via steroids including P.
Expression regulated by FSH, LH
Comment Retinoic acid promotes in vitro follicle activation in the cat ovary by regulating expression of matrix metalloproteinase 9. Fujihara M et al. (2018) Retinoic acid (RA) facilitates tissue morphogenesis by regulating matrix matalloproteinase (MMPs) expression. Our objective was to examine the influence of RA on in vitro development of follicles enclosed within domestic cat ovarian tissues. Ovarian cortices from 9 prepubertal and 13 adult cats were incubated for 7 d in medium containing 0 (control), 1 or 5 μM RA and then analyzed for viability. Cortices from additional three animals of each age group were cultured in the same condition and follicle morphology, stage and size were histologically evaluated. In a separate study, cortices from 14 donors (7 prepubertal; 7 adult cats) were incubated in 0 or 5 μM RA for 7 d and assessed for (1) MMP1, 2, 3, 7, 9 and TIMP1 expression by qPCR and (2) protein expression of MMP9 by immunohistochemistry. Donor age did not influence follicle response to RA. Collective data from both age groups revealed that percentages of primordial follicles in 5 μM RA treatment were lower (P < 0.05; 40.5 ± 4.5%) than in fresh cortices (66.7 ± 5.3%) or controls (60.1 ± 4.0%) with 1 μM-RA treatment producing intermediate (56.3 ± 4.0%) results. Proportion of primary follicles in 5 μM RA (21.7 ± 3.3%) was higher than in fresh cortices (4.9 ± 2.9%) and controls (9.0 ± 2.8%) with 1 μM-RA treatment producing an intermediate value (13.8 ± 2.0%). Furthermore, proportion of secondary follicles increased after 7 d in the presence of 5 μM RA (9.5 ± 2.7%) compared to other groups (fresh, 1.9 ± 0.8%; control, 2.6 ± 1.1%; 1 μM RA, 2.5 ± 0.2%). MMP9 transcript and protein were upregulated, whereas MMP7 mRNA was suppressed by 5 μM-RA treatment compared to fresh counterparts. RA did not impact MMP1, 2, 3, 13 or TIMP1 expression. In summary, RA activated cat primordial follicle growth likely via a mechanism related to upregulation of MMP9 and down-regulation of MMP7 transcripts.//////////////////Expression and Regulation of MMP1, MMP3, and MMP9 in the Chicken Ovary in Response to Gonadotropins, Sex Hormones, and TGFB1. Zhu G 2014 et al. Matrix metalloproteinases (MMPs) are a specific class of proteolytic enzymes that play critical roles in follicular development and luteinization in mammals. However, the role of MMPs in avian ovary remains largely unknown. We found that three MMP genes (MMP1, MMP3, and MMP9) were significantly up-regulated in 23-week-old (laying phase) chicken ovaries compared with 6-week-old (pre-pubertal phase). In reproductively active chicken ovary, MMP1 expression (both mRNA and protein) remained low in pre-hierarchical and pre-ovulatory follicles but increased in post-ovulatory follicles (POF). Both MMP3 and MMP9 expression levels increased during follicular maturation. MMP3 reached maximal expression in the first largest follicle (F1), while MMP9 levels continued to rise in POF1 and POF2 after ovulation. Immunohistochemistry, Western blotting and zymography experiments indicated that MMP1, MMP3 and MMP9 were synthesized and secreted by granulosa cells of different follicles in the chicken ovary. The mRNA expression of MMP1 and MMP3 in the granulosa cells was stimulated by follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone and estrogen but not by transforming growth factor beta 1 (TGFB1). However, the mRNA of MMP9 was induced by TGFB1 but not FSH, LH, progesterone or estrogen. Luciferase reporter and mutagenesis analysis indicated the AP1 and NFkappaB elements located in the promoter region from -1700 to -2400 bp were critical for both basal and TGFB1 induced MMP9 transcription. These data provide the first spatial-temporal expression analysis of MMP system in the chicken ovary. /////////////////////////
Ovarian localization Granulosa, Luteal cells
Comment Differential Release of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases by Human Granulosa-Lutein Cells and Ovarian Leukocytes. Fedorcs?P et al. Tissue reorganization during ovulation and corpus luteum formation involves a coordinated action of matrix metalloproteinases (MMPs) and tissue MMP inhibitors (TIMPs). In this study we investigated the cellular source of ovarian MMPs and TIMPs. Cells isolated from the preovulatory human follicle were cultured after immunobead depletion of CD45-expressing cells, which allowed differential assessment of leukocyte and granulosa-lutein cell fractions. Secretion of MMP-9 by follicular fluid-derived cells was associated with the presence of leukocytes. Granulosa-lutein cells synthesized low levels of MMP-9 but failed to secrete this enzyme that presumably accumulated in the cytoplasm, indicated by an increased MMP-9 expression of luteinized cells in sectioned midluteal phase corpora lutea. Synthesis and secretion of TIMP by follicular fluid-derived cells was associated with granulosa-lutein cells. TIMPs derived by granulosa-lutein cells failed to inhibit MMP-related pericellular proteolysis. The findings support a two-cell model of periovulatory MMP/TIMP release, in which leukocytes secrete MMPs and granulosa-lutein cells release TIMP, suggesting that there exists an intriguing interaction among cells that intertwingle during ovulation and corpus luteum formation. Shalev E, et al reported the balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells and comparison between women with PCOS and normal ovulatory women. They assessed the differences in production of MMP-2, MMP-9 and TIMP-1 by cultured luteinized granulosa cells from women with PCOS and normal ovulatory women after ovarian stimulation for IVF treatment. In follicular fluid from women with PCOS, levels of MMP-9 and MMP-2 were higher than the normal group, as was the basal production of these proteins by cultured cells. Basal production of TIMP-1 by cultured cells was not different between PCOS and normal groups. A time-dependent increase in the production of MMP-9 was observed in cells from both normal and PCOS women, although the increase was more pronounced in the latter Thus the MMP-TIMP balance is shifted toward greater MMP activity in luteinized granulosa cells from women with PCOS. Characterization of Matrix Metalloproteinase-2 and -9 and their inhibitors in equine granulosa cells in vivo and in vitro. Sessions DR et al. Matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) regulate tissue remodeling events necessary for ovulation. Thus, changes in MMP and TIMP expression and protein enzyme activity were examined in vivo and in vitro during follicular development and atresia in the horse. Equine granulosa cells and follicular fluid from medium (15 to 29 mm) healthy and atretic follicles and from large (>30 mm) healthy and preovulatory follicles were collected by transvaginal aspiration. The cells were either snap frozen (in vivo study) or cultured for 48 h (in vitro study) to determine gene expression and protein enzyme activity of MMP-2 and -9 and TIMP-1 and -2. Concentrations of progesterone and estradiol were determined by RIA in follicular fluid and conditioned media and were used along with follicle dynamics to classify follicles. In vivo, expression of MMP-2 and TIMP-2 was increased (P < 0.05) in large preovulatory follicles, while TIMP-1 was decreased. The ratio of MMP-2:TIMP-2 expression was decreased (P < 0.05) in medium healthy and large preovulatory follicles, while MMP-9:TIMP-1 ratio was increased only in large preovulatory compared to large healthy follicles. Estradiol was greatest (P < 0.05) in fluid of large healthy and large preovulatory follicles. However, medium atretic follicles were associated with the lowest estradiol concentrations, both in vivo and in vitro. Progesterone concentrations were greatest (P < 0.05) in large preovulatory follicles both in vivo and in vitro. In healthy follicles in vivo, the diameter correlated to estradiol concentration, estradiol:progesterone ratio, MMP-9 and TIMP-1 expression, and MMP-2 and -9 protein activity. In contrast to in vivo studies, the ratio of MMP-9:TIMP-1 expression was increased (P < 0.05) in medium healthy follicles; TIMP-2 expression decreased in large preovulatory follicles in vitro. In addition, MMP-9 protein activity was decreased (P < 0.05) in the media samples of cells from large healthy compared to medium healthy follicles. These results indicate changes in MMP-2 and -9 activities may be essential to the tissue reorganization necessary for ovulation in the equine ovary.
Follicle stages Preovulatory, Corpus luteum
Comment Pitzel L, et al 2000 reported the secretion and gene expression of metalloproteinases and gene expression of their inhibitors in porcine corpora lutea at different stages of the luteal phase. Oksjoki S, et al 1999 reported the cyclic expression of mRNA transcripts for connective tissue components in the mouse ovary.
Phenotypes
Mutations 1 mutations

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: By targeted disruption in embryonic stem cells, Vu et al. (1998) created homozygous mice with a null mutation in the MMP9/gelatinase B gene. These mice exhibited an abnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes developed normally, apoptosis, vascularization, and ossification were delayed, resulting in progressive lengthening of the growth plate to about 8 times normal. After 3 weeks postnatal, aberrant apoptosis, vascularization, and ossification compensated to remodel the enlarged growth plate and ultimately produced an axial skeleton of normal appearance. Transplantation of wildtype bone marrow cells rescued vascularization and ossification in MMP9-null growth plates, indicating that these processes are mediated by MMP9-expressing cells of bone marrow origin, designated chondroclasts. Dubois, et al 2000 reported that gelatinase B deficiency impairs reproduction.

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Phenotypes and GWAS show phenotypes and GWAS
Links
OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
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created: May 3, 2001, 10:42 a.m. by: hsueh   email:
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last update: Dec. 3, 2018, 10:37 a.m. by: hsueh    email:



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