NCBI Summary:
This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down the interstitial collagens, including types I, II, and III. The gene is part of a cluster of MMP genes on chromosome 11. Mutations in this gene are associated with chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
General function
Enzyme, Peptidase/Protease
Comment
Cellular localization
Secreted
Comment
candidate123
Ovarian function
Ovulation, Follicle rupture, Luteinization
Comment
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.
Gelatinase A and membrane-type matrix metalloproteinases 1 and 2 are responsible for follicle rupture during ovulation in the medaka Ogiwara K, et al .
Identification of the hydrolytic enzymes involved in follicle rupture during vertebrate ovulation remains a central challenge for research in reproductive biology. Here, we report a previously uncharacterized approach to this problem by using an in vitro ovulation system in the medaka, Oryzias latipes, which is a small freshwater teleost. We found that follicle rupture in the medaka ovary involves the cooperation of at least three matrix metalloproteinases (MMPs), together with the tissue inhibitor of metalloproteinase-2b protein. We determined the discrete roles of each of these proteins during follicle rupture. Our results indicated that gelatinase A induces the hydrolysis of type IV collagen constituting the basement membrane, membrane-type 2 MMP degrades type I collagen present in the theca cell layer, and MT1-MMP and the tissue inhibitor of metalloproteinase-2b are involved in the production and regulation of gelatinase A. These findings will help clarify the mechanism of follicle wall degradation during ovulation in mammalian species.
Gelatinase A and membrane-type matrix metalloproteinases 1 and 2 are responsible for follicle rupture during ovulation in the medaka Ogiwara K, et al .
Identification of the hydrolytic enzymes involved in follicle rupture during vertebrate ovulation remains a central challenge for research in reproductive biology. Here, we report a previously uncharacterized approach to this problem by using an in vitro ovulation system in the medaka, Oryzias latipes, which is a small freshwater teleost. We found that follicle rupture in the medaka ovary involves the cooperation of at least three matrix metalloproteinases (MMPs), together with the tissue inhibitor of metalloproteinase-2b protein. We determined the discrete roles of each of these proteins during follicle rupture. Our results indicated that gelatinase A induces the hydrolysis of type IV collagen constituting the basement membrane, membrane-type 2 MMP degrades type I collagen present in the theca cell layer, and MT1-MMP and the tissue inhibitor of metalloproteinase-2b are involved in the production and regulation of gelatinase A. These findings will help clarify the mechanism of follicle wall degradation during ovulation in mammalian species.
Expression regulated by
LH, Steroids
Comment
Expression of matrix metalloproteinases in bovine luteal cells induced by prostaglandin F2α, interferon γ and tumor necrosis factor α. Abe H et al. (2015) We recently demonstrated that luteal cells flow out from the ovary via lymphatic vessels during luteolysis. However, the regulatory mechanisms of the outflow of luteal cells are not known. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basal membrane, and tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs. To test the hypothesis that MMP expression in luteal cells is regulated by luteolytic factors, we investigated the effects of prostaglandin F2α (PGF), interferon γ (IFNG) and tumor necrosis factor α (TNF) on the mRNA expression of MMPs and TIMPs in cultured luteal cells. Luteal cells obtained from the CL at the mid-luteal stage (days 8-12 after ovulation) were cultured with PGF (0.01, 0.1, 1 μM), IFNG (0.05, 0.5, 5 nM) and TNF (0.05, 0.5, 0.5 nM) alone or in combination for 24 h. PGF and IFNG significantly increased the expression of MMP-1 mRNA. In addition, 1 μM PGF in combination with 5 nM IFNG stimulated MMP-1 and MMP-9 mRNA expression significantly more than either treatment alone. In contrast, IFNG significantly decreased the level of MMP-14 mRNA. The mRNA expression of TIMP-1, which preferentially inhibits MMP-1, was suppressed by 5 nM INFG. One μM PGF and 5 nM IFNG suppressed TIMP-2 mRNA expression. These results suggest a new role of MMPs: luteal MMPs stimulated by PGF and IFNG break down the extracellular matrix surrounding luteal cells, which accelerates detachment from the CL during luteolysis, providing an essential prerequisite for outflow of luteal cells from the CL to lymphatic vessels.//////////////////
Induction of proteinases in the human preovulatory follicle of the menstrual cycle by human chorionic gonadotropin. Rosewell KL et al. (2014) To explore the temporal expression in granulosa and theca cells of key members of the MMP and ADAMTS families across the periovulatory period in women to gain insight into their possible roles during ovulation and early luteinization. Experimental prospective clinical study and laboratory-based investigation. University medical center and private IVF center. Thirty-eight premenopausal women undergoing surgery for tubal ligation and six premenopausal women undergoing assisted reproductive techniques. Administration of hCG and harvesting of follicles by laparoscopy and collection of granulosa-lutein cells at oocyte retrieval. Expression of mRNA for matrix metalloproteinase (MMPs) and the A disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) in human granulosa cells and theca cells collected across the periovulatory period of the menstrual cycle and in cultured granulosa-lutein cells after hCG. Localization of MMPs and ADAMTSs by immunohistochemistry. Expression of MMP1 and MMP19 mRNA increased in both granulosa and theca cells after hCG administration. ADAMTS1 and ADAMTS9 mRNA increased in granulosa cells after hCG treatment, however, thecal cell expression for ADAMTS1 was unchanged, while ADAMTS9 expression was decreased. Expression of MMP8 and MMP13 mRNA was unchanged. Immunohistochemistry confirmed the localization of MMP1, MMP19, ADAMTS1, and ADAMTS9 to the granulosa and thecal cell layers. The collection of the dominant follicle throughout the periovulatory period has allowed the identification of proteolytic remodeling enzymes in the granulosa and theca compartments that may be critically involved in human ovulation. These proteinases may work in concert to regulate breakdown of the follicular wall and release of the oocyte.//////////////////
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.
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Ovarian localization
Granulosa, Luteal cells
Comment
Gonadotropin Surge-Induced Differential Upregulation of Collagenase-1 (MMP-1) and Collagenase-3 (MMP-13) mRNA and Protein in Bovine Preovulatory Follicles.
Bakke LJ, et al .
The ovulatory process is characterized by focalized extracellular matrix degradation at the apex of preovulatory follicles. Many studies have implicated the matrix metalloproteinases (MMPs) as potential mediators of follicle rupture. Objectives of this study were to determine localization and effect of the gonadotropin surge on temporal expression of MMP-1 and MMP-13 in bovine preovulatory follicles. Samples were collected at 0, 6, 12, 18, 24, and 48 h (corpora lutea) after GnRH injection (n = 5-6 per time point) and amounts of MMP-1 and MMP-13 mRNA and protein determined using dot blot or semiquantitative RT-PCR and Western blot analyses. Samples were also collected at 0 and 20 h after GnRH injection for immunohistochemical localization of MMP-1 and MMP-13. Results indicate that follicular expression of MMP-1 and MMP-13 increased following the gonadotropin surge. Abundance of MMP-1 mRNA increased at 6, 12, and 48 h post-GnRH injection. Immunoreactive MMP-1 was localized to granulosal and thecal layers of preovulatory follicles. Amounts of MMP-1 protein increased in both the apex and the base of preovulatory follicles. Abundance of MMP-13 mRNA increased at 6, 24, and 48 h post GnRH injection. Amounts of MMP-13 protein also increased in the follicular apex and base. Immunoreactive MMP-13 was localized to granulosal and thecal layers of preovulatory follicles. Results indicate MMP-1 and MMP-13 are increased in bovine preovulatory follicles following the gonadotropin surge but do not support a requirement for differential up-regulation of MMP-1 and MMP-13 (follicular apex vs. base) for the preovulatory collagenolysis required for follicle rupture.
Follicle stages
Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the presence of polycystic ovary syndrome in Caucasian women. Walch K et al. (2005) A common -1607 GG/G polymorphism of the matrix metalloproteinase-1 (MMP1) gene promoter was investigated in a series of Caucasian women with polycystic ovary syndrome (PCOS) and controls, by direct sequencing. In this prospective case-control study, the odds for women with at least one mutant GG allele of the MMP1 promoter to be diagnosed with PCOS was 2.7.//////////////////