Matrix metalloproteinases (MMPs) are zinc-binding endopeptidases that degrade various components of the extracellular
matrix. They have been implicated in normal and pathologic processes including tissue remodeling, wound healing,
angiogenesis, and tumor invasion.
Using an MMP similarity search of the EST database, Cossins et al. (1996) identified a partial cDNA clone that encodes the
3-prime end of a putative MMP, which they called MMP18 but which has officially designated MMP19. They
PCR-amplified the 5-prime end and cloned and sequenced the full-length cDNA. MMP19 contains an open reading frame of
508 amino acids with a predicted molecular weight of 57,238 and has all the characteristic features of the MMP family.
MMP-19 mRNA is expressed in a wide variety of normal human tissues, including mammary
gland, placenta, lung, pancreas, ovary, small intestine, spleen, thymus, prostate, testis, colon, and heart, but is not detected in
brain, skeletal muscle, kidney, liver, or peripheral blood leucocytes.
NCBI Summary:
This gene encodes a member of a family of proteins that 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 protein is secreted as an inactive proprotein, which is activated upon cleavage by extracellular proteases. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Jan 2013]
General function
Enzyme
Comment
Cellular localization
Extracellular Matrix, Secreted
Comment
Ovarian function
Ovulation, Follicle rupture, Luteolysis
Comment
At the time of ovulation, proteolytic degradation of the follicular wall is required to release the mature oocyte. Extracellular
proteases, such as serine proteases and matrix metalloproteinases (MMPs), are thought to play important roles in this process.
Hagglund et al have examined the regulation of 11 MMPs and 3 tissue inhibitors of metalloproteinases (TIMPs)
during gonadotropin-induced ovulation in the PMSG-pretreated immature mouse using Northern blot hybridization.
Most of the MMPs and TIMPs were expressed at a constitutive
level throughout the periovulatory period. However, MMP-19 and TIMP-1 revealed a different expression pattern; they were both induced 5-10 times by hCG and reached their maximum levels at 12 h after hCG treatment, corresponding to the time of ovulation. At this time point, MMP-19 and TIMP-1 messenger RNA were localized to the granulosa and thecal-interstitial cells of large preovulatory and ovulating follicles. This temporal and spatial regulation pattern suggests that MMP-19 might be involved in the tissue degradation that occurs during follicular rupture and that TIMP-1 could have a role in terminating MMP activity after ovulation.
Expression regulated by
LH, Steroids
Comment
Estrogen Receptor β controls MMP-19 expression in mouse ovaries during ovulation. Nalvarte I et al. (2015) Estrogen receptor beta (ERβ) has a central role in mouse ovaries, as ERβ knockout mice are subfertile due to an increase in fibrosis around the maturing follicle and a decrease in blood supply. This has as a consequence that these follicles rarely rupture to release the mature oocyte. Matrix metalloproteinases (MMPs) are modulators of the extracellular matrix, and the expression of one specific MMP, MMP-19, is normally increased in granulosa cells during their maturation until ovulation. In this study we demonstrate that MMP-19 levels are downregulated in ERβ knockout mouse ovaries. Using human MCF-7 cells that overexpress ERβ we could identify MMP-19 to be a transcriptional target of ligand-bound activated ERβ acting on an Sp1 binding site. These data provide a molecular explanation for the observed follicle rupture defect that contributes to the subfertility of female ERβ knockout mice.//////////////////
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.//////////////////
Regulation of Matrix Metalloproteinase-19 Messenger RNA Expression in the Rat Ovary.
Jo M, et al 2004 .
Matrix metalloproteinases (MMPs) are instrumental in the constant tissue remodeling in the ovary. An induction of MMP-19 mRNA in periovulatory follicles has been reported in mouse ovaries. However, little is known about MMP-19 expression during the follicular and luteal period, or about the ovarian regulation of MMP-19 mRNA expression. We examined the expression pattern of MMP-19 mRNA during various reproductive phases and the periovulatory regulation of MMP-19 mRNA in the rat ovary. In gonadotropin-primed immature rat ovaries, levels of MMP- 19 mRNA transiently increased during both follicular growth and ovulation. MMP-19 mRNA was localized to the theca-interstitial layer of growing follicles and to the granulosa and theca-interstitial layer of periovulatory follicles. A similar expression pattern of MMP-19 mRNA in periovulatory follicles was observed in ovaries from naturally cycling adult rats. Accumulation of MMP-19 mRNA was detected in regressing CL. The regulation of MMP-19 mRNA expression during the periovulatory period was investigated via in vivo studies and through in vitro culture studies on follicular cells. The hCG-induction of MMP-19 mRNA was mimicked by treating granulosa cells, but not theca-interstitial cells, from preovulatory follicles with LH or activators of the PKA or PKC pathways. Cyclohexamide blocked the LH or forskolin- induced MMP-19 mRNA expression, demonstrating the requirement for new protein synthesis. In contrast, blocking the activation of the progesterone receptor or prostaglandin synthesis had no effect on the increase in MMP-19 mRNA expression. In conclusion, the induction of MMP-19 mRNA suggests an important role of this proteinase during follicular growth, ovulation, and luteal regression.