Gasson et al. (1985) isolated a cDNA molecular clone
encoding a 28,000 MW glycoprotein of this class, called erythroid-potentiating activity (EPA).
The nucleotide sequence of the gene for human tissue inhibitor of metalloproteinase
(TIMP) is identical to that of EPA (Docherty et al., 1985) . TIMP is also the same as collagenase
inhibitor. Human collagenase inhibitor (HCI) appears to play a major role in modulating the activity of interstitial
collagenase as well as a number of connective tissue metalloendoproteases. HCI functions through the formation of a tight
1:1 complex with active collagenase.
Collagenase and related metalloproteinases are responsible for
much of the remodeling that occurs in connective tissue. The extracellular activity of these enzymes is regulated by
TIMP.
NCBI Summary:
This gene belongs to the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function. Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction. [provided by RefSeq, Jul 2008]
General function
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. McIntush EW, et al. reviewed the role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function.
Cellular localization
Extracellular Matrix, Secreted
Comment
ECM-Regulator timp Is Required for Stem Cell Niche Organization and Cyst Production in the Drosophila Ovary. Pearson JR et al. (2016) The extracellular matrix (ECM) is a pivotal component adult tissues and of many tissue-specific stem cell niches. It provides structural support and regulates niche signaling during tissue maintenance and regeneration. In many tissues, ECM remodeling depends on the regulation of MMP (matrix metalloproteinase) activity by inhibitory TIMP (tissue inhibitors of metalloproteinases) proteins. Here, we report that the only Drosophila timp gene is required for maintaining the normal organization and function of the germline stem cell niche in adult females. timp mutant ovaries show reduced levels of both Drosophila Collagen IV α chains. In addition, tissue stiffness and the cellular organization of the ovarian niche are affected in timp mutants. Finally, loss of timp impairs the ability of the germline stem cell niche to generate new cysts. Our results demonstrating a crucial role for timp in tissue organization and gamete production thus provide a link between the regulation of ECM metabolism and tissue homeostasis.//////////////////
Neutralizing TIMP1 Restores Fecundity in a Rat Model of Endometriosis and Treating Control Rats with TIMP1 Causes Anomalies in Ovarian Function and Embryo Development. Stilley JA et al. Human and rat endometriotic lesions synthesize and secrete tissue inhibitor of metalloproteinase 1 (TIMP1). More TIMP1 localizes in the ovarian theca in an established rat model for endometriosis (Endo) when compared to surgical controls (Sham). We hypothesized that endometriotic TIMP1 secreted into peritoneal fluid (PF) negatively impacts ovarian function and embryogenesis by altering the balance of matrix metalloproteinases (MMPs) and TIMPs. Three experiments were performed modulating TIMP1 in vitro and in vivo to investigate ovarian and embryonic anomalies. The first experiment demonstrated control embryos treated in vitro with endometriotic PF concentrations of TIMP1 developed abnormally. In the second experiment where TIMP1 was modulated in vivo, TIMP1 treated Sham rats had fewer zygotes, ovarian follicles and corpora lutea (CLs) and poorer embryo quality and development, analogous to Endo rats. Importantly, Endo rats treated with a TIMP1 function blocking antibody had zygote, follicle and CL numbers and embryo quality similar to Sham rats. More TIMP1 inhibitory activity was found in ovaries from Endo and TIMP1 treated Sham rats than in ovaries from Sham or TIMP1 antibody-treated Endo rats. In experiment three, control rats (no surgery) treated with Endo PF had fewer follicles and CLs and increased TIMP1 localization in the ovarian theca whereas Endo PF stripped of TIMP1 or Sham PF had no effect, providing further evidence that endometriotic TIMP1 sequesters in the ovary and inhibits MMPs necessary for ovulation. Collectively, these results showed that excessive TIMP1 was deleterious to ovulation and embryo development. Thus, novel TIMP1 modulating therapies may be developed to alleviate infertility in women with endometriosis.
Regulation and Function of Tissue Inhibitor of Metalloproteinases 1 (TIMP1) and Tissue Inhibitor of Metalloproteinases 3 (TIMP3) in Periovulatory Rat Granulosa Cells. Li F et al. In the ovary, the matrix metalloproteinases (MMPs) and the TIMPs have been postulated to regulate extracellular matrix remodeling associated with ovulation. In the present study, we investigated the regulatory mechanisms controlling expression of Timp1 and Timp3 mRNA in periovulatory granulosa cells. Granulosa cells were isolated from immature PMSG-primed (10 IU) rat ovaries and treated with hCG (1 IU/ml). At 4h after hCG treatment, Timp1 expression was highest and then decreased gradually over the remaining 24h of culture. In contrast, hCG induced a biphasic increase of Timp3 expression at 2h and 16h. The hCG stimulated expression of Timp1 and Timp3 mRNA was blocked by inhibitors of the PKA (H89), PKC (GF109203) and MAP kinase (SB2035850) pathways. To further explore Timp1 and Timp3 regulation, cells were cultured with the progesterone receptor antagonist RU486 which blocked the hCG induction of Timp3 expression while the EGF receptor tyrosine kinase inhibitor AG1478 blocked the hCG stimulation of both Timp1 and Timp3 expression. The prostaglandin-endoperoxide synthase 2 inhibitor NS-398 had no effect. The potential function of TIMP3 was investigated with Timp3-specific siRNA treatment. Timp3 siRNA resulted in a 20% decrease in hCG induced progesterone levels and microarray analysis revealed an increase in cytochrome P450 Cyp 17, ubiquitin conjugating enzyme E2T, and heat shock protein 70. IGFBP5, stearyl-CoA desaturase, and annexin A1 were decreased. The differential regulation between Timp1 and Timp3 may correlate with their unique roles in the processes of ovulation and luteinization. For TIMP3, this may include regulating fatty acid synthesis, steroidogenesis, and protein turnover.
Hagglund et al 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.
Warren B. Nothnick 2003 reported that tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Deficient Mice Display Reduced Serum Progesterone Levels during Corpus Luteum Development .
TIMP-1 has been suggested to play a role in progesterone production, but reports are conflicting. To more thoroughly examine the role of TIMP-1 in steroidogenesis during early luteal development in vivo, immature wild-type and TIMP-1 null female mice were primed with gonadotropins. Mice were sacrificed at 0, 24, and 48 h post hCG administration and serum was collected for determination of estradiol (E2) or progesterone (P4) concentrations. In the 24 h hCG groups, ovulation was assessed by counting the number of shed ova. Serum P4 concentrations were significantly lower in the TIMP-1 null mice, both at 24 and 48-h post hCG compared to wild-type counterparts. No differences were detected in the number of ovulations between genotypes at the 24 h time point. In both the 24 and 48 h post-hCG groups, null mice had significantly higher ovarian wet weights. Interestingly, ovarian MMP activity was greater in the null mice at 24 h post hCG but higher in the wild-type at 48 h post hCG administration. These observations suggests that expression of TIMP-1 during early luteal development may participate in regulation of progesterone production via its ability to regulate ovarian MMP activity.
Expression regulated by
FSH, LH, Steroids, prolactin, progesterone, T3
Comment
Molecular characterization and hormonal regulation of tissue inhibitor of metalloproteinase 1 in goat ovarian granulosa cells. Peng JY et al. (2015) Tissue inhibitor of metalloproteinase 1 (TIMP1) belongs to a group of endogenous inhibitors that control the activity of matrix metalloproteinases and other metalloproteinases. TIMP1 is ubiquitously expressed and implicated in many physiological and pathologic processes. In this study, the full-length complementary DNA of goat (Capra hircus) Timp1 was cloned from adult goat ovary for the first time to better understand the regulatory role of TIMP1. The putative TIMP1 protein shared a high amino acid sequence identity with other species. Real-time polymerase chain reaction results showed that Timp1 was widely expressed in adult goat tissues, and messenger RNA expression was higher in the ovary than in other tissues; meanwhile, increasing expression of Timp1 was also discovered during the process of follicle growth and corpus luteum. We then investigated Timp1 expression patterns in different types of ovarian follicular cells from goats. In small or large antral follicles, Timp1 expression was higher (P < 0.05) in theca cells than in granulosa cells, cumulus cells, and oocytes. Increasing expression of Timp1 in theca and granulosa cells was observed as the variation of the follicle size. Immunohistochemical analyses further revealed the presence of the TIMP1 proteins in follicles at all antral stages of development. The most intense staining for TIMP1 was observed in the theca cells and granulosa cells of large antral follicles and corpus luteum. Timp1 was highly (P < 0.05) induced in granulosa cells in vitro after treatment with the luteinizing hormone agonist, human chorionic gonadotropin. Treatments with forskolin, phorbol 12-myristate 13-acetate, or phorbol 12-myristate 13-acetate + forskolin could also stimulate Timp1 messenger RNA expression. The effects of human chorionic gonadotropin were reduced (P < 0.05) by the inhibitors of protein kinase A, protein kinase C, MAPK kinase, or p38 kinase, indicating that Timp1 expression could be adjusted by luteinizing hormone-initiated activation of these signaling mediators. Our results suggested that TIMP1 may be involved in regulating ovarian follicle development and ovulation.//////////////////
Goldman S, et al. reported that triiodothyronine and follicle-stimulating hormone, alone and additively together, stimulate production of the tissue
inhibitor of metalloproteinases-1 in cultured human luteinized granulosa cells.
O'Sullivan MJ, et al. reported the gonadotrophin regulation of production of tissue inhibitor of metalloproteinases-1 by luteinized human granulosa cells.
Hirsch B, et al. reported the stimulation of matrix-metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 gene expression in rats by the preovulatory prolactin peak.
Ovarian localization
Granulosa, Theca
Comment
Chun SY, et al. examined the regulation and cellular localization of tissue inhibitor of metalloproteinase type-1 (TIMP-1) mRNAs by in situ hybridization in ovarian sections of eCG-primed immature rats treated with hCG. Before hCG treatment, low expression of TIMP-1 mRNA was observed in theca cells, but not in granulosa cells. After hCG treatment, TIMP-1 mRNA was greatly stimulated in theca cells irrespective of
follicle size, while the expression in granulosa cells was limited to large antral follicles.
Inderdeo DS et al studied the spatiotemporal expression of individual
TIMP genes during the natural ovulatory cycle. TIMP-1 mRNA was elevated at early
proestrus and D18 and was maximal at late proestrus and postpartum (PP1). In situ hybridization localized TIMP-1 mRNA to the corpus luteum at D18 and PP1, and to oocytes at specific stages of follicular development.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Liu et al examined the physiological regulation pattern and cellular distribution of messenger RNAs coding for tissue inhibitor of MMPs type 1 (TIMP-1) in the CL of adult pseudopregnant (psp) rat. TIMP-1 was induced during both the formation and regression of the CL, suggesting that this inhibitor modulates MMP activity during these processes.
To test whether the induction of TIMP-1 is coupled with luteal regression, Liu et al prolonged the luteal phase by performing hysterectomies, and induced premature luteal regression by treating the pseudopregnant rats with a PGF2alpha analog, cloprostenol. In both treatments, TIMP-1 were induced only after the serum level of progesterone had decreased, suggesting that TIMP-1 is induced by physiological signals, which initiate functional luteolysis to play a role in tissue degradation during structural luteolysis.
Duncan WC et al on day 10 of the normal luteal
phase and 12 and 24 h after induced luteolysis, with either gonadotrophin-releasing hormone (GnRH) antagonist or
prostaglandin F2 alpha analogue. Expression of
TIMP-1 was investigated by in situ hybridisation. TIMP-1 was found to be highly expressed in the marmoset
corpus luteum. Luteolysis induced with either prostaglandin F2 alpha or GnRH antagonist was associated with a significant
fall in TIMP-1 expression in luteal tissue. TIMP-1 mRNA was also localised to ovarian follicles throughout the ovarian
cycle. Expression occurred in the thecal layer of smaller follicles (< 1.5 mm) and the granulosal layer of larger pre-ovulatory
follicles. In atretic follicles, TIMP-1 was highly expressed at the interface between the thecal and granulosal cells.
Duncan WC et al reported that a 30 kDa protein consistent with TIMP-1 was detected in human corpora lutea.
This protein was localized to the granulosa lutein cells in all tissues examined. The expression and localisation of TIMP-1 did
not change throughout the luteal phase and was not altered by luteal rescue. The function of this uniform expression of
TIMP-1 in the corpus luteum is not clear but these data suggest that the inhibition of structural luteolysis during maternal
recognition of pregnancy is not mediated by regulation of TIMP-1 expression.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:Nothnick WB et al assessed the function of TIMP-1 during the periovulatory period in vivo. Twenty-three-day-old TIMP-1-deficient and wild-type female mice were injected with 5 IU eCG, followed 48 h later by an ovulation-inducing dose of hCG (5 IU). Animals were killed at the time of hCG
injection (0-h hCG), at 12 h (12-h hCG), or at 24 h post-hCG (24-h hCG) administration.
TIMP-1-deficient females in the 0-h hCG group showed reduced levels of ovarian TIMP-2
and TIMP-3 expression compared to wild-type counterparts. No significant difference was
detected between genotypes in the 0-h hCG group for number of healthy or atretic follicles or for serum estradiol-17beta
concentrations. Additionally, no significant differences were detected between genotypes in the 12- and 24-h hCG groups for
serum progesterone concentrations, ovarian TIMP-2 and TIMP-3 expression, or number of oocytes released.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Nothnick WB. 2001 reported a reduction in reproductive lifespan of tissue inhibitor of
metalloproteinase 1 (TIMP-1)-deficient female mice.
Mice deficient in TIMP-1 protein display altered reproductive parameters, which
include reduced serum progesterone concentrations and abnormal uterine morphology.
As these abnormalities could lead to altered reproductive performance, the objective of
this study was to examine whether TIMP-1 deficiency is associated with a reduction in
the reproductive lifespan of female mice in which the TIMP-1 gene is disrupted.
Wild-type (n = 50) and TIMP-1 null mice (n = 90) were mated with males of proven
fertility from the same genotype for 12 months during which the number of litters
delivered and the number of pups per litter were determined. Significantly fewer
TIMP-1 null females achieved pregnancy (47 of 90 or 52%) compared with the
wild-type mice (39 of 50 or 78%; P < 0.05). TIMP-1-deficient female mice that
achieved and maintained pregnancy had significantly fewer litters during the 12 months
(2.9 +/- 0.8 versus 3.5 +/- 0.8; P < 0.01) and significantly fewer pups per litter (5.7 +/-
1.3 versus 4.7 +/- 1.1; P < 0.05) than did wild-type mice. Females of both genotypes
produced two con-secutive litters, after which significantly fewer TIMP-1 null mice
became pregnant. Mating of females with males of proven fertility from the other
genotype confirmed that these abnormalities were not due to the inability of TIMP-1
null males to produce offspring. These data indicate that the absence of TIMP-1 is
associated with a reduction in the reproductive lifespan of female mice, which may be
? manifested at the ovary, uterus or both organs.