NCBI Summary:
This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]
General function
Comment
Cellular localization
Secreted
Comment
Ovarian function
Steroid metabolism, Luteinization
Comment
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.
Expression regulated by
LH
Comment
Ovarian Expression, Localization, and Function of Tissue Inhibitor of Metalloproteinase 3 (TIMP3) During the Periovulatory Period of the Human Menstrual Cycle. Rosewell KL 2013 et al.
Ovulation involves reorganization of the extracellular matrix of the follicle. This study examines the expression, localization and potential function of the tissue inhibitor of metalloproteinase 3 (TIMP3) during ovulation in women. The dominant follicle of the menstrual cycle was collected at specified times throughout the ovulatory process: pre, early, late, and post ovulatory. For quantitative studies, the follicle was bisected; granulosa and theca cells separated and collected. For immunohistochemistry (IHC), the intact follicle was embedded and TIMP3 localized. Additionally, granulosa cells were collected from women undergoing in vitro fertilization (IVF), treated with increasing concentrations of recombinant TIMP3 and cell viability was assessed. Real time PCR for TIMP3 mRNA revealed an increase in TIMP3 mRNA expression in granulosa cells from the early to the late ovulatory stage. Thecal TIMP3 mRNA expression was constitutive across the periovulatory period. TIMP3 protein was localized by IHC to the granulosa and theca cell layers in pre, early and late ovulatory follicles as well as to the vascular bed. The staining was most intense in the granulosa and theca cells in the late ovulatory group. Treatment of human granulosa-lutein cells with exogenous recombinant TIMP3 for 24 h decreased cell viability by 60%. Using human follicles collected throughout the periovulatory period of the menstrual cycle, we have demonstrated that TIMP3 mRNA expression increases and that TIMP3 protein is in the appropriate cellular layers to regulate proteolytic remodeling as the follicle progresses toward ovulation. In addition, we have shown that elevated levels of TIMP3 leads to decreased cell viability.
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Ovarian localization
Granulosa, Theca, Luteal cells, Ovarian tumor
Comment
Expression and regulative function of tissue inhibitor of metalloproteinase 3 in the goat ovary and its role in cultured granulosa cells. Peng J et al. (2015) Tissue inhibitor of metalloproteinase 3 (TIMP3) played a key role in female reproduction. However, its expression and function in goat are still unclear. In the present study, the full-length cDNA of goat TIMP3 was cloned from adult goat ovary; meanwhile, we demonstrated that putative TIMP3 protein shared a highly conserved amino acid sequence with known mammalian homologs. Real-time PCR results showed that TIMP3 was widely expressed in the tissues of adult goat. In the ovary, increasing expression of TIMP3 mRNA was discovered during the growth process of follicle and corpus luteum. Immunohistochemistry results suggested that TIMP3 protein existed in oocytes of all types of follicles, corpus luteum and granulosa and theca cells of primary, secondary, and antral but not primordial follicles. In vitro, human chorionic gonadotropin (hCG) stimulated the expression of TIMP3 in goat granulosa cells. hCG-induced TIMP3 mRNA expression was reduced by the inhibitors of protein kinase A, protein kinase C, MAPK kinase, or p38 kinase. Functionally, over-expression of TIMP3 significantly increased apoptosis and decreased the viability of cultured granulosa cells. Knockdown of TIMP3 could decrease hCG-induced progesterone secretion and the mRNA abundance of key steroidogenic enzymes (StAR, p450scc and HSD3B) as well as ECM proteins (DCN and FN). These findings provided evidence that the hCG induced expression of TIMP3 may play an important role in regulating goat granulosa cells survival and steroidogenesis.//////////////////
Liu K, et al reported the expression pattern and functional studies of matrix degrading proteases and
their inhibitors in the mouse corpus luteum.
The formation of the corpus luteum (CL) is accompanied with angiogenesis and tissue remodeling
and its regression involves tissue degradation. Matrix degrading proteases such as plasminogen
activators (PAs) and matrix metalloproteinases (MMPs) are thought to play important roles in such
controlled proteolytic processes. In this study, in situ hybridization has been used to examine the
regulation and expression pattern of mRNAs coding for proteases and protease inhibitors belonging
to the PA- and MMP-systems during the life cycle of the CL in an adult pseudopregnant mouse
model. Of the nine proteases and five protease inhibitors that were studied, the majority were found
to be temporally expressed during the formation and/or the regression of the CL. However, the
mRNAs coding for urokinase type PA (uPA), membrane-type 1 MMP (MT1-MMP), and tissue
inhibitor of metalloproteinases type-3 (TIMP-3) were constantly expressed in the mouse CL
throughout its whole life span. To study the functional role of uPA in the CL, we analyzed luteal
formation and function in uPA deficient mice. Our results revealed no significant difference in
ovarian weight, serum progesterone levels, and blood vessel density in the functional CL between
uPA deficient and wild type control mice. The temporal and spatial expression pattern of proteases
and protease inhibitors during the CL life span suggests that members of the PA- and MMP-systems
may play important roles in the angiogenesis and tissue remodeling processes during CL formation,
as well as in the tissue degradation during luteal regression. However, the absence of reproductive
phenotypes in mice lacking uPA and several other matrix degrading proteases indicates that there
are redundancies among different matrix degrading proteases or that tissue remodeling in the ovary
may involve other additional unique elements.
Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma. Ripley D et al. The objective of this study was to determine the spatial expression of matrix metalloproteinases (MMPs) and their physiologic inhibitors, the tissue inhibitor of MMP (TIMP)-3 and TIMP-4, in ovarian carcinoma compared to normal ovaries. Immunohistochemistry was carried out in this study. Tissue sections prepared from normal ovarian tissues from throughout the menstrual cycle (N= 20) and ovarian carcinomas (N= 45) characterized as stage I (N= 5), stage III/IV (N= 40) were immunostained using polyclonal antibodies to the latent and the active form of MMP-26, TIMP-3, and a monoclonal antibody to TIMP-4. Immunoreactive MMP-26, TIMP-3, and TIMP-4 were detected in all the ovarian cell types in normal and tumor tissues. In normal ovarian tissues, theca externa and luteal cells immunostained with high intensity for MMP-26 and TIMPs while theca/granulosa cell staining intensity increased as lutenization progressed. There was low immunostaining of the ovarian stromal and surface epithelial cells for MMP-26, with moderate staining for TIMPs. In the carcinoma specimens, cancer cells and vascular endothelial cells displayed the highest staining intensity compared to adjacent nontumor areas. The immunostaining intensity of MMP-26 and TIMP-3 increased with stage of tumor with the invading tumor cells displaying the strongest immunostaining. MMP-26, TIMP-3, and TIMP-4 are expressed in normal ovarian as well as ovarian tumors with elevated expression in the invasive tumor cells suggesting a potential role for MMP-26 in normal ovary and ovarian cancer biologic function.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
ADAMTS-1/METH-1 and TIMP-3 expression in the primate corpus luteum: divergent patterns and stage-dependent regulation during the natural menstrual cycle.
Young KA, et al .
Studies were designed to determine if ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin repeats-1) is expressed in the rhesus monkey corpus luteum (CL), is regulated by endocrine (LH) or local (progesterone) factors, and is correlated with tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), an inhibitor of ADAMTS-1. PCR analyses indicated that ADAMTS-1 mRNA is expressed in luteinized granulosa cells during controlled ovarian stimulation cycles, and peaks in CL during the early luteal phase of the menstrual cycle, before decreasing (P<0.05) by the mid-late stage. Immunostaining for ADAMTS-1 was detected in luteal cells, peaking in early CL. LH and/or steroid depletion at mid-late luteal stage decreased (P<0.05) ADAMTS-1 mRNA levels compared to controls; LH but not progestin (R5020) replacement prevented this decrease. In contrast, LH and/or steroid ablation-replacement in the early CL did not affect ADAMTS-1 levels. TIMP-3 mRNA levels were lowest during the early CL and rose progressively (P<0.05), peaking in late CL. The divergent expression patterns during the CL lifespan suggest that an imbalance between ADAMTS-1 and TIMP-3 is important during luteal formation (ADAMTS-1 predominates) and regression (TIMP-3 predominates). Also, LH, perhaps via steroids other than progesterone, promotes ADAMTS-1 expression as a function of the stage of the CL.