| ADAM metallopeptidase with thrombospondin type 1 motif 1 | OKDB#: 895 |
| Symbols: | ADAMTS1 | Species: | human | ||
| Synonyms: | C3-C5, METH1 | Locus: | 21q21.3 in Homo sapiens |
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| General Comment |
A disintegrin and metalloproteinase with thrombospondin motifs 1
(ADAMTS-1) is known to cleave extracellular matrix in acutely inflamed tissues.
The ADAMs belong to a disintegrin-like and metalloproteinase-containing protein family that are
zinc-dependent metalloproteinases. These proteins share all or some of the following domain
structure: a signal peptide, a propeptide, a metalloproteinase, a disintegrin, a cysteine-rich, and an
epidermal growth factor (EGF)-like domains, a transmembrane region, and a cytoplasmic tail.
ADAMs are widely distributed in many organs, tissues, and cells, such as brain, testis, epididymis,
ovary, breast, placenta, liver, heart, lung, bone, and muscle. These proteins are capable of four
potential functions: proteolysis, adhesion, fusion, and intracellular signaling Stone et al 1999 .
NCBI Summary: This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene contains two disintegrin loops and three C-terminal TS motifs and has anti-angiogenic activity. The expression of this gene may be associated with various inflammatory processes as well as development of cancer cachexia. This gene is likely to be necessary for normal growth, fertility, and organ morphology and function. [provided by RefSeq, Jul 2008] |
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| General function | Cell adhesion molecule, Enzyme, Hydrolase, Peptidase/Protease | ||||
| Comment | ADAMTS1 Cleavage of Versican Mediates Essential Structural Remodeling of the Ovarian Follicle and Cumulus-Oocyte Matrix During Ovulation in Mice. Brown HM et al. Remodeling of ovarian follicle extracellular matrix is essential for ovulation and vascularization of the corpus luteum (CL). Formation of the cumulus matrix around oocytes also plays an important role in ovulation and subsequent fertilization of oocytes. ADAMTS1 is an extracellular metalloprotease induced in ovarian follicles by ovulatory hormones and required for fertility. In this study we identified ADAMTS1-mediated structural and morphological changes in remodeling of the follicle and cumulus oocyte complex (COC). In Adamts1(-/-) mice ovulation rate was 77% reduced and fertilization of ovulated oocytes was reduced a further 63% resulting in reduced number of litters and pups per litter. Morphological assessment of peri-ovulatory ovaries revealed abnormal morphogenesis with a lack of thecal/vascular invagination in the basal region of follicles. Cleavage of the ADAMTS1-substrate, versican, at these invaginating regions was abundant in Adamts1(+/-), but undetectable in Adamts1(-/-) ovaries indicating that processing of versican by ADAMTS1 is involved in ovulating follicle remodeling. Versican and hyaluronan localization was abnormal during COC matrix expansion and versican persisted beyond the expected time of fertilization in Adamts1(-/-) but was catabolized and cleared from control COC. The results demonstrate that ADAMTS1 is critical in both ovulation and fertilization processes in vivo. The protease activity of ADAMTS1 mediates neomorphogenesis of the ovulating follicle wall and COC matrix necessary for successful ovulation and fertilization as well as subsequent catabolism of versican required for degradation of COC matrix after fertilization. Kaushal et al 2000 reviewed the function of ADAMTSs, potentially multifunctional metalloproteinases of the ADAM family. Metalloproteinases belong to a superfamily of zinc-dependent proteases known as metzincins. Based on sequence and structural similarities, metzincins are grouped in four distinct subfamilies: the astacins, the matrixins (matrix metalloproteinases), the adamalysins ((reprolysins, or snake venom metalloproteinases (SVMPs), and ADAMs)), and the serralysins (large bacterial proteinases) . ADAMs are a family of membrane-associated multidomain zinc-dependent metalloproteinases with high sequence homology and domain organization, similar to the SVMPs of the adamalysin subfamily . The term "ADAM" stands for a disintegrin and metalloproteinase, which represent the two key structural domains in these molecules. Thus, ADAMs are distinct among cell surface proteins in containing features of both adhesive proteins and proteinases, and their roles in cell-cell interactions have attracted particular interest. In addition, ADAM proteins contain a prodomain, as well as cysteine-rich, EGF-like, transmembrane, and cytoplasmic tail domains. These specialized structural domains suggest a possible role for ADAMs in cell-cell and cell-matrix interactions. Vazquez et al 1999 reported that METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. | ||||
| Cellular localization | Extracellular Matrix, Secreted | ||||
| Comment | others123 | ||||
| Ovarian function | Follicle development, Cumulus expansion, Ovulation, Follicle rupture, Luteinization, Oocyte maturation | ||||
| Comment | ADAMTS1 is regulated by the EP4 receptor in the zebrafish ovary. Baker SJC et al. (2021) Prostaglandins (PGs) are a class of fatty-acid derived hormones that are essential in ovulation of teleosts, but their exact role remains unknown. One putative target of PGs in ovulation is regulation of the expression of members of the A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) family, which are implicated in follicular rupture. This study investigated the regulation of ADAMTS, other proteases, and their inhibitors in response to treatment with PGE2 or PGF2α. Four members of the ADAMTS family, ADAMTS1, ADAMTS5, ADAMTS9, and ADAMTS16 were shown to be expressed in the ovary of zebrafish, but only adamts1 was upregulated in full-grown follicles following treatment with PGE2. Inhibitors of the PG receptors EP1 and EP2 had no effect on PGE2-stimulated adamts1 expression, while treatment of full-grown follicles with both PGE2 and GW627368x, an inhibitor of EP4 function, prevented the PGE2-induced increase in adamts1 expression. Treatment of full-grown follicles with the maturation-inducing hormone 17α,20β-dihydroxy-4-pregnen-3-one (17,20β-P) in vitro had no effect on the expression of adamts1 mRNA. These findings suggest that expression of ADAMTS1 in zebrafish ovarian follicles is regulated by the prostaglandin PGE2 via the EP4 series prostaglandin receptor.//////////////////Espey et al 2000 reported the expression of a Disintegrin and Metalloproteinase with Thrombospondin Motifs During Ovulation in the Gonadotropin-Primed Immature Rat. In this reverse transcription-polymerase chain reaction differential display study, gonadotropin-primed immature rats were used to detect ovarian expression of a relatively new type of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1) that is known to cleave extracellular matrix in acutely inflamed tissues. Immature Wistar rats were primed with 10 IU eCG s.c., and the temporal pattern of expression of the ADAMTS-1 gene was delineated by extracting ovarian RNA at 0, 2, 4, 8, 12, and 24 h after induction of ovulation by injecting the primed animals with 10 IU hCG s.c. The differential display data, Northern analyses, and in situ hybridization micrographs all showed significant up-regulation of ADAMTS-1 gene expression by 8 h after hCG administration. The in situ data indicated that the ADAMTS-1 mRNA was in the granulosa layer of mature follicles. Expression reached a peak at 12 h and remained elevated at 24 h after hCG. ADAMTS-1 gene expression was impaired by the antiprogesterone agent epostane, but this inhibition could be overcome by exogenous progesterone. ADAMTS-1 expression was not affected when ovulation was blocked by treatment of the animals with the anti-eicosanoid agent indomethacin. Down-regulated expression of ADAMTS-1 by progesterone receptor antagonist is associated with impaired expansion of porcine cumulus-oocyte complexes Shimada M, et al 2004 . ADAMTS-1, a member of the A disintegrin and metalloproteinase family of proteases, is expressed in rodent follicles via progesterone receptor (PR)-dependent pathways. However, the functional relationship between ADAMTS-1 expression and PR has not been studied extensively in other species. In the present study, we investigated the time dependent changes in ADAMTS-1 expression in cumulus cells of porcine cumulus-oocyte complexes (COCs), and the roles of ADAMTS-1 in cumulus expansion during in vitro maturation of oocytes. ADAMTS-1 message was not detected in cumulus cells at the time of collection from the follicles. In response to gonadotropins, ADAMTS-1 mRNA was dramatically up-regulated and reached a maximum at 20 h. The level of mature ADAMTS-1 protein increased in time dependent manner with a maximum level at 40 h. The induction of ADAMTS-1 mRNA and protein was significantly decreased by the addition of progesterone receptor antagonist RU486 to the cultures. However, RU486 did not affect the expression of ADAMTS-4 or factors that had been reported to be required for COC expansion (TSG-6, Versican, HAS-2). COCs cultured with FSH and LH for 40 h exhibited prominent cumulus expansion. The expansion was reduced significantly by the addition of either RU486, or Galardin, a broad-spectrum matrix metalloproteinase inhibitor. These results suggest that the expression and induction of ADAMTS-1 through receptor-mediated action of progesterone in cumulus cells is one of the essential requirements for gonadotropin-regulated cumulus expansion of porcine COCs. Development and Hormonal Regulation of the Ovarian Lymphatic Vasculature. Brown HM et al. The lymphatic vasculature plays a number of essential physiological roles including maintaining fluid homeostasis, providing a network for the transport of immune cells, and facilitating the uptake of fat-soluble nutrients from the gastrointestinal tract. Although the critical importance and remodeling capacity of the blood vasculature has been well described within the ovary, just a few reports describe the lymphatic vasculature. Using histological and molecular techniques, we report the kinetics of ovarian lymphangiogenesis and the hormonal regulation of lymphangiogenic growth factors associated with key stages of ovarian follicle growth. We exploited the Adamts1-null mouse model, a model with a previously characterized lymphatic defect to further interrogate the mechanisms controlling ovarian lymphangiogenesis. The establishment and development of the ovarian lymphatic vascular network in postnatal developing ovaries was associated with the presence and hormonal regulation of the lymphangiogenic growth factors and their receptors, including Vegfc, Vegfd, and Vegfr3. We characterized the hormonally regulated remodeling of the ovarian lymphatic vasculature in response to FSH and estradiol. The lymphatic network was defective in the Adamts1-null ovary, clearly demonstrating both the involvement of FSH/estradiol and the Adamts1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) protease in ovarian lymphangiogenesis. This study provides the first evidence of a malleable lymphatic system responsive to hormonal changes of the female reproductive cycle, at least in the mouse ovary, suggesting a role for lymphatic vessel functions in normal folliculogenesis. | ||||
| Expression regulated by | LH, Steroids, Growth Factors/ cytokines, progesterone, CTGF | ||||
| Comment | Transcriptional profiling of long noncoding RNAs and their target transcripts in ovarian cortical tissues from women with normal menstrual cycles and primary ovarian insufficiency. Yao G et al. (2019) Previous studies have shown that long noncoding RNAs (lncRNAs) show a highly tissue- and disease-specific expression pattern and that they regulate the expression of neighboring genes. Because lncRNAs have been shown to be secreted into the general circulation, they may be used as diagnostic tools for some diseases. Primary ovarian insufficiency (POI) is a disease in which women have menstrual cessation before the age of 40, accompanied by elevated follicle stimulating hormone and decreased estrogen levels. In this study, ovarian cortical tissues from five women with normal menstrual cycles and from five POI patients were used for next-generation RNA sequencing. We found 20 differentially expressed lncRNAs with 12 upregulated and eight downregulated lncRNAs in cortical tissues of POI ovaries, compared with normal controls (fold change ≥ 2 and false discovery rateFDR] ≤ 0.05). We also found 52 differentially expressed messenger RNA transcripts, with 33 upregulated and 19 downregulated ones (foldchange ≥ 2 and FDR ≤ 0.05). Functional annotation showed that these differentially expressed transcripts were associated with follicular development and granulosa cell function. Thirteen differentially expressed lncRNAs and their targeted neighboring transcripts were coregulated in ovarian cortical tissues, including lnc-ADAMTS1-1:1/ADAMTS1, lnc-PHLDA3-3:2/CSRP1, lnc-COL1A1-5:1/COL1A1, lnc-SAMD14-5:3/COL1A1, and lnc-GULP1-2:1/COL3A1. Furthermore, serum levels of these lncRNAs in POI patients were significantly different from those in normal patients ( p < 0.05), and expression differences were consistent with those in ovarian cortical tissues. This study showed that key lncRNAs were differentially expressed in both ovarian cortical tissues and serum samples between women with normal menstrual cycles and POI patients. Further studies on the regulation of ovarian lncRNAs during follicular development are critical in understanding the etiologies of POI. Analyses of lncRNA expression in serum samples might provide a basis for early diagnosis and treatment of POI.//////////////////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.////////////////// Molecular Characterization and Transcriptional Regulation of a Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (ADAMTS1) in Bovine Preovulatory Follicles. Sayasith K et al. The ovulatory process involves a complex remodeling of the extracellular matrix during which a desintegrin and metalloproteinase with thrombospondin motif 1 (ADAMTS1) is thought to play a key role, but its transcriptional regulation in bovine follicles remains largely unknown. The objectives of this study were to characterize the regulation of ADAMTS1 in bovine follicles before ovulation and to determine its transcriptional control in bovine granulosa cells. Regulation of ADAMTS1 was assessed using total RNA isolated from bovine preovulatory follicles obtained at various times after human chorionic gonadotropin treatment. Results from RT-PCR analyses showed that levels of ADAMTS1 mRNA were very low at 0 hours but increased at 6- to 24 hours after human chorionic gonadotropin in granulosa cells. To determine the regulatory mechanisms controlling ADAMTS1 gene expression in vitro, primary cultures of bovine granulosa cells were established, and treatment with forskolin up-regulated ADAMTS1 mRNA levels. Promoter activity assays, 5` deletion, and site-directed mutagenesis identified a minimal region conferring full-length basal and forskolin-stimulated ADAMTS1 promoter activities, with both being dependent on Ebox cis-acting elements. EMSAs revealed upstream stimulating factor (USF) proteins as key trans-activating factors interacting with Ebox. Chromatin immunoprecipitation assays confirmed such interactions between USF and Ebox in vivo, and USF binding to Ebox elements was increased by forskolin treatment. ADAMTS1 promoter activity and mRNA expression were increased by forskolin and overexpression of the catalytic subunit of protein kinase A, but not by cotreatment with inhibitors of protein kinase A, ERK1/2, and epidermal growth factor receptor signaling pathways. Furthermore, treatment with a soluble epidermal growth factor induced ADAMTS1 mRNA expression in granulosa cells. Collectively, results from this study describe the gonadotropin/forskolin-dependent up-regulation of ADAMTS1 mRNA in granulosa cells of bovine preovulatory follicles in vivo and in vitro and identify for the first time some of the molecular mechanisms responsible for ADAMTS1 promoter activation in follicular cells of a large monoovulatory species. Connective Tissue Growth Factor Is Required for Normal Follicle Development and Ovulation. Nagashima T et al. Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-?superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-?family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-?and progesterone signaling cascades and is necessary for normal follicle development and ovulation. Coordinate Transcription of the ADAMTS-1 Gene by Luteinizing Hormone and Progesterone Receptor Doyle KM, et al . ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin-like motifs) is a multifunctional protease that is expressed in periovulatory follicles. Herein we show that induction of ADAMTS-1 message in vivo and transcription of the ADAMTS-1 promoter in cultured granulosa cells are dependent on separable but coordinate actions of LH and the progesterone receptor (PR). To analyze the molecular mechanisms by which LH and PR regulate this gene, truncations and site-specific mutants of ADAMTS-1 promoter-luciferase reporter constructs (ADAMTS-1-Luc) were generated and transfected into rat granulosa cell cultures. Three regions of the promoter were found to be important for basal activity, two of which were guanine cytosine-rich binding sites for specificity proteins Sp1/Sp3 and the third bound a nuclear factor 1-like factor. Despite the absence of a consensus PR DNA response element in the proximal ADAMTS-1 promoter, cotransfection of a PRA (or PRB) expression vector stimulated ADAMTS-1 promoter activity, a response that was reduced by the PR antagonist ZK98299. Forskolin plus phorbol myristate acetate also increased promoter activity and, when added to cells cotransfected with PRA, ADAMTS-1 promoter activity increased further. Activation of the ADAMTS-1 promoter by PRA involves functional CAAT enhancer binding protein beta, nuclear factor 1-like factor, and three Sp1/Sp3 binding sites as demonstrated by transfection of mutated promoter constructs. In summary, LH and PRA/B exert distinct but coordinate effects on transactivation of the ADAMTS-1 gene in granulosa cells in vivo and in vitro with PR acting as an inducible coregulator of the ADAMTS-1 gene. | ||||
| Ovarian localization | Cumulus, Granulosa, Theca, Luteal cells | ||||
| Comment | ADAMTS-1: a new human ovulatory gene and a cumulus marker for fertilization capacity. Yung Y et al. ADAM-metallopeptidase-with-thrombospondin-type-1-motif-1 (ADAMTS-1) null female mice show impaired follicular development and ovulatory processes. However, ADAMTS-1 expression and function in human normal ovulation and folliculogenesis have not yet been determined. The objective of this study is to study the expression patterns of ADAMTS-1 in human granulosa cells (GCs) obtained from follicles aspirated during in vitro maturation (IVM) and in vitro fertilization (IVF) procedures. We found that ADAMTS-1 expression is a luteinizing hormone/human chorionic gonadotropin (LH/hCG)-induced gene whose expression in the mural GCs directly correlated with antral follicular growth. Interestingly, we were able to show a significant correlation between ADAMTS-1 expression in cumulus cells and the fertilization capacity of the related oocyte. In conclusion, human ADAMTS-1 is an ovulatory gene and its expression is LH/hCG- and follicle-size dependent. The correlation between its expression in cumulus GCs and oocyte fertilization capacity suggests a role for ADAMTS-1 in human cumulus function. The progesterone receptor (PR), a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, R. L. Robker et al 2000 show that the matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of progesterone receptor (PR) action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of these regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation. 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 | Systematic Analysis of Protease Gene Expression in the Rhesus Macaque Ovulatory Follicle: Metalloproteinase Involvement in Follicle Rupture. Peluffo MC et al. Protease genes were identified that exhibited increased mRNA levels before and immediately after rupture of the naturally selected, dominant follicle of rhesus macaques at specific intervals after an ovulatory stimulus. Quantitative real-time PCR validation revealed increased mRNA levels for matrix metalloproteinase (MMP1, MMP9, MMP10, and MMP19) and a disintegrin and metalloproteinase with thrombospondin-like repeats (ADAMTS1, ADAMTS4, ADAMTS9, and ADAMTS15) family members, the cysteine protease cathepsin L (CTSL), the serine protease urokinase-type plasminogen activator (PLAU), and the aspartic acid protease pepsinogen 5 (PGA5). With the exception of MMP9, ADAMTS1, and PGA5, mRNA levels for all other up-regulated proteases increased significantly (P < 0.05) 12 h after an ovulatory human chorionic gonadotropin (hCG) bolus. MMP1, -10, and -19; ADAMTS1, -4, and -9; CTSL; PLAU; and PGA5 also exhibited a secondary increase in mRNA levels in 36-h postovulatory follicles. To further determine metalloproteinase involvement in ovulation, vehicle (n = 4) or metalloproteinase inhibitor (GM6001, 0.5 ?g/follicle, n = 8) was injected into the preovulatory follicle at the time of hCG administration. Of the eight GM6001-injected follicles, none displayed typical stigmata indicative of ovulation at 72 h after hCG; whereas all four vehicle-injected follicles ovulated. No significant differences in mean luteal progesterone levels or luteal phase length occurred between the two groups. Subsequent histological analysis revealed that vehicle-injected follicles ruptured, whereas GM6001-injected follicles did not, as evidenced by an intact stroma and trapped oocytes (n = 3). These findings demonstrate metalloproteinases are critical for follicle rupture in primates, and blocking their activity would serve as a novel, nonhormonal means to achieve contraception. Russell DL,et al reported the processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. 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. ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs-1) is a member of the ADAMTS family of metalloproteases which, together with ADAMTS-4 and ADAMTS-5, has been shown to degrade members of the lectican family of proteoglycans. ADAMTS-1 mRNA is induced in granulosa cells of periovulatory follicles by the LH surge through a progesterone receptor (PR) dependent mechanism. Female progesterone receptor knockout (PRKO) mice are infertile primarily due to ovulatory failure and lack the normal periovulatory induction of ADAMTS-1 mRNA. Antibodies against two specific peptide regions, the pro-domain and the metalloprotease domain, of ADAMTS-1 were generated. Pro-ADAMTS-1 of 110 kDa was identified in mural granulosa cells and appears localized to cytoplasmic secretory vesicles. The mature (85 kDa pro-domain truncated) form accumulated in extracellular matrix of the cumulus oocyte complex (COC) during the process of matrix expansion. Each form of ADAMTS-1 protein increased greater than ten-fold after the ovulatory LH surge in wild-type but not PRKO mice. Versican is also localized selectively to the ovulating COC matrix and was found to be cleaved yielding a 70 kDa N-terminal fragment immunopositive for the neoepitope DPEAAE generated by ADAMTS-1 and ADAMTS-4 protease activity. This extracellular processing of versican was reduced in ADAMTS-1 deficient PRKO mouse ovaries. These observations suggest that one function of ADAMTS-1 in ovulation is to cleave versican in the expanded COC matrix and that the anovulatory phenotype of PRKO mice is at least partially due to loss of this function. Shimada M,et al reported that down-regulated expression of a disintegrin and metalloproteinase with thrombospondin-like repeats-1 by progesterone receptor antagonist is associated with impaired expansion of porcine cumulus-oocyte complexes. ADAMTS-1, a member of the A disintegrin and metalloproteinase family of proteases, is expressed in rodent follicles via progesterone receptor (PR)-dependent pathways. However, the functional relationship between ADAMTS-1 expression and PR has not been studied extensively in other species. In the present study, we investigated the time-dependent changes in ADAMTS-1 expression in cumulus cells of porcine cumulus-oocyte complexes (COCs), and the roles of ADAMTS-1 in cumulus expansion during in vitro maturation of oocytes. ADAMTS-1 message was not detected in cumulus cells at the time of collection from the follicles. In response to gonadotropins, ADAMTS-1 mRNA was dramatically up-regulated and reached a maximum at 20 h. The level of mature ADAMTS-1 protein increased in a time-dependent manner with a maximum level at 40 h. The induction of ADAMTS-1 mRNA and protein was significantly decreased by the addition of PR antagonist RU486 to the cultures. However, RU486 did not affect the expression of ADAMTS-4 or factors that had been reported to be required for COC expansion (TSG-6, versican, HA synthase-2). COCs cultured with FSH and LH for 40 h exhibited prominent cumulus expansion. The expansion was reduced significantly by the addition of either RU486 or Galardin, a broad-spectrum matrix metalloproteinase inhibitor. These results suggest that the expression and induction of ADAMTS-1 through receptor-mediated action of progesterone in cumulus cells is one of the essential requirements for gonadotropin-regulated cumulus expansion of porcine COCs. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
7 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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