Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of gelatinases/matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in neonatal and gonadotropin-primed immature rat ovaries was studied by immunofluorescent microscopy. Immature female Long-Evans rats were primed with 15 IU pregnant mare's serum gonadotropin (PMSG) in 100 microliters PBS. Two days later, to induce ovulation, the rats were injected with human chorionic gonadotropin (hCG, 5 IU/100 microliters PBS). The animals were killed at appropriate times and the ovaries removed and processed for cryostat or paraffin sectioning. Ovaries were also obtained from 7-day-old neonatal rats and processed as above. In the neonatal rat ovary, MMP-2 was present in the follicle and in the ovarian surface epithelium. MMP-9 was not detectable in the neonatal ovary. TIMP-1 was present in the oocyte and in the surface epithelium. In the PMSG-primed ovary, MMP-2 was present in the granulosa and thecal cells of the ovary. MMP-9 distribution, however, was restricted to the interstitial and thecal cells. TIMP-1 was mainly present in the blood vessels and thecal cells, with minor staining in the granulosa cells. In the developing corpus luteum, luteal and endothelial cells were positive for MMP-2. MMP-9 localization was restricted to the plasma membrane of the luteal and interstitial cells. TIMP-1 was clearly observed in the luteal capillaries and, to a lesser extent, in the luteal cell plasma membrane. This distribution of MMP-2, MMP-9, and TIMP-1 in the corpus luteum persisted throughout the life span of the corpus luteum. The spatial and temporal distribution of the gelatinases and TIMP-1 suggests unique roles for these proteins in the rat ovary.
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PMID:Differential distribution of gelatinases and tissue inhibitor of metalloproteinase-1 in the rat ovary. 977 66

Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP-1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl(4)), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti-TIMP-1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl(4)-treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle alpha-actin (alpha-SMA). Compared to controls, rats administered anti-TIMP-1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti-TIMP-1 resulted in a marked decrease in alpha-SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP-2. In conclusion, administration of a TIMP-1 antibody attenuated CCl(4)-induced liver fibrosis and decreased HSC activation and MMP-2 activity.
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PMID:Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. 1538 76

Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To assess the effects of TIMP-3 gene transfer to glioma cells, a replication-defective adenovirus encoding TIMP-3 (Ad.TIMP-3) was employed. Ad.TIMP-3 infection of a panel of glioma cell cultures decreased the proliferative capacity of these cells and induced morphologic changes characteristic for apoptosis. Next, a conditionally replicating adenovirus encoding TIMP-3 was constructed by inserting the TIMP-3 expression cassette into the E3 region of the adenoviral backbone containing a 24-bp deletion in E1A. This novel oncolytic adenovirus, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-3 was shown in s.c. glioma xenografts. The functional activity of TIMP-3 was imaged noninvasively using a near-IR fluorescent MMP-2-activated probe. Tumoral MMP-2 activity was significantly reduced by 58% in the AdDelta24TIMP-3-treated tumors 24 hours after infection. A study into the therapeutic effects of combined oncolytic and antiproteolytic therapy was done in both a s.c. and an intracranial model for malignant glioma. Treatment of s.c. (U-87MG) or intracranial (U-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent.
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PMID:Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma. 1623 Apr 3

A hallmark of renal cell carcinoma (RCC) invasion is its ability to degrade ECM by local production of gelatinase enzymes. Although many studies on RCC have demonstrated the importance of MMPs, very little information is currently known regarding the effect of inducers and inhibitors. We therefore investigated the effect of inducers and inhibitors on RCC 786-0 in vitro. Human RCC 786-0 (ATCC) was grown in RPMI medium supplemented with 10% FBS, penicillin, and streptomycin in 24-well tissue plates. At near confluence, the cells were washed with PBS; the serum-free medium was incubated with various inducers: phorbol ester (PMA), tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-1beta) and lipopolysaccharides (LPS). Cells were also incubated with inhibitors: EGCG, doxycycline, and a nutrient mixture with and without PMA; retinoic acid, dexamethasone, H-7; actinomycin D, or cyclohexamide. After 24 h, the medium was removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography. RCC 786-0 secreted two bands, a major band corresponding to MMP-2 and a faint band corresponding to MMP-9. PMA and TNF-alpha, with increased concentration, increased MMP-9 secretion, while IL-1beta and LPS did not significantly modify MMP-9 activity. MMP-2 secretion was not affected by any of the inducers. All the inhibitors tested without and with PMA showed a dose-dependent decrease in both MMP-2 and -9 expression. Further studies are in progress to confirm the role of MMP-9 on Matrigel invasion using PMA, cytokines, and LPS.
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PMID:Modulation of human renal cell carcinoma 786-0 MMP-2 and MMP-9 activity by inhibitors and inducers in vitro. 1672 Sep 25

The aim of the present study was to assess genes expressed in maternal uterine tissue and pre-implantation embryos which are presumably involved in maternal recognition and establishment of canine pregnancy. For this purpose, 10 pregnant bitches were ovariohysterectomized between days 10 and 12 after mating. Four non-pregnant bitches served as controls. Early pregnancy was verified by flushing the uterine horns with PBS solution. The collected embryos (n = 60) were stored deep-frozen (-80 degrees C). Uterine tissue was excised, snaps frozen in liquid nitrogen and homogenized using TRI Reagent. All embryos from one litter were thawed together and also homogenized in TRI Reagent. RT-PCR was performed to prove mRNA expression of progesterone receptor, key enzymes of the prostaglandin synthesis pathway, selected growth factors, cytokines, immune cell receptors, major histocompatibility complex (MHC) and matrix-metalloproteinases (MMP). Only pregnant uteri revealed the presence of mRNA for interferon (IFN)-gamma, IL-4 and CD-8, which resembles the milieu in humans and other mammalians. Similarly, in day 10 embryos, mRNA for transforming growth factor-beta, insulin-like growth factor-1,-2, hepatocyte growth factor, leukaemia inhibitor factor, tumour necrosis factor-alpha, interleukin-1beta,-6,-8, cyclooxygenase-2, CD4(+) cells, and MMP-2 and -9 were detected, but not MHC-I or -II. We therefore suppose that the canine embryo, like its human counterpart, actively initiates measures to prevent attacks from the maternal immune system to prepare its own adhesion, nidation, growth and further development.
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PMID:Expression of genes in the canine pre-implantation uterus and embryo: implications for an active role of the embryo before and during invasion. 1839 90

Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy determine clinical outcomes. The effects of mesenchymal stem cell (MSC) transplantation upon determinants of ECM composition in pressure overload hypertrophy have not been studied. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After an absolute decrease in fractional shortening of 25% from baseline, 1 x 10(6) MSC (n = 28) or PBS (n = 20) was randomly injected intracoronarily. LV protein analysis, including matrix metalloproteinases (MMP-2, MMP-3, MMP-6, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3), was performed after sacrifice on postoperative day 7, 14, 21 or 28. Left ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 were demonstrated to be decreased in the MSC group compared with controls after 28 days. Expression of MMP-2 and TIMP-2 remained relatively stable in both groups. Successful MSCs delivery was confirmed by histological analysis and visualization of labelled MSCs. In this model of pressure overload hypertrophy, intracoronary delivery of MSCs during heart failure was associated with specific changes in determinants of ECM composition. LV reverse remodeling was associated with decreased ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3, which were upregulated in the control group as heart failure progressed. These effects were most significant at 28 days following injection.
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PMID:Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy. 1906 45

MMP-2 and MMP-9 secretion is elevated in several types of human cancers and their elevated expression has been associated with poor prognosis. Expression of MMPs is highly regulated by cytokines and signal transducation pathways, including those activated by phorbol 12-myristate 13-acetate (PMA). The aim of this study was to examine the effect of PMA on MMP-2 and MMP-9 secretion in 42 different human cancer cell lines, selected on the basis of their organ malignancies. They were cultured in the recommended media supplemented with 10% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with PBS, 0.5 ml of medium was added, and the cultures were incubated. Parallel sets of cultures were also treated with PMA for induction of enzymes. After 24 h the media were collected and MMP-2 and MMP-9 levels were assayed by gelatinase zymography. Based on MMP-2 and MMP-9 secretion without and with PMA treatment, the various human cancer cell lines fell into one of two major groups. The first group characterized by low basal MMP-9 secretion fell into three different categories of susceptibility to PMA induction of MMP-9 expression: resistant, moderately susceptible and highly susceptible. High basal MMP-9 levels responsive to PMA induction characterized the second group. Most cancer cell lines examined exhibited basal levels of MMP-2, MMP-9 or both. MMP-2 secretion was not induced by PMA in any of the cancer cells examined.
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PMID:Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. 1936 Mar 11

Cardiac remodeling is associated with hypertrophy and fibrosis processes, which may depend on the activity of matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinases" (ADAMs). We investigated whether ADAM-17 (tumor necrosis factor-alpha-converting enzyme [TACE]) plays a role in agonist-induced cardiac remodeling and the relationships established among TACE, MMP-2, and ADAM-12. We targeted TACE in rodent models of spontaneous and agonist-induced hypertension using RNA interference combined with quantitative RT-PCR, activity determinations, and functional studies. Treatment of spontaneously hypertensive rats with previously validated TACE small-interfering RNA for 28 days resulted in systemic knockdown of TACE expression. TACE knockdown effectively stopped the development of cardiac hypertrophy. Mice receiving angiotensin II (1.4 mg/kg per day for 12 days) exhibited cardiac hypertrophy, as well as fibrosis, which was associated with elevated myocardial expression of molecular markers of hypertrophy (alpha-skeletal actin, beta-myosin heavy chain, and brain natriuretic peptide) and fibrosis (collagen types I and III and fibronectin), as well as MMP-2 and ADAM-12. Treatment with TACE small-interfering RNA (but not with PBS or luciferase small-interfering RNA) inhibited TACE expression, thus preventing angiotensin II-induced cardiac hypertrophy and fibrosis. Moreover, knockdown of TACE inhibited angiotensin II-induced overexpression of markers of myocardial hypertrophy and fibrosis, as well as ADAM-12 and MMP-2. These findings provide the first in vivo evidence that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TACE, which acts through novel pathways involving transcriptional regulation of ADAM-12 and MMP-2. Targeting TACE has potential therapeutic importance for modulating agonist-induced cardiac remodeling.
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PMID:Tumor necrosis factor-alpha-converting enzyme is a key regulator of agonist-induced cardiac hypertrophy and fibrosis. 1958 99

Matrix metalloproteinases (MMPs) secreted by lung cancer (LC) and malignant mesothelioma (MM), especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens and inhibitors on MMP-2 and MMP-9 expression in LC and MM cell lines. Human LC (A-549) and MM (MSTO-211H) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. LC expressed MMP-2 whereas MM expressed MMP-2 and MMP-9. TNF-alpha, IL-1beta, LPS and PMA, stimulated MMP-2 in LC and inhibited MMP-2 in MM, but had no effect on MMP-9. Doxycycline, EGCG and NM inhibited MMP-2 and MMP-9 expression, in both cell lines. Actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in both cancer cell lines and inhibited MMP-9 in MM. Our results show that cytokines and inhibitors have an up- or down-regulatory effect on MMP-2 and MMP-9 expression in LC and MM, suggesting the clinical value of targeting these proteases for management of LC and MM and their pathogenesis.
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PMID:Modulation of MMP-2 and MMP-9 by cytokines, mitogens and inhibitors in lung cancer and malignant mesothelioma cell lines. 1988 78

The inflammatory response to an implanted tissue engineered construct alters the remodeling that occurs and this can diminish the intended therapeutic effect. It was hypothesized that the use of a hydroxamate-based matrix metalloproteinase (MMP) sequestering biomaterial (MI) in the form of approximately 200 microm microspheres would lower the amount and activity of MMP in vivo in response to a subcutaneous, degradable implant (gelatin or Integra disc). MMP degrade extracellular matrix, facilitating inflammatory cell migration and local remodeling of the implant environment. Gelatin or Integra discs were implanted subcutaneously in the backs of CD1 mice together with 30 mg of MI microspheres or with 30 mg of similarly sized control poly(methyl methacrylate) (PMMA) microspheres in a paired study. To sample the implant space, weakly adsorbed protein or attached cells were recovered from explanted discs by soaking the discs in PBS overnight at 4 degrees C. Unexpectedly, MMP-2, -8, -9, and TIMP-1 levels were surprisingly similar in this recovered fluid for the two treatments. Also, there were significantly more (and at day 4 an order of magnitude more) leukocytes recovered from the gelatin discs coimplanted with the MI microspheres than with the PMMA control. It is suggested that the MI microspheres disturbed the natural MMP control pathway leading to high-leukocyte numbers, especially at early times. These results highlight the challenge associated with controlling the fate of tissue engineered constructs in vivo.
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PMID:MMP levels in the response to degradable implants in the presence of a hydroxamate-based matrix metalloproteinase sequestering biomaterial in vivo. 1991 83


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