Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effects of a new synthetic inhibitor of mammalian tissue collagenase, CI-1 (N-[3-N-(benzyloxycarbonyl)amino-1-(R)carboxypropyl]L-leucyl-O-methyl-L- tyrosine N-methylamide; G. D. Searle SC 40827), and a general metalloproteinase inhibitor, 1,10-phenanthroline, on ovulation, as judged by the observation of follicular rupture, and on progesterone production of the perfused rat ovary. Ovaries of PMSG (20 IU)-primed rats were perfused for 21 h, and samples of medium were taken for analysis of progesterone concentration. The number of ovulations was estimated by counting the number of oocytes released into the perfusion chamber. Ovaries were stimulated with LH (0.1 micrograms/ml) plus 3-isobutyl-1-methylxanthine (IBMX; 0.2 mM), and this treatment resulted in a mean of 17.2 ovulations/treated ovary. 1,10-Phenanthroline dose-dependently inhibited ovulation, with 0, 0.2, and 12.5 ovulations/treated ovary at 1.0, 0.1, and 0.01 mM, respectively. This inhibition of ovulation closely paralleled the inhibition of extracted collagenase from uterus and ovary. However, 1,10-phenanthroline also suppressed progesterone release in a dose-dependent manner. Addition of the collagenase inhibitor (CI-1; 25 microM) 1 h after LH plus IBMX inhibited ovulation (6.3 ovulations/treated ovary). Its relatively inactive stereoisomer (CI-2; 25 microM) did not suppress ovulation (20.0 ovulations/treated ovary). CI-1 inhibited extracted uterine collagenase 50% at a concentration of 2 microM, whereas CI-2 was only 1/15th as effective. There was an 80% loss of CI-1 from the medium during the perfusions. Neither CI-1 nor CI-2 had any effect on LH plus IBMX-stimulated progesterone release. These data demonstrate that the general metalloproteinase inhibitor 1,10-phenanthroline is able to inhibit ovulation, but also inhibits steroidogenesis. The more specific inhibitor of collagenase, CI-1, can inhibit ovulation without affecting steroid production. These data indicate an important role for collagenase in the ovulatory process.
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PMID:Inhibitors of mammalian tissue collagenase and metalloproteinases suppress ovulation in the perfused rat ovary. 245 70

Rat uterine tissue was dissociated by enzymatic digestion with collagenase and viable mast cells were obtained. Their viability was assessed by the ability to exclude trypan blue dye and to respond functionally to different stimuli. Challenge with anti-IgE gave a calcium-dependent histamine release of 49%, whilst the undigested uterine fragments gave 23%. Moreover, they were capable of releasing histamine on challenge with the compound 48/80, suggesting a similarity with connective tissue mast cells. This similarity was further supported by their insensitivity to aldehyde blocking of dye binding. The final dispersed cell preparation contained 3 X 10(5) mast cells/g of uterine tissue, representing about 2% of total nucleated cells. The total histamine content of the undigested uterus was 2.5 micrograms/g of tissue, whilst after digestion the histamine determined was 1.2 pg per mast cell with a yield of 14%. The total histamine content of the uterus changed throughout the reproductive cycle, increasing before ovulation, reaching a maximum during ovulation and then decreasing after embryo implantation. This suggests that the implanting embryo, interacting with the uterus, may be capable of inducing the release of histamine. The embryo-derived histamine releasing factor (EHRF) that we have described previously is capable of inducing 22% histamine-release on uterine mast cells, thus supporting this hypothesis.
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PMID:Dispersal of rat uterine mast cells and their functional response to an embryo-derived histamine releasing factor: a possible model for embryo implantation. 246 97

The possible hemopoietic origin of certain precursors of uterine decidual cells appearing during normal murine pregnancy was investigated in semiallogeneic hemopoietic chimeras with retained or regained fertility. Chimeras were produced by three different methods in two donor-host combinations: F1 [BALB/c female x C3H/HeJ male] cells introduced into the parental strain BALB/c female hosts or F1 [CBA/J female x C57BL/6 male] cells introduced into CBA/J female hosts. Prenatal chimeras (PN) were made by reconstituting mouse fetuses (day 13-17) with 10(6)-10(7) adult bone marrow or fetal liver cells through the yolk sac and they were allowed to be delivered naturally. Neonatal chimeras (NN) were made by injecting 1-2 x 10(7) adult bone marrow cells into the anterior facial vein of neonatal mice (less than 24 hr old). In both cases, experimental animals were raised to maturity. Ovary-transplanted chimeras (OT) were made by injecting 10(7) bone marrow cells into lethally irradiated (9.5 Gy) young adult female mice, followed 6 weeks later with bilateral orthotopic transplants of syngeneic ovary grafts to restore fertility. All female chimeras produced by the three different methods were mated with syngeneic male partners to produce normal pregnancy. The extent of chimerism at the cellular level was determined in all cases by a radioautographic identification of the H-2 phenotype of splenic lymphocytes and decidual cells and macrophages in the collagenase-dispersed decidua at day 11-16 of normal pregnancy, following a sandwich labelling with monospecific anti-H-2 antibodies and 125I-protein A. Morphological discrimination of typical decidual cells from macrophages in the collagenase-dispersed decidua was carried out on the basis of several distinctive markers: presence of surface Dec-1 and Thy-1 and absence of surface F4/80 or latex phagocytosis for decidual cells, in contrast to macrophages which were phagocytic and expressed F4/80 but not Dec-1 or Thy-1. While the degree of hemopoietic chimerism (judged by the incidence of donor-derived lymphocytes in the spleen) varied from animal to animal, in all three groups (PN, NN, and OT) comprising a total of 26 chimeras, the percentage of typical decidual cells expressing donor H-2 phenotype showed an excellent correlation with that for small lymphocytes in the spleen. These results reveal that at least a subpopulation of typical decidual cells of the pregnant uterus has a hemopoietic genealogy. A possible familial relationship of these cells to granulated metrial gland cells remains unclear.
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PMID:Hemopoietic origin of certain decidual cell precursors in murine pregnancy. 278 80

The collagenase produced by rat uterine cells in culture has been examined for its ability to degrade denatured collagen. Acting as a gelatinase, rat uterus collagenase was able to successfully degrade the denatured chains of collagen types I through V. In addition, the enzyme produced multiple cleavages in these chains and displayed values for Km of 4-5 microM, compared to values of 1-2 microM when native collagen was used as substrate. Furthermore, rat uterus collagenase degraded the alpha 2 chain of denatured type I collagen at a significantly faster rate than the alpha 1 chain, as previously observed for human skin fibroblast collagenase. In contrast to the action of human skin collagenase, however, the rat uterus enzyme was found to be a markedly better gelatinase than a collagenase, degrading the alpha chains of denatured type I guinea pig skin collagen at rates some 7-15-fold greater than native collagen. Human skin collagenase degrades the same denatured chains at rates ranging from 13-44% of its rate on native collagen. Rat uterus collagenase, then, is approximately 50 times better a gelatinase than is human skin collagenase. In addition to its ability to cleave denatured collagen chains at greater rates than native collagen, the rat uterus collagenase also attacked a wider spectrum of peptide bonds in gelatin than does human skin collagenase. In addition to cleaving the Gly-Leu and Gly-Ile bonds characteristic of its action on native collagen, rat uterus collagenase readily catalyzed the cleavage of Gly-Phe bonds in gelatin. The rat enzyme was also capable of cleaving Gly-Ala and Gly-Val bonds, although these bonds were somewhat less preferred by the enzyme. The cleavage of peptide bonds other than Gly-Leu and Gly-Ile appears to be a property of the collagenase itself and not a contaminating protease. Thus, it appears that the collagenase responsible for the degradation of collagen during the massive involution of the uterus might also act as a gelatinase to further degrade the initial products of collagenolysis to small peptides suitable for further metabolism.
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PMID:The gelatinolytic activity of rat uterus collagenase. 299 74

Relaxin (Rlx) classically causes uterine quiescence during pregnancy and cervical dilatation prior to parturition. Its actions involve major changes in the components of the extracellular matrix of these tissues. The activities of three enzymes, collagenase, proteoglycanase and beta-glucuronidase, major determinants of the integrity of the extracellular matrix have been measured in the rat uterus and cervix in different reproductive states. The results show that there are marked differences in the changes of these enzymes occurring in the uterus and cervix during the course of pregnancy and the puerperium. It was not possible to directly relate these changes to a single hormonal event over this period of major endocrine fluctuations. Two models have therefore been used in an attempt to delineate the effects of oestrogen and Rlx on the tissue enzyme levels or their secretion into culture medium. In the first model cyclic animals were treated with oestrogen alone or oestrogen followed by Rlx and tissue enzyme levels measured. The addition of Rlx treatment reversed an inhibiting effect of oestrogen alone on both uterine and cervical collagenase and proteoglycanase activities, at the same time as completely obliterating the stimulating effect of oestrogen on uterine and cervical beta-glucuronidase activity. A second model used in vivo oestrogen priming of cyclic rats followed by in vitro Rlx treatment and measurement of the enzymes secreted into the culture medium over 7 days. The results showed as in the first model that Rlx treatment could in particular overcome the inhibiting effect of oestrogen on uterine proteoglycanase secretion without affecting beta-glucuronidase levels. In contrast, the effect of Rlx on the cervix was to decrease collagenase and proteoglycanase secretion whilst not affecting the beta-glucuronidase levels.
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PMID:The effect of oestrogen and relaxin on uterine and cervical enzymes: collagenase, proteoglycanase and beta-glycuronidase. 300 78

A specific antiserum to rabbit bone collagenase was raised in a sheep and shown to react with collagenase from several mammalian species. This antiserum was used to demonstrate that only active collagenase binds to and can be immunolocalized on collagen fibrils and, by indirect immunofluorescence, the secretion of latent collagenase by stimulated rabbit chondrocytes and cells of the post-partum involuting rabbit uterus. The ionophore monensin was used to demonstrate intracellular accumulation of collagenase in the Golgi apparatus of both stimulated chondrocytes and involuting uterine cells. Collagenase was not detectable in either normal cartilage or non-gravid uterus. These results are discussed in relation to other studies of collagenase immunolocalization reported in the literature.
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PMID:Characterization of a specific antiserum for mammalian collagenase from several species: immunolocalization of collagenase in rabbit chondrocytes and uterus. 301 93

Rabbit uterine cervical fibroblast-like cells maintained in fetal calf serum-free medium were found to biosynthesize and secrete a collagenase inhibitor into the culture medium. All the properties of this inhibitor were similar to those that have been described so far for the tissue inhibitor of metalloproteinases. Both progesterone and 17 beta-estradiol significantly increased the level of collagenase inhibitor without the proliferation of cells. These data suggest that both progesterone and estradiol regulate collagenolysis in the uterus bifunctionally by acceleration of the inhibitor production in addition to their known inhibitory actions towards collagenase biosynthesis.
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PMID:Hormonal control of collagenase inhibitor production in rabbit uterine cervical fibroblast-like cells. 301 18

A monospecific antibody to rat uterine collagenase has been produced and employed to study the cell of origin and the time course of production of this enzyme in the involuting rat uterus. The specificity of the anti-collagenase antibody was confirmed by immunoprecipitation, Western analysis, and by its ability to inhibit the activity of collagenase. Parallel measurements of functional enzyme, both latent and active, bound to tissue collagen were also made in nonpregnant, gravid, and postpartum rat uteri. Immunohistochemical staining of collagenase in sections of rat uterus showed the enzyme to be present in the perinuclear region of the smooth muscle cells only of the involuting myometrium. No detectable collagenase was present in the prepartum or nonpregnant uterus. Identity of the smooth muscle cells was confirmed using an anti-smooth muscle actin antibody. In addition, the cultured uterine cells from which the immunizing antigen was obtained were also identified as smooth muscle cells. Specificity of the tissue staining was confirmed by the ability of pure rat uterine collagenase to block the reaction of the antibody with the tissue. These observations indicate that smooth muscle cells are capable of producing collagenase and are consistent with the hypothesis that this enzyme presides over the massive collagen degradation seen in postpartum uterine involution. Furthermore, measurement of collagenase bound to uterine collagen revealed that collagenase activity could be detected only at the time that the cells could be seen to be producing the enzyme by immunolocalization. These findings support the concept that collagenase is produced only as needed and not stored, either intra- or extra-cellularly.
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PMID:Collagenase production by smooth muscle: correlation of immunoreactive with functional enzyme in the myometrium. 302 62

The characteristics of the stromal reaction to invasion by cancer were studied in 23 cases of cervical squamous cell carcinoma (stage Ib to IIb) and 86 control cases of benign disease of the uterus. Tissues taken from sites adjacent to tumor or from comparable sites in the nonmalignant uteri were analyzed for number of round cells, density of collagen and reticular fibers, and collagenase activity. The results were correlated with the depth of invasion and the histologic appearances of the tissues adjoining the cancer. Plasma cells and reticular fibers were most numerous in patients with slight invasion and no direct contact between the malignant and benign tissues (C type in CPL classification of Imai). Glycosaminoglycans (mainly hyaluronic acid and chondroitin sulfate) were present in the greatest amounts in C type stroma. The prognosis showed no correlation with either collagen content or collagenase activity but it was a better prognosis correlated with the collagen/collagenase ratio. It is concluded that increased numbers of plasma cells and reticular fibers and a high collagen/collagenase ratio are among the mechanisms protective against the invasiveness of cervical carcinoma.
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PMID:Stromal reactions to squamous cell carcinoma of the cervix. 303 58

Plasminogen activator (PA) activity in the rat uterus was measured at fixed intervals post partum in order to determine whether this serine protease increases during the acute remodelling of tissue which occurs in the involuting uterus. Plasminogen activator activity was measured by an indirect method based on the hydrolysis of the chromogenic substrate S-2251 by PA-generated plasmin. At the time of parturition the control level of PA activity was 0.033 +/- 0.018 (S.D.) mumol/4 mg uterine wet weight per 30 min. This activity increased fourfold to a peak of 0.131 +/- 0.036 at 3 days post partum, and then it declined steadily towards the control level during the next 7 days. Concomitantly, uterine weight decreased to 25% of the control weight by 3 days post partum, and it continued to decrease until day 15. In the 30 days post partum during which PA activity was monitored there was no significant change in plasmin inhibitors in the uterine extracts. The results suggest a correlation between PA activity and the process of tissue remodelling which occurs during involution of the rat uterus. This increase in PA might serve to activate a latent collagenase since the measured peak in PA activity happens to coincide with a reported increase in collagenolytic activity in the involuting rat uterus.
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PMID:Increase in plasminogen activator in the involuting uterus of the postpartum rat. 315 89


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