Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uterus of the rat contains a small metalloproteinase that digests Azocoll and proteoglycan. The activity of this enzyme is elevated in the postpartum uterus and parallels the rate of breakdown of matrix proteoglycan (Sellers, A. and Woessner, J.F., Jr., Biochem. J. 189: 521, 1980). The enzyme has been purified to homogeneity. Its molecular weight is 28,000 for the latent form of the enzyme and 19,000 for the active form, as determined by SDS/PAGE. The enzyme has no action on collagens of type I, III, IV or V, but it does digest gelatins of these 4 types. Digestion of type I gelatin is most pronounced for the alpha-2 chain, which is cleaved to two major bands. The B chain of insulin is cleaved at Ala14-Leu15 and Tyr16-Leu17. Proteoglycan is degraded, but no action can be detected against elastin. Both zinc and calcium ions are required for activity. Low levels of phosphoramidon or Zincov are not inhibitory. Detailed comparisons with human gelatinase (matrix metalloproteinase 2) and stromelysin (matrix metalloproteinase 3) show that the uterine proteinase has a distinctive pattern of specificity. The properties match those of human Pump-1 as reported by Quantin et al., Biochemistry 28: 5327, 1989. It is proposed to designate this proteinase as matrix metalloproteinase 7.
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PMID:The small matrix metalloproteinase of the rat uterus. 148 88

A small metalloproteinase that digests Azocoll was found in the uterus of the rat. Its activity increased to high levels during the postpartum period in parallel with the breakdown of the extracellular matrix exclusive of collagen (Sellers, A., and Woessner, J.F., Jr. (1980) Biochem. J. 189, 521-531). This enzyme has now been purified almost 7,000-fold to homogeneity from 12 g of tissue using molecular sieve chromatography, blue sepharose chromatography, and zinc-chelate chromatography. Gel electrophoresis with sodium dodecyl sulfate and dithiothreitol gives Mr = 28,000 for the latent form of the enzyme and Mr = 19,000 for the active form that arises spontaneously or by treatment with aminophenylmercuric acetate. The enzyme digests components of the extracellular matrix including gelatins of types I, III, IV, and V, fibronectin, and proteoglycan. It digests the alpha 2(I) chain of gelatin in preference to the alpha 1(I) chain and cleaves dinitrophenyl-Pro-Leu-Gly-Ile-Ala-Gly-Pro-D-Arg. It cleaves the B chain of insulin at two points: Ala14-Leu15 and Tyr16-Leu17. It has no action on collagens of types I, III, IV, or V at 26 degrees C and no action on elastin or phenylazo-Pro-Leu-Gly-Pro-D-Arg. The pH optimum is at pH 7 and the pI at 5.9. The enzyme requires zinc and calcium ions for activity; cobalt and strontium can partially replace these metal ions. The enzyme is not inhibited by low levels of phosphoramidon or Zincov. Its properties clearly distinguish it from collagenase, gelatinase (matrix metalloproteinase 2), and stromelysin (matrix metalloproteinase 3); it therefore constitutes a further member of the family of extracellular matrix metalloendopeptidases. The name matrix metalloproteinase 7 is proposed.
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PMID:Purification and properties of a small latent matrix metalloproteinase of the rat uterus. 318 22

To explore the role of the matrix metalloproteinase matrilysin (MAT) in normal tissue remodeling, we cloned the murine homologue of MAT from postpartum uterus using RACE polymerase chain reaction and examined its pattern of expression in embryonic, neonatal, and adult mice. The murine coding sequence and the corresponding predicted protein sequence were found to be 75% and 70% identical to the human sequences, respectively, and organization of the six exons comprising the gene is similar to the human gene. Northern analysis and in situ hybridization revealed that MAT is expressed in the normal cycling, pregnant, and postpartum uterus, with levels of expression highest in the involuting uterus at early time points (6 h to 1.5 days postpartum). The mRNA was confined to epithelial cells lining the lumen and some glandular structures. High constitutive levels of MAT transcripts were also detected in the small intestine, where expression was localized to the epithelial Paneth cells at the base of the crypts. Similarly, MAT expression was found in epithelial cells of the efferent ducts, in the initial segment and cauda of the epididymis, and in an extra-hepatic branch of the bile duct. MAT transcripts were detectable only by reverse transcription-polymerase chain reaction in the colon, kidney, lung, skeletal muscle, skin, stomach, juvenile uterus, and normal, lactating, and involuting mammary gland, as was expression primarily late in embryogenesis. Analysis of MAT expression during postnatal development indicated that although MAT is expressed in the juvenile small intestine and reproductive organs, the accumulation of significant levels of MAT mRNA appears to correlate with organ maturation. These results show that MAT expression is restricted to specific organs in the mouse, where the mRNA is produced exclusively by epithelial cells, and suggest that in addition to matrix degradation and remodeling, MAT may play an important role in the differentiated function of these organs.
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PMID:The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. 757 99

Human pregnancy is associated with extensive growth and remodelling of the uterus and placenta, and restructuring of these tissues during specific stages of gestation likely involves the degradative activity of various matrix metalloproteinases (MMPs). In this investigation, we used in situ hybridization and immunohistochemistry to identify the sites and cell source of collagenase-1 (MMP-1), stromelysin-1 (MMP-3), matrilysin (MMP-7), and 92 kDa gelatinase (MMP-9), a subgroup of MMPs with the combined ability to degrade essentially all matrix proteins. Human tissues were recovered from uncomplicated pregnancies at various gestational ages and from pregnancies complicated by chorioamnionitis, pre-eclampsia, and placenta accreta. Our results show prominent expression of all four MMPs in specific cells of human placentae involved in trophoblast invasion and placental maturation. Collagenase-1 and stromelysin-1 were detected in cells of the amnion, decidua, and chorionic villi at all stages of pregnancy. Ninety-two kilodalton gelatinase was present in granulocytes whenever present. Matrilysin was seen in cytotrophoblasts and syncytiotrophoblasts during early pregnancy but only in cytotrophoblasts by the third trimester. In addition, we found that matrilysin is over expressed and is produced by more cell types in placentae from pregnancies complicated by pre-eclampsia suggesting that the proteolytic activity of this MMP contributes to the pathology of this condition. We conclude that certain MMPs produced by resident cells of the human placenta, and in particular trophoblasts, participate in the physiological progress human gestation and parturition.
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PMID:Collagenase-I, stromelysin-I, and matrilysin are expressed within the placenta during multiple stages of human pregnancy. 891 3

Evidence indicates that matrix metalloproteinases (MMPs) are essentially involved in the postpartum involution of the uterus. As little information exists about the gene regulation of those MMPs in the uterus, this study aimed to characterize the time course of messenger RNA (mRNA) levels of rat collagenase (MMP-13) and matrilysin (MMP-7) in virgin, late pregnant (18th and 21st day), and postpartum rats (1, 2, 3, and 4 days postpartum). Rat collagenase (MMP-13) mRNA levels were very low in virgin and pregnant animals, but increased transiently 30-fold postpartum, reaching a maximum on the second day postpartum. The temporal course of mRNA levels of matrilysin (MMP-7) shows similarity with that of collagenase mRNA levels, but at any stage the abundance of matrilysin mRNA was at least 100-fold higher than that of collagenase. In virgin animals, matrilysin mRNA levels were dependent on the estrous cycle, being 3- to 4-fold higher in the estrous and diestrous stages than during metestrus. MMP-7 shows an approximately 25-fold induction when comparing the mRNA levels in late pregnancy and 2 days postpartum. In cervexes of virgin, pregnant, and postpartum groups, collagenase mRNA was not detectable. Matrilysin in cervix shows temporal mRNA expression similar to that in uterus, with a maximum on day 1 postpartum. In cervix, we found a 14-fold induction when comparing levels in late pregnancy and those 1 day postpartum. Taken together, our findings suggest that the increased activity of MMPs in the postpartum uterus is due to a strong increase in the mRNA levels of MMP-13 and MMP-7.
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PMID:Messenger ribonucleic acid levels of collagenase (MMP-13) and matrilysin (MMP-7) in virgin, pregnant, and postpartum uterus and cervix of rat. 894 Mar 67

Matrilysin was first discovered in the involuting rat uterus; it has also been known as uterine metalloproteinase, putative metalloproteinase (Pump-1), and matrix metalloproteinase 7 (MMP-7). It is the smallest member (28 kDa) of a family of 15 MMPs that together are able to degrade most of the macromolecules of the extracellular matrix. This family is briefly reviewed; all members are zinc metalloproteinases that occur in zymogen form with the active site zinc blocked by cysteine. Matrilysin can degrade a wide range of gelatins, proteoglycans, and glycoproteins of the matrix and can activate several other MMPs including collagenase. With respect to the uterus, matrilysin is localized to epithelial cells and varies in amount with the estrus cycle and is found in high levels during postpartum involution. There is evidence for a role in the last stage of cervical ripening and immediately postpartum. Induction of premature delivery by onapristone and prostaglandin E2 advances these changes in matrilysin. Regulation of the enzyme levels in the uterus are considered from four viewpoints: control of protein synthesis (particularly in response to hormones), activation of the proenzyme to functional protease, retention of enzyme by binding to matrix components such as heparan sulfate, and inhibition by natural inhibitors such as tissue inhibitor of metalloproteinases (TIMPs) and alpha 2-macroglobulin.
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PMID:Regulation of matrilysin in the rat uterus. 916 47

The expression patterns of matrix metalloproteinase (MMP) family members during the murine estrous cycle and postpartum uterine involution were analyzed, and the consequence of removing specific MMPs during uterine functions was determined using mice deficient in either matrilysin (MAT) or stromelysin-1 (STR-1). In wild-type animals, MAT, STR-1, STR-2, STR-3, and gelatinase A were consistently expressed during the most active phases of the estrous cycle, estrus and proestrus. The messenger RNA for these MMPs as well as collagenase-3 and the tissue inhibitors of metalloproteinases were also expressed during uterine involution, as determined by Northern analysis and in situ hybridization. Notably, MAT, STR-2, and collagenase-3 messenger RNA levels were elevated at early times of involution and rapidly decreased with time, whereas the transcripts for other MMPs remained elevated throughout the involution process. Involution proceeded normally in mice lacking MAT or STR-1; however, the expression of STR-1 and STR-2 was dramatically up-regulated in MAT nullizygous mice, and the expression of MAT and STR-2 was moderately up-regulated in STR-1-deficient animals. We conclude that the concerted action of several MMPs is likely to play an important role in the remodeling of the postpartum uterus, and that mechanisms that compensate for the loss of a specific MMP during this process appear to exist.
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PMID:Coordinate expression of matrix metalloproteinase family members in the uterus of normal, matrilysin-deficient, and stromelysin-1-deficient mice. 934 21

Neutrophil collagenase or collagenase 2 (MMP-8) is unique among the family of matrix metalloproteinases (MMPs) because of its exclusive pattern of expression in inflammatory conditions. At present, no evidence of the occurrence of this enzyme in tissues other than human has been reported. In this work, we have cloned the murine homologue of human collagenase 2. The isolated cDNA contains an open reading frame coding for a polypeptide of 465 amino acids, which is 74% identical to its human counterpart. The mouse collagenase 2 exhibits the domain structure characteristic of several MMPs, including a signal sequence, a prodomain with the cysteine residue essential for enzyme latency, an activation locus with the Zinc-binding site, and a COOH-terminal fragment with sequence similarity to hemopexin. It also contains the three conserved residues (Tyr-209, Asp-230, and Gly-232) located around the Zinc-binding site and are distinctive of the collagenase subfamily. Northern blot analysis of RNAs isolated from a variety of mouse tissues revealed that collagenase 2 is expressed at late stages during mouse embryogenesis, coinciding with the appearance of hematopoietic cells. In addition, collagenase 2 was highly expressed in the postpartum uterus starting at 1 day postpartum and extending up to 5 days. Enzymatic analysis revealed that matrilysin, another MMP overexpressed in uterine tissue, is able to activate murine procollagenase 2. These data suggest that both enzymes could form an activation cascade resulting in the generation of the collagenolytic activity required during the process of massive connective tissue resumption occurring in the involuting uterus.
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PMID:Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. 972 11

During human placentation, fetal cytotrophoblast stem cells differentiate and then invade the uterine wall and its associated spiral arteries. This process anchors the placenta to the uterus and supplies maternal blood to the fetus. Cytotrophoblast invasion in vitro requires the expression of matrix metalloproteinase-9 (MMP-9). Recently, we showed that cytotrophoblasts produce interleukin-10 (IL-10), a potent immunomodulatory cytokine that could have paracrine effects on the maternal immune system. IL-10 synthesis is dramatically downregulated after the first 12 h of culture, while MMP-9 secretion is rapidly upregulated and the cells acquire an invasive phenotype. These observations prompted us to investigate whether IL-10 is an autocrine regulator of cytotrophoblast MMP-9 production. We found that the cells expressed IL-10 receptor mRNA, suggesting that autocrine effects are possible. Adding recombinant IL-10 to cytotrophoblast cultures significantly decreased the cells' MMP-9 expression at both protein and mRNA levels, but did not affect mRNA levels of the tissue inhibitor of metalloproteinase-3. Thus, IL-10 may alter the proteinase/inhibitor balance. IL-10 treatment further caused a net decrease in MMP activity, thereby reducing cytotrophoblast invasiveness. An antibody that neutralized endogenous IL-10 function had the opposite effect in all experiments. Together, these data suggest that IL-10 is an autocrine inhibitor of cytotrophoblast MMP-9 activity and invasiveness.
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PMID:IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion. 988 7

The objective of this study was to follow changes in the activity of the small matrix metalloproteinase matrilysin (MMP-7) in the rat uterus during the oestrous cycle and embryo implantation. Matrilysin was extracted from rat uteri, partially purified and separated into active and latent forms. The two forms of the enzyme were quantified at all stages of the oestrous cycle and after oestradiol and progesterone treatment. The activity was also measured during the first 7 days of pregnancy. Both latent and active forms of MMP-7 reached a peak during the pro-oestrous stage of the cycle; the concentrations were three times higher than at dioestrus and metoestrus. In rats treated with 0.1 mg oestradiol at metoestrus, both latent and active forms of the enzyme increased by more than two-fold after 24 h. In rats treated at pro-oestrus with 0.4 mg progesterone, there was a 70% increase in latent MMP-7, but no change in the active form. The highest concentrations of MMP-7 were observed on the first day of pregnancy. Between days 3 and 7 of pregnancy, the concentrations were relatively constant and comparable to the low concentrations at dioestrus. Enzyme activities were not different at implantation sites compared with remote sites.
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PMID:Matrilysin activity in the rat uterus during the oestrous cycle and implantation. 1007 Mar 64


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