Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Human gingival fibroblasts in culture were shown to secrete a 72 kDa progelatinase, of which a proportion in the medium was found to be complexed with tissue inhibitor of metalloproteinases-2 (TIMP-2). A purification procedure was devised to purify free enzyme and inhibitor. We also describe the purification of both 95 kDa progelatinase bound to TIMP-1 and free 95 kDa progelatinase from the medium of U937 cells. A polyclonal antiserum to TIMP-2 was prepared and it was shown that TIMP-1 and TIMP-2 are antigenically distinct. The ability to form stable complexes and the relative inhibitory activities of TIMP-1 and TIMP-2 towards 95 kDa and 72 kDa gelatinases, collagenase, stromelysins 1 and 2 and punctuated metalloproteinase were determined; only minor differences were found. Complex-formation between TIMP-2 and 72 kDa progelatinase was demonstrated not to reduce the metalloproteinase-inhibitory activity of TIMP-2, a finding that led to the characterization of high-molecular-mass TIMP activity. Competition experiments between progelatinases and active gelatinases for TIMPs indicated that the affinity of TIMPs for progelatinases is weaker than that for active gelatinases. In a study of the effects of TIMP-1 and TIMP-2 on progelatinase self-cleavage we found that both TIMP-1 and TIMP-2 inhibit the conversion of 95 kDa and 72 kDa progelatinases and prostromelysin into lower-molecular-mass forms. TIMP capable of complexing with progelatinase was shown to be no more efficient an inhibitor of gelatinase self-cleavage than TIMP not able to complex with progelatinase.
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PMID:The purification of tissue inhibitor of metalloproteinases-2 from its 72 kDa progelatinase complex. Demonstration of the biochemical similarities of tissue inhibitor of metalloproteinases-2 and tissue inhibitor of metalloproteinases-1. 190 13

Sequence-based inhibitors of collagenase bearing an hydroxamate group capable of chelating the active site zinc atom were synthesized and tested. The effect of one of these molecules (RP 59794; Ki about 10(-8) M) on the formation of the TIMP: collagenase complex was also tested. RP 59794 blocks complex formation and can partially dissociate established TIMP: collagenase complexes. It exhibits the same stereospecificity in this activity as in its inhibition of collagenase suggesting that TIMP and RP 59794 both interact with the active site region of collagenase.
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PMID:Low molecular weight, sequence based, collagenase inhibitors selectively block the interaction between collagenase and TIMP (tissue inhibitor of metalloproteinases). 196 13

Previous studies demonstrated that tetracyclines (TCs) inhibited Type I (interstitial) and Type IV collagenases from different mammalian sources, but there are no studies of TCs effect on osteoblast collagenase (C'ase). The present study assessed the effect of TCs on C'ase activity from osteosarcoma cells. Semiconfluent UMR 106-01 cells were treated with minocycline or chemically modified tetracycline (CMT) at 10 micrograms/ml in the presence or absence of bovine parathyroid hormone, b-PTH-(1-34), at 10(-7)M for 24, 48, 72 and 96 hours. Media were collected at each time point and assayed following concentration, destruction of TIMP by reduction/alkylation, activation with p-aminophenylmercuric acetate (APMA), and incubation with 3H-methylated collagen substrate (approximately 100,000 dpm) at 27 degrees C for 18 hours. Collagenase activity from media was also analyzed by SDS-PAGE and fluorography. b-PTH appeared to stimulate C'ase 60-fold compared to controls; minocycline and CMT reduced PTH stimulation approximately 65% and 90%, respectively. Moreover, TCs incubated with partially purified osteoblastic collagenase directly, inhibited its activity in vitro as indicated by a lack of degradation to collagen alpha A chains. Therefore, TCs ability to inhibit bone resorption in organ culture, reported previously, may be due, in part, to reduced osteoblast collagenase activity.
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PMID:The effect of tetracyclines on collagenase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. 196 17

A new bone resorption model was developed by using living bone substrates and devitalized bones for isolated osteoclasts to act on. The extent of bone resorption was assessed by measuring the area and depth of resorption pits. The area and depth of pits made on living bones were greater than those of pits made on devitalized bone substrates. TIMP (100 micrograms/ml) reduced resorption on living bone in area and depth to the same amount of resorption on devitalized bone. E-64 (60 microM) significantly inhibited the resorption of devitalized bones. TGF-alpha (100 ng/ml) did not have significant effect on the resorption of any substrate. Indomethacin (100 ng/ml) reduced resorption on living bone to the same level of that on devitalized bone. These results suggest that resorption on living bone is aided by osteocyte-synthesis of metalloproteinases, among them collagenase, to degrade bone collagen through prostaglandin synthesis by viable cells in the substrates. The stimulation of bone resorption by TGF-alpha observed in organ culture appears not to be mediated by direct stimulation of osteoclast activity.
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PMID:Different resorption modes on living and devitalized bones by isolated osteoclasts in vitro. The effects of TIMP, E-64, and TGF-alpha. 209 95

Human keratinocytes in culture are known to produce collagenase. As part of studies to ascertain the physiologic stimuli for collagenase production by keratinocytes, we wanted to determine whether extracellular matrix could modulate the production of collagenase in vitro. Immunoprecipitable collagenase from the conditioned medium of cells grown on different types of matrix was measured. Metabolically labeled human keratinocytes were cultured in 0.1 mM calcium in serum-free medium on colloidal gold-coated coverslips plus type IV collagen, type I collagen, or laminin or in the absence of matrix. Immunoprecipitation of the conditioned medium with anti-collagenase antiserum was performed and the immunoprecipitates were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, fluorography, and densitometry. The keratinocytes cultured on type IV or type I collagen produced more collagenase than did those cultured on laminin or in the absence of matrix. This effect did not reflect a general increase in secreted proteins, because the production of tissue inhibitor of metalloproteinase, or TIMP, did not increase under the same conditions. Phagocytosis of the gold salts by the keratinocytes migrating on types I or IV collagen did not account for the increased collagenase produced by these cells since the effect persisted in the absence of the colloidal gold and phagocytosis of latex beads did not augment collagenase production.
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PMID:Enhanced synthesis of collagenase by human keratinocytes cultured on type I or type IV collagen. 215 73

To investigate the effects of mechanical deformation on matrix degradation in fibrous joints, coronal suture explants from neonatal rabbits were stressed in vitro for 24 hours in an established tooth-movement model system. The metalloproteinase collagenase (CL) and its inhibitor, TIMP (tissue inhibitor of metalloproteinases), were immunolocalized in two ways by a two-step indirect technique: (1) extracellularly by immunoprecipitation at the site of secretion, and (2) intracellularly by incubation of the explants with the ionophore monensin. Immunoprecipitates of CL and TIMP were distributed throughout the sutural and periosteal tissues of nonstressed explants. In stressed explants, however, CL immunoprecipitates were predominantly associated with an area of rounded cells between the bone ends. In explants treated with monensin a significant increase in the number of CL-positive cells was observed in this cellular area; active enzyme was suggested by the demonstration of CL bound to collagen. Extracellular TIMP was not seen within the area of rounded cells of stressed explants, but intracellular TIMP was detectable; this suggests that insufficient TIMP was available to immunoprecipitate with anti-TIMP, probably because it had become irreversibly complexed with active CL. Since the area of rounded cells corresponds to the site of increased cell proliferation in this and other animal models of tooth movement, these data suggest that collagenase production and cell proliferation might be correlated. We speculate that matrix degradation is an essential prerequisite for cell proliferation as it creates room to accommodate an increase in cell population.
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PMID:Immunolocalization of collagenase and tissue inhibitor of metalloproteinases (TIMP) in mechanically deformed fibrous joints. 215 35

Evidence has recently accumulated suggesting that osteoblasts play a direct role in bone resorption by producing collagenase. In this paper we describe studies carried out with explants of bone from osteopetrotic grey lethal (gl/gl) mice and show that despite the lack of osteoclastic activity the production of both active and latent collagenase and its specific inhibitor TIMP (tissue inhibitor of metalloproteinases) is similar to that of normal bones. Synthesis of collagenase was stimulated by the bone resorptive agent vitamin A (retinol); concomitantly, TIMP levels fell to zero and active enzyme was detected in the culture medium. This work supports the view that bone collagenase is produced by cells other than osteoclasts, since the response of the osteoblastic population to resorptive signals appears normal.
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PMID:Osteopetrotic (grey-lethal) bone produces collagenase and TIMP in organ culture: regulation by vitamin A. 216 Dec 16

Human fibrosarcoma cells derived from a patient with multiple metastases extensively degrade artificial basement membranes (BM) and secrete interstitial type of collagenase, a proteolytic enzyme responsible for degradation of type I collagen. Exposure of invasive cell line to TGF beta abrogates destruction of BM.TGF beta reduces collagenase activity and stimulates specific metalloproteinase inhibitor (TIMP) in invasive tumor cells. We preassume that TGF beta could play a protective role in tumor invasion.
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PMID:Protective role of transforming growth factor beta (TGF beta) in tumor-induced degradation of basement membranes. 216 65

We have recently described the characterization and expression of a murine gene highly homologous to the human tissue inhibitor of metalloproteinases/erythroid potentiating activity (TIMP/EPA) gene. We have also reported that expression of this gene is regulated in response to virus infection. In the present report we describe the use of a cDNA clone derived from mRNA isolated from Newcastle disease virus-induced murine cells to direct in vitro synthesis of proteins encoded by this murine TIMP/EPA gene. This approach was used to analyze structural and functional parameters of the TIMP/EPA protein. Translation experiments using microsomes revealed a murine protein similar in size to that of human TIMP: Mr of approximately 22,000 for the core protein and 28,000 for the processed protein. Processing in microsomes involved N-glycosylation and cleavage of the signal peptide. Both the processed and unprocessed proteins were able to inhibit degradation of collagen by collagenase but unable to inhibit virus replication. Synthesis of truncated TIMP proteins showed that the collagenase-inhibiting activity was not encoded within a delimited portion of the molecule. This result suggests that conformation is probably essential for TIMP activity.
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PMID:In vitro synthesis of the active tissue inhibitor of metalloproteinases encoded by a complementary DNA from virus-infected murine fibroblasts. 244 90

FK506, a neutral macrolide with immunosuppressive properties, was shown to selectively and rapidly inhibit the accumulation of IL-2 mRNA, as well as the mRNAs of other early (E) phase T cell activation genes such as IL-3, IL-4, GM-CSF, TNF alpha, IFN-gamma, and c-myc in activated human peripheral blood T cells. The activity of FK506, when compared to Cyclosporin A, another immunosuppressant, was 10 to 100x more potent in its ability to inhibit IL-2 mRNA synthesis. FK506 inhibited IL-2 mRNA accumulation in Con A, Con A plus PMA, Ionomycin plus PMA, anti-CD3, and anti-CD3 plus PMA activated T cells. Transcripts from other T cell gene classes such as the immediate early (IE) phase gene, c-fos, the late phase (L) genes, transferrin receptor, IL-2R alpha-chain, and TNF-beta, and the constitutive class genes glyceraldehyde-3-phosphate dehydrogenase and class I MHC HLA-B7 were not affected by FK506. The macrolide Rapamycin, which is structurally related to FK506, had no inhibitory effect on IE, E, L, or constitutive class mRNAs, but it appeared to increase the levels of the E-phase transcripts that were inhibited in FK506 treated T cells. The effect of FK506 on inducible genes in non-T and non-lymphoid human cells was studied in LPS-induced monocytes and PMA or IL-1 activated synovial fibroblasts. FK506 did not affect expression of the mRNAs for IL-1 alpha or IL-1 beta in human monocytes, or of stromelysin, collagenase, or TIMP in synovial fibroblasts. Nuclear run-off transcription studies indicate that FK506 inhibits transcription of the IL-2 gene. These studies suggest that Cyclosporin A and FK506 may effect a common early event in the T cell activation pathway.
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PMID:The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. 247 51


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