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)

Cultured mononuclear cells from human peripheral blood produce a soluble factor (MCF) that stimulates collagenase and prostaglandin E2 (PGE2) release by cultured rheumatoid synovial cells up to several hundred fold. These target rheumatoid synovial cells lack conventional macrophage markers. To determine which mononuclear cells are the source of MCF, purified populations of monocyte-macrophages, thymus-derived (T) lymphocytes, and bone marrow-derived (B) lymphocytes were prepared. The monocyte-macrophages alone produced levels of MCF that were proportional to cell density but unaffected by phytohemagglutinin or pokeweed mitogen. No detectable collagenase activity was produced by the cultured monocyte-macrophages or lymphocytes. Purified T lymphocytes produced levels of MCF approximately or equal to 1--3% those of purified monocyte-macrophages in the presence or absence of the above lectins. Purified T lymphocytes modulated the production of MCF by the monocyte-macrophages, however, in a manner dependent upon relative cell densities and the presence of lectins. For example, at optimal ratios of T lymphocytes: monocyte-macrophages, MCF production was markedly stimulated by pokeweed mitogen. Thus, interactions of T lymphocytes and monocyte-macrophages could be important in determining levels of MCF, which regulate collagenase and PGE2 production by target synovial cells in inflammatory arthritis.
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PMID:Participation of monocyte-macrophages and lymphocytes in the production of a factor that stimulates collagenase and prostaglandin release by rheumatoid synovial cells. 22 33

Connective tissue destruction is a major characteristic of chornic rheumatoid arthritis (RA). This process is accompanied by local cellular and humoral inflammatory reactions. Long-term cultures of adherent synovial cells (ASC) from patients with RA produce large amounts of collagenase and prostaglandin (PGE2), two substances that play a role in the degradation of joint structures. Lvels of collagenase and PGE2 can be stimulated (up to several hundred-fold) with a soluble factor (MCF) from cultured peripheral blood mononuclear cells (MW approximately 14,000). The monocyte-macrophages alone produce MCF but can be stimulated directly with Fc fragments of immunoglobulin or concanavalin A to increase MCF production. Addition of T lymphocytes in the presence of lectin or antigen significantly enhances the production of MCF. MCF affects other biological processes in synovial cells such as the rate of collagen synthesis, cell proliferation and sensitivity to PGE2 as well as collagen itself can further modulate collagenase release by the synovial cells and function in an amplificative loop. The understanding of these interactions between cells, mediator-effector substances and connective tissue substrates may provide a basis for devising more rational approaches to therapy of the destructive lesions which characterize RA.
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PMID:Collagenase and prostaglandin in connective tissue destruction: cell-cell and humoral interactions. 23 69

The effect of a cAMP derivative (N6, O2-dibutyryl cyclic adenosine 3',5'-monophosphate: dBcAMP) on the cell cycle and on the synthesis of typical extracellular matrix (ECM) components, i.e. collagen and glycosaminoglycans (GAG), was studied in two hormone-responsive human breast cancer cell lines VHB-1 and MCF-7. The data showed that dBcAMP induced a decrease in the proportion of cells in S + G2 + M phases due to an increase of the non-cycling (G0 phase) cell number as revealed by the Ki-67 antigen immunocytochemical study. The collagen synthesis, estimated by [3H] proline incorporation into the cellular proteins followed by an enzymatic digestion with highly purified bacterial collagenase, was not modified by dBcAMP. In contrast, the GAG synthesis, analysed by [3H] glucosamine incorporation, was increased two-fold in the dBcAMP treated cells. As a comparison we also tested 4-hydroxy-Tamoxifen (4-OH-Tam) since it induces similar cell cycle perturbations as dBcAMP. However, we did not observe a stimulation of the GAG synthesis following 4-OH-Tam treatment. These data demonstrated that the increased GAG synthesis is due to cAMP and is not a consequence of perturbations in the cell cycle. We can therefore assume that the ECM modifications induced by dBcAMP may contribute to the growth inhibition of the hormone-responsive human breast cancer cells.
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PMID:cAMP effect on extracellular matrix synthesis in human breast cancer cells. 133 23

Invasion of basement membranes by cancer cells is a critical step in metastasis, which requires the coordinated expression of specific genes such as laminin receptors and metalloproteinases. Estradiol and progesterone modulate the clinical progression of steroid-sensitive breast cancers; however, little is known about the molecular regulation of the invasive phenotype by these hormones. We therefore examined the effects of 10 nM estradiol and/or 10 nM progestin R5020 on the expression of 2 non-integrin laminin binding proteins, the 67-kDa laminin receptor (67LR) and HLBP31 as well as the 72-kDa type-IV collagenase (MMP-2) and its inhibitor, TIMP-2, in steroid-receptor-positive (T47D and MCF-7) and -negative (MDA-MB 231) human breast-cancer cells. The relative steady-state level of 67LR mRNA was increased 2- to 3-fold by estradiol in both MCF-7 (p < 0.001) and T47D (p < 0.001) cells, also by R5020, alone or in combination with estradiol, in T47D cells (p < 0.001) and to a much less extent in MCF-7 cells. HLBP31 mRNA and protein levels were increased 2- to 3-fold (p < 0.001) by R5020 alone or in combination with estradiol, but not by estradiol alone. None of the steroid treatments affected the expression or activity of MMP-2. Interestingly, however, TIMP-2 mRNA levels and protein expression in MCF-7 and T47D cells were 50% down-regulated (p < 0.001) by treatment with R5020 or R5020 plus estradiol, but not by treatment with estradiol alone. None of these genes were modulated in steroid-independent MDA-MB231 cells. The data suggest that estradiol and progesterone might act as coordinators regulating specific genes in the steroid-sensitive breast-cancer cell, leading to the acquisition of the metastatic phenotype.
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PMID:Genes involved in tumor invasion and metastasis are differentially modulated by estradiol and progestin in human breast-cancer cells. 139 48

Three-dimensional cellular structures formed by MCF-7 human mammary carcinoma cells within collagen gels were isolated with collagenase and cultivated on plastic substratum to examine whether the cytoskeleton specific for cells forming cellular structures (S-type) changes to that specific for cells grown as monolayers (M-type). The cytoskeleton isolated as 0.05% Triton-insoluble fraction from the cellular structures after culture for 1 day on plastic was exclusively S-type. However, both types of cytoskeletons were observed in the cellular structures cultivated for 7 days on plastic as well as in the cells grown as monolayers for 2 days after dissociation of the cellular structures with trypsin. By use of an antibody raised against a 65-kD polypeptide that was specific for the M-type cytoskeleton, the presence of the polypeptide was found to be restricted to the cells grown out as monolayers from the edge of the cellular structures. In the cells grown for 2 days as monolayers, a mixture of cells both having and lacking the polypeptide was observed. After a 7-day culture of the dissociated cells as monolayers on plastic, however, most of the cells had M-type cytoskeletons. The present results show that the apparent change in the cytoskeleton of MCF-7 cells from S-type to M-type does not occur in cells involved in the three-dimensional cellular structures even in the absence of collagen gels, but that it occurs in cells which are grown as monolayers for at least 7 days on plastic substratum.
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PMID:Regulation of cytoskeletal structure in human mammary carcinoma cells MCF-7 by culture substrata. 208 49

Interleukin 1 (IL-1) possesses multiple biological activities that may be blocked selectively by different inhibitors. Some known inhibitors block the lymphocyte activating factor (LAF/IL-1) but not the mononuclear cell factor (MCF/IL-1) measured by its capacity to stimulate prostaglandin E2 (PGE2) and collagenase production. The presence of IL-1 in vivo may be difficult to detect due to the presence of inhibitor(s) and the level of the inhibitor(s) may vary depending upon pathological conditions. We have found that urine from three patients with monocytic leukemia (M5) contained high levels of inhibitor(s) of MCF/IL-1, whereas urine of normal subjects did not contain significant amounts. Urine from two patients with other blood neoplasic diseases also contained little inhibitory activity. The MCF/IL-1 inhibitor(s), which also acts on human recombinant IL-1 beta, is approximately 25-35 kD, is not retained on concanavalin A-Sepharose column and can be partially destroyed with urea and boiling. At this stage of the purification the fraction containing the MCF/IL-1 inhibitor(s) also inhibits the LAF/IL-1 assay. However, this inhibitor(s) is probably distinct from other inhibitors already described.
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PMID:Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). 302 90

Articular chondrocytes and synovial cells were stimulated to produce collagenase, neutral casein and proteoglycan-degrading proteinases by conditioned medium from human peripheral blood mononuclear cells. Collagenase, neutral casein and proteoglycan-degrading proteinase secretion was inhibited by SR 41319, a new bisphosphonate, in a concentration-dependent manner. Complete inhibition was achieved at about 0.3 mM. EHDP exhibited the same general profile but was about 10-fold less active and never completely inhibited the enzyme secretion. When added before MCF, SR 41319 had a protective effect against subsequent activation of the cells by MCF. SR 41319 also inhibited the increase of enzyme secretion by cells previously stimulated with MCF. The results suggest that the ability of SR 41319 to inhibit the MCF-mediated secretion of neutral enzymes involved in cartilage destruction could be valuable in the management of connective tissue damage in rheumatoid arthritis.
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PMID:Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells. 393 18

Cultured adherent rheumatoid synovial cells with fibroblast properties release large amounts of collagenase and prostaglandin E2 (PGE2) into the medium. With age in culture and passage of the cells, the levels of collagenase and PGE2 decrease, but can be increased by a factor (MCF; mononuclear cell factor) released by cultured human blood monocyte-macrophages. The magnitude of the stimulation varies with different synovial cell strains. To determine some of the mechanisms which regulate the collagenase response, synovial cells were exposed to a cyclooxygenase inhibitor (indomethacin) and substances which alter the cytoskeleton (cytochalasin B or colchicine) or interact with Ca2+ X calmodulin (trifluoperazine). The collagenase response was retained even when PGE2 synthesis was totally blocked with indomethacin. The collagenase response, however, was blunted at high indomethacin concentrations (greater than 10 microM) and paradoxically augmented at lower indomethacin concentrations (0.001 microM). In some synovial cell strains, the blunting effect of 10 microM indomethacin was reversed by the addition of low concentrations of exogenous PGE2 (10 ng/ml). Preincubation of synovial cells for 1 or 24 hr with colchicine or cytochalasin B (1-10 microM) resulted in an augmented collagenase and PGE2 response to MCF. Cells preincubated or incubated with 1-50 microM trifluoperazine, a phenothiazine, also augmented collagenase stimulation by MCF, but, in contrast to colchicine or cytochalasin B, trifluoperazine suppressed the PGE2 response. Thus, although PGE2 and collagenase production by synovial cells may be dissociated, altering ambient PGE2 levels affected basal collagenase production and modulated the collagenase response to MCF.
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PMID:Effects of prostaglandin E2, indomethacin, trifluoperazine and drugs affecting the cytoskeleton on collagenase production by cultured adherent rheumatoid synovial cells. 608 39

Adherent synovial cells (ASC) were obtained from minced synovium from patients with rheumatoid arthritis by dissociating the lining cells from the extracellular matrix and dispersing them with proteases. These cells produce high levels of latent collagenase in primary culture. With passage of ASC, collagenase levels decrease but can be stimulated by a soluble factor (MCF) released in vitro from cultured human blood monocyte-macrophages. Monocyte cultures exposed to aggregated immunoglobulin, Fc fragments of immunoglobulin or concanavalin A (Con A) increase production of MCF several-fold more than the control cultures. MCF production by monocytes exposed to Fab fragments does not differ from controls. Although aggregated immunoglobulin, Fc fragments, and Con A stimulate PGE2 synthesis and secretion by human monocytes, the effects on MCF production are not mediated by PGE2 since concentrations of indomethacin that completely block PGE2 production do not inhibit MCF production. These findings of increased production of MCF by monocytes in response to substances that probably exert their effects via surface receptors could be relevant in interpreting the in vivo role of immune complexes in diseases associated with connective tissue destruction.
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PMID:Interactions among rheumatoid synovial cells and monocyte-macrophages: production of collagenase-stimulating factor by human monocytes exposed to concanavalin A or immunoglobulin Fc fragments. 624 27

Using human articular chondrocytes in monolayer culture as an experimental system, we have been studying mechanisms of control of production and activity of neutral proteases which degrade connective tissue matrices. Soluble factors from cultured human blood mononuclear cells (MCF) or synovial fragment cultures (SF) stimulate the production of collagenase and proteoglycanase by chondrocytes. Chondrocytes also release a collagenase inhibitor (mol. wt. 26-31,000), which is similar to the tissue inhibitor of metalloproteinases (TIMP) synthesized by cultured mammalian tissues and this is reduced in cultures exposed to MCF or SF. Retinol and dexamethasone partially inhibit the factor-stimulated collagenase, but increase the amount of inhibitor, restoring it to control levels in the presence of MCF or SF. The effects of these agents in cellular interactions in vitro will be discussed in relation to their possible roles in the control of connective tissue turnover in vivo.
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PMID:Interactions in connective tissues involving monocyte/macrophages and control of production of proteinases and proteinase inhibitors. 629 11


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