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PubMed1992

Extracellular matrix and neurite outgrowth.

The complex relationship between neuronal cells and the extracellular matrix molecules with which they interact both positively and negatively is currently being investigated on many fronts. Major areas of experimental emphasis include the characterization of an increasing number of extracellular matrix and cell surface associated molecules, the identification of receptors for these molecules, and the analysis of the function of extracellular matrix molecules with respect to neuronal process outgrowth.

Animals↗
PubMed1993

Molecular cloning of olfactomedin, an extracellular matrix protein specific to olfactory neuroepithelium.

The extracellular mucous matrix of olfactory neuroepithelium is a highly organized structure in intimate contact with chemosensory cilia that house the olfactory transduction machinery. Here we describe the molecular cloning and primary structure of olfactomedin, which is the major component of this extracellular matrix. Olfactomedin is expressed exclusively in olfactory neuroepithelium and its amino acid sequence shows no homologies to any known protein. This olfactory tissue-specific glycoprotein contains cysteines which form disulfide-linked polymers that constitute the primary architecture of the olfactory extracellular matrix. By analogy to other extracellular matrix proteins of the nervous system, olfactomedin may influence the maintenance, growth, or differentiation of chemosensory cilia on the apical dendrites of olfactory neurons.

Amino Acid Sequence↗
PubMed1997

Growth factors in the extracellular matrix.

Much recent research has focused on the study of the expression of growth factor genes and on the identification of growth factor signaling mechanisms inside cells. However, growth factor signaling can also be regulated outside of cells by extracellular matrix proteins and proteolytic enzymes. The ability of extracellular proteins to process complex information in the absence of new protein synthesis is illustrated in blood clotting and complement pathways. An increasing number of growth factors, including IGFs, FGFs, TGF-beta's, and HGF, have been found to associate with the extracellular matrix proteins or with heparan sulfate. Rapid and localized changes in the activity of these factors can be induced by release from matrix storage and/or by activation of latent forms. These growth factors, in turn, control cell proliferation, differentiation, and synthesis and remodeling of the extracellular matrix. It is therefore likely that much of the information processing necessary for construction of complex multicellular organisms occurs in the extracellular environment. This suggests that extracellular matrix plays a major role in the control of growth factor signaling.

Animals↗
PubMed1988

In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells.

It has been proposed that proteases secreted by cancer cells facilitate metastasis by degrading extracellular matrix. Estrogen receptor-positive breast cancer cells secrete a Mr 52,000 pro-cath-D under estrogen stimulation, whereas this protease is produced constitutively by estrogen receptor-negative cancer cells. We report on the degradation in vitro of extracellular matrix by purified Mr 52,000 cathepsin D (cath-D) and by conditioned media prepared from different cell lines. The purified Mr 52,000 pro-cath-D was autoactivated at pH 4.5 into a Mr 51,000 cath-D and found to digest the extracellular matrix of endothelial bovine corneal cells labeled with [3H]proline or [35S]methionine. Culture medium conditioned by estrogen-treated MCF7 cells had a similar effect at pH 4.5 but not at pH 7.4. Matrix degradation was totally inhibited by pepstatin. Other breast cancer cells (BT20, MDA-MB231, T47D cells, etc.) and other cancer cells also secreted a pepstatin-sensitive proteinase able to degrade extracellular matrix. By contrast, the U2 variant of MCF7 cells, which lacks the Mr 52,000 cath-D gene, and the nontumoral epithelial mammary cells secreted a negligible amount of this proteinase. In all conditioned media, the pepstatin-dependent extracellular matrix degrading activity was highly correlated to the Mr 52,000 cath-D concentration measured by immunoenzymatic assay. We conclude that the Mr 52,000 cath-D is the major acidic protease secreted by mammary cancer cells. We suggest that this protease may degrade basement membrane and consequently facilitate tumor invasion when it is released in an acidic microenvironment.

Breast Neoplasms↗
PubMedDate not supplied

Progressive renal disease: fibroblasts, extracellular matrix, and integrins.

Progressive renal disease is characterized by expansion of the tubulo-interstitium and accumulation of extracellular matrix within this tissue compartment. Interstitial fibroblasts are the primary producers of the interstitial matrix, and in the evolution of tubulo-interstitial fibrosis these cells undergo changes, namely increased proliferation, differentiation to myofibroblasts, and altered extracellular matrix metabolism, all of which, in other cell types, have been shown to be regulated by the major family of extracellular matrix receptors, the integrins. In the normal kidney, interstitial fibroblasts express alpha1, alpha4, alpha5, and beta1 integrins, and fibrosis is associated with increased expression of alpha1, alpha2, alpha5, alphav, and beta1 integrins. In particular, alpha5, beta1, and alphav are suggested to be linked with the fibrotic process. In vitro, renal fibroblasts express a similar range of integrins, and ligation of selected receptors is associated with specific functions. Ligation of alpha6 stimulates proliferation, while alpha5 promotes expression of myofibroblastic phenotype, and beta1 integrin has been implicated in cell contraction. Recent studies suggest that renal fibroblasts also express the non-integrin matrix receptors, discoidin domain receptors, and that changes in activation of these receptors may be associated with fibrogenic events. Thus the current, albeit limited, data suggest an important role for receptors for extracellular matrix molecules in the pathogenesis of progressive renal fibrosis.

Animals↗
PubMed2001

MlrA, a novel regulator of curli (AgF) and extracellular matrix synthesis by Escherichia coli and Salmonella enterica serovar Typhimurium.

Production of curli (AgF) adhesins by Escherichia coli and Salmonella enterica serovar Typhimurium (S. typhimurium) is associated with extracellular matrix production and is optimal at low temperature during stationary phase. Curli and extracellular matrix synthesis involves a complex regulatory network that is dependent on the CsgD (AgfD) regulator. We have identified a novel regulator, termed MlrA, that is required for curli production and extracellular matrix formation. Two cosmids from a genomic library of avian pathogenic E. coli chi7122 conferred mannose-resistant haemagglutination (HA) and curli production to E. coli HB101, which is unable to produce curli owing to a defective regulatory pathway. The rpoS gene, encoding a known positive regulator of curli synthesis, and the E. coli open reading frame (ORF) of unknown function, yehV, identified on each of these cosmids, respectively, conferred curli production and HA to E. coli HB101. We have designated yehV as the mlrA gene for MerR-like regulator A because its product shares similarities with regulatory proteins of the MerR family. HA and curli production by strain chi7122 were abolished by disruption of rpoS, mlrA or csgA, the curli subunit gene. Both csgD and csgBA transcription, required for expression of curli, were inactive in an mlrA mutant grown under conditions that promote curli production. An mlrA homologue was identified in S. typhimurium. Analysis of mlrA-lac operon fusions demonstrated that mlrA was positively regulated by rpoS. mlrA mutants of wild-type S. typhimurium SL1344 or SR-11 no longer produced curli or rugose colony morphology, and exhibited enhanced aggregation and extracellular matrix formation when complemented with the mlrA gene from either S. typhimurium or E. coli present on a low-copy-number plasmid. However, inactivation of mlrA did not affect curli production and aggregative morphology in an upregulated curli producing S. typhimurium derivative containing a temperature- and RpoS-independent agfD promoter region. These results indicate that MlrA is a newly defined transcriptional regulator of csgD/agfD that acts as a positive regulator of RpoS-dependent curli and extracellular matrix production by E. coli and S. typhimurium.

Adhesins, Bacterial↗
PubMed1998

Vascular extracellular matrix remodeling in cerebral aneurysms.

OBJECT: The occurrence of cerebral aneurysms has been linked to alterations in the extracellular matrix and to matrix-degrading proteases. The purpose of the present study was to determine whether active extracellular matrix remodeling occurs within cerebral aneurysms. METHODS: Aneurysm tissue was collected from 23 patients (two of whom had a ruptured aneurysm and 21 of whom had an unruptured aneurysm) and compared with 11 control basilar arteries harvested at autopsy. Active proteinases capable of gelatin lysis were identified by performing in situ zymography in the presence and absence of a metalloproteinase inhibitor (ethylenediamine tetraacetic acid) and a serine proteinase inhibitor (phenylmethylsulfonyl fluoride). Immunohistochemical analysis was used to localize plasmin, tissue-type (t)-plasminogen activator (PA), urokinase-type (u)-PA, membranetype (MT1)-matrix metalloproteinase (MMP), MMP-2, MMP-9, and tenascin. Focal areas of gelatin lysis occurred in most cerebral aneurysm tissue samples (17 of 21), but rarely in control arteries (two of 11) (p = 0.002). Both serine proteinases and MMPs contributed to gelatin lysis; however, the MMPs were the predominant enzyme family. Plasmin (p = 0.04) and MT1-MMP (p = 0.04) were expressed in the aneurysm tissue but were unusual in control tissue. The MMP-2 was also expressed more commonly in aneurysm than in control tissue (p = 0.07). The MMP-9 and t-PA were expressed in both groups; however, different staining patterns were observed between aneurysm and control tissue. Tenascin staining was commonly present in both groups, whereas u-PA staining was rarely present. CONCLUSIONS: Aneurysm tissue demonstrates increased proteolytic activity capable of lysing gelatin and increased expression of plasmin, MT1-MMP, and MMP-2 when compared with normal cerebral arteries. This activity may contribute to focal degradation of the vascular extracellular matrix and may be related to aneurysm formation and growth.

Adolescent↗
PubMed1992

Cultured rat aortic vascular smooth muscle cells digest naturally produced extracellular matrix. Involvement of plasminogen-dependent and plasminogen-independent pathways.

Vascular smooth muscle (VSM) cell migration and proliferation play a major role in the development of atherosclerotic lesions, graft occlusion, and restenosis after angioplasty. Cell migration implies the digestion of the surrounding extracellular matrix. Cell-associated proteolysis has been extensively studied in neoplastic and inflammatory cells, but very little is known about the proteolytic properties of VSM. We have evaluated the ability of rat cultured VSM cells to solubilize [3H]amino acid-labeled extracellular matrices produced by bovine VSM. When plated at a density of 30,000 cells per well in 24 multiwell plates, VSM cells were able to solubilize 63.3 +/- 7.0% of the extracellular matrix after 10 days in culture. Extracellular matrix digestion occurred also when the cells were cultured in plasminogen-depleted serum but was higher in the presence of 10 micrograms/ml purified plasminogen (net percent digestion after the subtraction of the appropriate control, 8.6 +/- 3.0% versus 21.2 +/- 3.5% after 3 days in culture, p less than 0.005, respectively). The involvement of other enzymes in addition to plasmin is confirmed by the ability of VSM cells to degrade extracellular matrices from which the plasmin-sensitive component was removed with plasmin pretreatment. Rat VSM cells were able to solubilize 52.3 +/- 2.0% of this residual extracellular matrix-associated radioactivity after 6 days in culture versus 26.1 +/- 1.5% in the control dishes (p less than 0.01, n = 5). Cell contact was required for extracellular matrix degradation: cell-conditioned medium did not have any effect on extracellular matrix digestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Hyaluronan is an abundant constituent of the extracellular matrix of Xenopus embryos.

The spatiotemporal distribution of hyaluronan (HA), a major constituent of the vertebrate extracellular matrix, was analyzed during early embryonic development of Xenopus laevis. This polysaccharide is abundantly present in ventricular structures such as the blastocoel, the archenteron as well as later on in the hepatic cavity, the brain ventricles and the developing heart. At the blastula stage, HA was detected in the extracellular matrix of the ecto- and mesodermal primordia. Shortly before gastrulation, it becomes enriched at the basal site of the superficial cell layer of the ectoderm. During gastrulation, enhanced synthesis of HA takes place in the involuting marginal zone, shortly before invagination starts, hence, resulting in a torus-like deposition in the deep layer of the equatorial mesodermal primordium. After gastrulation, HA appears to accumulate within the extracellular matrix demarcating the primary germ layers. During tailbud stages, it is found highly enriched in many mesodermal derivatives, e.g., in mesenchyme, the heart, precordal cartilage and the lung primordia. Furthermore, extracellular matrix of the ventral mesodermal cell layer in the trunk region and the immediate proximity of blood vessels contain high amounts of HA.

Animals↗
PubMed1994

Effects of epidermal growth factor on invasiveness through the extracellular matrix in high- and low-metastatic clones of RCT sarcoma in vitro.

We investigated the invasiveness of tumor cells through the extracellular matrix and the influence of epidermal growth factor (EGF) on tumor cell invasion using in vitro systems in high-[RCT(+)] and low-metastatic [RCT(-)] clones established from poorly differentiated murine RCT sarcoma in C3H/He mice. In the invasion assay using a filter coated with reconstituted basement membrane (Matrigel) in a Boyden chamber, RCT(+) cells were more invasive than RCT(-) cells. The attachment of RCT(+) cells to extracellular matrix components and the degradation of type IV collagen by the cells were significantly greater than with RCT(-) cells. However, there was no significant difference in the migration of cells to the extracellular matrix components between cultured RCT(+) and RCT(-) cells. These findings suggested that the different invasiveness of these clone cells was associated with the difference in the ability of attachment to and degradation of the matrix. The level of laminin receptor expression in RCT(+) cells was about four-fold that in RCT(-) cells and laminin stimulated the type IV collagenolytic activity of RCT(+) cells, suggesting that RCT(+) cell attachment to laminin via laminin receptor on the cell surface induced the production of type IV collagenase by the tumor cells. EGF did not affect the invasiveness of RCT(-) cells. In RCT(+) cells, EGF stimulated the invasiveness through Matrigel, the attachment to extracellular matrix components and the degradation of type IV collagen through high-affinity EGF receptors (EGFR), with Kd of pM order, while the migration to the matrix was not influenced by EGF. These findings suggest that the stimulatory effect of EGF on invasion is related to the acceleration of cell adhesion, and the degradative cascade of the extracellular matrix and high-affinity EGFRs play an important role in the effect of EGF on in vitro invasiveness in this tumor.

Animals↗
PubMed1993

Alterations in the extracellular matrix of the myocardium in essential hypertension.

Hypertension produces myocyte hypertrophy and increases the extracellular matrix. In order to determine the composition of the extracellular matrix we studied the hearts from 14 hypertensive patients by immunohistochemistry using antibodies against collagen I, III, IV and V, fibronectin, myoglobin, muscular specific actin, Factor VIII, CD 34 and vimentin. The myocardium showed a focal increase in fibronectin, collagen I and III and diffuse deposition of laminin, collagen IV and V. Cells positive for vimentin, Factor VIII and CD 34 were also increased, but with considerable variation from case to case. We found no relation between matrix variation and the degree of hypertension or the time elapsed from the beginning of the disease. We conclude that the main role of the matrix in hypertension may be remodelling of the heart so that it entraps muscle fibres and increases their contractility.

Adult↗
PubMed1996

Long-term extracellular matrix metabolism by cultured human osteogenesis imperfecta osteoblasts.

Osteopenia due to deficient extracellular matrix synthesis is a hallmark of osteogenesis imperfecta (OI), Previous studies carried out within 72 h of osteoblast subculture, at an early stage of matrix synthesis, indicated that for osteoblasts derived from human OI patients the total amounts of collagen, osteonectin, and three proteoglycans were significantly reduced, while total amounts of thrombospondin, fibronectin, and matrix hyaluronan were elevated compared with age-matched controls. The current study was undertaken to follow OI osteoblast matrix metabolism as that matrix is synthesized, deposited, and matured. Steady-state metabolic radiolabeling was used to follow the metabolism of collagen, hyaluronan, and total proteoglycan by OI and normal osteoblasts for up to 5 weeks. Trabecular osteoblasts from non-OI controls showed an increase in total and matrix-associated collagen synthesis during the first and second week, reaching steady-state levels by week 4. In contrast, cultured OI osteoblasts did not increase either the total (medium + matrix-associated) or matrix-associated collagen during the entire 5-week period. Proteoglycan synthesis exhibited a pattern similar to that for collagen. OI-derived proteoglycans differed from controls in that levels in OI cultures did not reflect the normal time-dependent increase in total proteoglycan and proteoglycan matrix deposition. OI osteoblast hyaluronan synthesis was increased when compared with age-matched controls during 4 weeks of culture. In contrast, the ratios of calcium to phosphorus solublized from control and the OI extracellular matrix were not statistically different. Thus, with respect to the synthesis of collagen, proteoglycans, and hyaluronan, OI osteoblasts fail to parallel controls in depositing and elaborating extracellular matrix during 35 days in culture.

Adolescent↗
PubMed2006

Role of extracellular matrix and its regulators in human airway smooth muscle biology.

Altered extracellular matrix (ECM) deposition contributing to airway wall remodeling is an important feature of asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanisms of this process are poorly understood. One of the key pathological features of these diseases is thickening of airway walls. This thickening is largely to the result of airway smooth muscle (ASM) cell hyperplasia and hypertrophy as well as increased deposition of ECM proteins such as collagens, elastin, laminin, and proteoglycans around the smooth muscle. Many growth factors and cytokines, including fibroblast growth factor (FGF)-1, FGF-2, and transforming growth factor (TGF)-beta1, that are released from the airway wall have the potential to contribute to airway remodeling, revealed by enhanced ASM proliferation and increased ECM protein deposition. TGF-beta1 and FGF-1 stimulate mRNA expression of collagen I and III in ASM cells, suggesting their role in the deposition of extracellular matrix proteins by ASM cells in the airways of patients with chronic lung diseases. Focus is now on the bidirectional relationship between ASM cells and the ECM. In addition to increased synthesis of ECM proteins, ASM cells can be involved in downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of metalloproteinases (TIMPs), thus eventually contributing to the alteration in ECM. In turn, ECM proteins promote the survival, proliferation, cytokine synthesis, migration, and contraction of human airway smooth muscle cells. Thus, the intertwined relationship of ASM and ECM and their response to stimuli such as chronic inflammation in diseases such as asthma and COPD contribute to the remodeling seen in airways of patients with these diseases.

Cell Movement↗
PubMedDate not supplied

Effects of glycosaminoglycans and extracellular matrix components on metastatic rat rhabdomyosarcoma tumor and myoblast cell proliferation.

Experiments were performed to determine the relative effects of glycosaminoglycans and extracellular matrix components alone or in association with various substrates, including extracellular matrix, on the proliferation of rat rhabdomyosarcoma (RMS) cell lines of different metastatic potential and nontumorigenic rat myoblast L6 cells. The assays used various substrates: tissue culture plastic, type I and IV collagen, fibronectin, laminin and extracellular matrix deposited by corneal endothelial cells. In control experiments, tumor cells grew faster on fibronectin and extracellular matrix than on the other substrates, and their proliferation rate was decreased slightly by laminin. Collagens were growth-inhibitory only for the highly metastatic line. The proliferation rate of L6 myoblasts was not greatly affected by the different substrates. The addition of exogenous glycosaminoglycans to the culture medium modified cell proliferation on the various substrates. Heparin inhibited the growth of all the cell lines tested, independent of the substrate. When cultured on laminin substrate the proliferation rates of the cell lines were depressed by addition of heparan sulfate to the medium, and this effect was more pronounced in the metastatic RMS lines. Chondroitin sulfate and dermatan sulfate enhanced the growth rates of the tumorigenic cells when cultured on collagen type I surfaces. Hydrocortisone, which induces myogenic differentiation, decreased the cell proliferation rates of all the cell lines tested and intensified the inhibitory effects of heparin when added simultaneously to the culture medium. The results showed that glycosaminoglycans and other matrix components can affect the proliferation rates of rhabdomyosarcoma cell lines.

Animals↗
PubMed1987

The microvascular extracellular matrix. Developmental changes during angiogenesis in the aortic ring-plasma clot model.

The composition of the extracellular matrix of developing microvessels in plasma clot cultures of rat aorta was studied with light and electron immunohistochemical techniques using affinity-purified antibodies against fibronectin, laminin, and collagen Types I, III, IV, and V. The extracellular matrix of solid endothelial sprouts in young cultures consisted of a delicate fibrillary network of fibronectin and Type V collagen and of patchy amorphous deposits of laminin and Type IV collagen. Rare fibrils of collagen Types I and III were also observed. Fibronectin stained intensely and appeared to be the predominant component of the provisional subendothelial matrix during vascular sprouting. As the cultures aged, laminin and Type IV collagen accumulated in the subendothelial space, forming a continuous feltwork around the newly formed microvessels. Patent microvessels were also surrounded by discontinuous deposits of fibronectin and by increased amounts of collagen Types I, III, and V. Ultrastructural studies revealed positive immunostaining for fibronectin, laminin, and collagen Types IV and V in the endoplasmic reticulum and in putative secretory vesicles, indicating active synthesis and secretion of these molecules by the endothelial cells. These observations indicate that the microvascular extracellular matrix undergoes significant dynamic changes during capillary development. The different composition and structural organization of the extracellular matrix at various stages of angiogenesis may have important effects on endothelial behavior and capillary morphogenesis.

Animals↗
PubMed1996

Isolation of a sponge-derived extracellular matrix adhesion protein.

The development of stable intercellular adhesions in the animal kingdom permitted the evolution of the metazoans, of which the sponges are primitive examples. Intercellular adhesion in these simple animals is mediated by a high affinity interaction between the sponge cell surface and aggregation factor, a 2 x 10(7)-Da proteoglycan that is one of the major components of the sponge extracellular matrix. This report describes a sponge cell surface and extracellular matrix ligand for the sponge proteoglycan, aggregation factor. The 210-kDa protein binds aggregation factor proteoglycan with high affinity (Kd = 7 x 10(-9) M). Importantly, in soluble form, it also inhibits aggregation factor-mediated cell adhesion. This glycoprotein is expressed on the sponge cell surface and within the extracellular matrix. This novel sponge extracellular matrix protein may represent a primitive antecedent of the extracellular matrix adhesion proteins of higher organisms.

Animals↗
PubMed1997

Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro.

The role of vitamin K in osteocalcin accumulation in the extracellular matrix of normal human osteoblasts in culture was investigated by using a human intact osteocalcin-specific assay system. Human osteoblasts produced osteocalcin by treatment with 10(-9) M 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) for 20 days in culture. With the addition of vitamin K2 (1.5-5.0 microM), osteocalcin accumulation in the extracellular matrix of the osteoblasts was increased, but the osteocalcin content in the conditioned medium decreased, in comparison with that treated with 10-9 M 1,25(OH)2D3 alone. The enhancement of osteocalcin accumulation induced by vitamin K2 was dependent on the duration of the treatment. The vitamin K2 plus 1,25(OH)2D3-induced osteocalcin accumulation was blocked by the addition of warfarin 2 days before the vitamin treatment. At that time, warfarin significantly reduced the mineralization by osteoblasts in vitro. Osteocalcin accumulated in the extracellular matrix was almost completely precipitated by a low concentration of hydroxyapatite, 10 mg/ml. Moreover, the gamma-carboxyglutamic acid (Gla)-containing osteocalcin level was increased by the vitamin K2 plus 1,25(OH)2D3 treatment. These results proved that vitamin K2 increased Gla-containing osteocalcin, which accumulated osteocalcin in the extracellular matrix, and facilitated mineralization in vitro. Vitamin K2 also enhanced the 1,25(OH)2D3-induced osteocalcin mRNA level, but vitamin K2 alone did not show osteocalcin mRNA expression. We thus demonstrated that vitamin K2 enhanced not only the accumulation of Gla osteocalcin, but also the osteocalcin production induced by 1,25(OH)2D3 in human osteoblasts in culture.

Bone Density↗