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PubMed1990

Cell-free interaction of the estrogen receptor with mouse uterine nuclear matrix: evidence of saturability, specificity, and resistance to KCl extraction.

An integral part of the mechanism of estrogen action is the interaction of estrogen receptor (ER) complexes with specific nuclear acceptor sites to effect alterations in genomic expression. The localization of nuclear acceptor sites has been in question, but an increasing body of indirect evidence implicates the nuclear matrix. To assess the binding characteristics of [3H]estradiol-receptor complexes (3HER) to nuclear matrix, ER from ovariectomized mice was partially purified by ammonium sulfate precipitation and incubated under cell-free conditions with mouse uterine nuclear matrix at 4 C. The binding capacity of the nuclear matrix was determined to be 36.4 +/- 5.7 fmol/100 micrograms DNA, with a Kd of 0.23 +/- 0.03 nM. Binding to nuclear matrix sites was specific, as determined by the ability of increasing concentrations of unlabeled ER complexes to inhibit binding of 3HER. Spleen, used as a nontarget tissue, contained fewer binding sites (n = 4.07 fmol/100 micrograms DNA) than matrix from liver (n = 14.2). The binding affinity was the same in all three tissues. Injection of animals with estradiol before death was associated with loss of assayable nuclear matrix binding sites, implying occupancy of sites by ER in vivo. Unbound receptor (R) also demonstrated the ability to bind to uterine matrix (n = 40.2 +/- 2.7 fmol/100 micrograms DNA; Kd = 0.26 +/- 0.05 nM) as well as to competitively inhibit the binding of 3HER complexes. However, heat-inactivated receptor displayed no binding or competing activity, nor did the progesterone receptor. The two forms of the receptor can be functionally distinguished by extraction with 0.6 M KCl; 43% of ER, but no R, were resistant to KCl extraction. These results indicate that nuclear acceptor sites are associated with the nuclear matrix. Furthermore, these sites demonstrate the criteria expected of specific binding sites, i.e. high affinity, limited capacity, hormone receptor, and relative tissue specificity. The apparent association of uncomplexed receptor to nuclear acceptor sites may explain the uterine tissue nuclear localization of ER in the absence of hormone.

Animals↗

PubMed1998

Concentration of insulin-like growth factor (IGF)-I and -II in iliac crest bone matrix from pre- and postmenopausal women: relationship to age, menopause, bone turnover, bone volume, and circulating IGFs.

Insulin-like growth factor-I (IGF-I) and -II are important local regulators of bone metabolism, but their role as determinants of human bone mass is still unclear. In the present study, we analyzed the concentration of IGF-I and -II in the bone matrix of 533 human biopsies from the iliac crest that were obtained during surgery for early breast cancer. There was an inverse association of bone matrix IGF-I concentration with age that was unaffected by menopause. Bone matrix IGF-I was positively associated with histomorphometric and biochemical parameters of bone formation and bone resorption and with cancellous bone volume. Based on the estimates of the linear regression analysis, women with a bone matrix IGF-I concentration 2 SD above the mean had a 20% higher bone volume than women with a bone matrix IGF-I concentration 2 SD below the mean. In contrast, serum IGF-I was neither correlated with bone turnover nor with bone volume and was only weakly associated with bone matrix IGF-I when adjusted for the serum concentration of IGF binding protein-3. Bone matrix IGF-II was positively associated with the osteoblast surface, but in contrast to IGF-I, tended to be positively associated with age and was unrelated to cancellous bone volume. In summary, our study suggests the following. 1) The concentration of IGF-I in cancellous bone undergoes age-related decreases that are similar to those of circulating IGF-I. 2) Menopause has no effect on this age-related decline. 3) Physiological differences in bone matrix IGF-I are associated with differences in iliac crest cancellous bone volume. 4) Bone matrix IGF-I is a better predictor of cancellous bone volume than circulating IGF-I. 5) The role of IGF-II in human bone tissue is clearly distinct from that of IGF-I.

Adult↗

PubMed2003

Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin.

The fibronectin matrix contains cryptic sites which are thought to modulate cellular biological responses. One of these sites, located in fibronectin's first type III repeat (III1c), influences signaling pathways that are relevant to cytoskeletal organization and cell cycle progression. The purpose of this study was to identify possible mechanisms responsible for the effects of III1c on cell behavior. Recombinant peptides representing various type III repeats of fibronectin were compared for their effects on fibronectin matrix organization and activation of intracellular signaling pathways. III1c and III13 but not III11c or III10 bound to monolayers of human skin fibroblasts in a dose- and time-dependent manner and were localized to the extracellular matrix. Binding of III13, but not III1c, to matrix was sensitive to heparitinase, suggesting that the association of III1c with the matrix was not dependent on heparan sulfate proteoglycans. Quantitative and morphological assessment indicated that, in contrast to previously published reports, the binding of III1c to cell layers did not result in the loss or disruption of matrix fibronectin. Binding of III1c but not III13 to the extracellular matrix did result in the loss of a conformationally sensitive epitope present within the EDA type III module of cellular fibronectin. III1c-induced loss of the EDA epitope did not require the presence of cells, occurred within 1 hour and was associated with the activation of p38 mitogen-activated protein kinase (MAPK) followed by the formation of filopodia. Maximal phosphorylation of p38 MAPK occurred within 1 hour, whereas cytoskeletal changes did not appear until 12 hours later. These findings are consistent with a model in which the binding of III1c to the extracellular matrix results in a conformational remodeling of the fibronectin matrix, which has both short- and long-term effects on cell physiology.

Cell Adhesion↗

PubMed1998

Mechanical compression alters proteoglycan deposition and matrix deformation around individual cells in cartilage explants.

We have used new techniques of cell-length scale quantitative autoradiography to assess matrix synthesis, deposition, and deformation around individual chondrocytes in mechanically compressed cartilage explants. Our objectives were to: (1) quantify the effects of static and dynamic compression on the deposition of newly synthesized proteoglycans into cell-associated and further-removed matrices; (2) measure cell-length scale matrix strains and morphological changes of the cell and matrix associated with tissue compression; and (3) relate microscopic physical stimuli to changes in proteoglycan synthesis as functions of compression level and position within mechanically compressed explants. Results indicate a high degree of structural organization in the extracellular matrix, with the pericellular matrix associated with the most rapid rates of proteoglycan deposition, and greatest sensitivity to mechanical compression. Static compression could stimulate directional deposition of secreted proteoglycans around chondrocytes, superimposed on an inhibition of proteoglycan synthesis; these events followed trends for compressive strain in the cell-associated matrix. Conversely, proteoglycan synthesis and pericellular deposition was stimulated by dynamic compression. Results suggest that cell-matrix interactions in the cell-associated matrix may be a particularly important aspect of the chondrocyte response to mechanical compression, possibly involving macromolecular transport limitations and morphological changes associated with fluid flow and local compaction of the matrix around cells.

Animals↗

PubMed2000

Beneficial effects of retinoic acid on extracellular matrix degradation and attachment behaviour in follicular thyroid carcinoma cell lines.

The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on important determinants of metastatic behaviour in FTC: the disengagement of tumour cells from the primary tumour and the degradation of extracellular matrix, focusing on the role of the plasmin activation system and the integrin and E-cadherin families of attachment molecules. Three FTC cell lines were studied: FTC-133, derived from the primary tumour; and FTC-236 and FTC-238, derived from metastases. FTC cell lines were cultured with 0.1, 1 and 10 microM 13-cis-RA or with the solvent DMSO for 1 and 5 days. Extracellular matrix degradation by these cell lines was studied by assessing the 48-h release of radioactivity from (35)S-methionine labelled extracellular matrix proteins synthesised by the MC3T3 cell line coated onto plastic. The involvement of constituents of the plasmin activation system was investigated by semi-quantitative RT-PCR and zymography. Attachment to extracellular matrix was studied by determining the number of adhering FTC cells to extracellular matrix coated onto plastic, 3 h after seeding. The involvement of attachment molecules was studied by RT-PCR with primers for integrin subclasses and E-cadherin and immunofluorescence for E-cadherin. Five days culturing with 10 microM RA reduced the degradation of extracellular matrix significantly in all cell lines: FTC-133 by 35%, FTC-236 by 74% and FTC-238 by 31%. Zymography revealed diminished activity of urokinase type plasminogen activator (uPA) in FTC-236 and FTC-238, but not in FTC-133 cultured with RA. mRNA expression of the uPA receptor was diminished in FTC-236. In the attachment assay, 10 microM RA for 5 days increased the number of adherent cells to extracellular matrix significantly by 91% in FTC-133, 64% in FTC-236 and 87% in FTC-238. No effects of RA on integrin or E-cadherin mRNA expression were observed. Immunofluorescence, however, revealed enhanced organisation of E-cadherin along the cell membrane by RA treatment. In conclusion, the present study demonstrates beneficial effects of RA on important determinants of metastatic behaviour in FTC cell lines, e.g. decreased degradation of extracellular matrix which may in part be explained by effects on the plasmin activation system and enhanced attachment to extracellular matrix. These findings may add to the explanations for beneficial effects of retinoids in thyroid cancer.

Adenocarcinoma, Follicular↗

PubMed2004

Macroscopic structure of articular cartilage of the tibial plateau: influence of a characteristic matrix architecture on MRI appearance.

OBJECTIVE: The purpose of our study was to describe the structural organization of the extracellular matrix of articular cartilage of the tibial plateau and its influence on MRI appearance. MATERIALS AND METHODS: Spin-echo images of 11 resected tibial plateaus acquired at 7 T were compared with the structure of the extracellular matrix as shown by fracture sectioning the samples in the plane of imaging. Four samples were scanned at two different orientations relative to the main magnetic field (B(0)). T2 maps were acquired in two orientations on three of these four samples. RESULTS: On the basis of the presence of reproducible regional variations in the shape of the matrix, a characteristic matrix architecture was described. The location of peak signal intensity and T2 on MRI correlated with the level at which the matrix was estimated to be aligned at approximately 55 degrees to B(0) (r = 0.91). This correlation of matrix orientation relative to B(0) with T2 and signal intensity on MRI was not altered by regional variations in the shape of the matrix or by imaging samples at two different orientations. CONCLUSION: The structure of the extracellular matrix, through its orientation-dependent influence on T2 decay, exerts a strong influence on the MRI appearance of cartilage. At the tibial plateau, a characteristic matrix architecture is associated with an equally characteristic MRI appearance.

Adult↗

PubMed1990

Matrix vesicles as a marker of endochondral ossification.

Endochondral ossification in bone development and repair, and in induced bone formation in mesenchymal tissues, involves recruitment of mesenchymal cells, their differentiation into chondrocytes, and calcification of the cartilagenous matrix. Stimulation of proteoglycan synthesis is used as a biochemical marker of chondrogenesis, however it does not distinguish among chondrogenic phenotypes. Chondrocytes derived from the resting zone and adjacent growth zone cartilage of the costochondral junction of young rats, produce matrix vesicles in culture which are enriched in alkaline phosphatase specific activity with respect to the plasma membrane. Matrix vesicles isolated from cultures of neonatal rat muscle mesenchymal cells are not enriched in this enzyme activity. Alkaline phosphatase in matrix vesicles produced by growth zone chondrocytes is stimulated by 1,25(OH)2D3; enzyme in matrix vesicles produced by resting zone chondrocytes is stimulated by 24,25(OH)2D3; enzyme in matrix vesicles isolated from mesenchymal cell cultures is responsive to neither metabolite. Matrix vesicle phospholipase A2 is stimulated by 1,25(OH)2D3 in growth zone chondrocytes cultures; inhibited by 24,25(OH)2D3 in resting zone chondrocyte cultures; and is unaffected by either metabolite in mesenchymal cell cultures. These observations suggest that matrix vesicle production, as defined by alkaline phosphatase enrichment, and responsiveness of matrix vesicle enzymes to vitamin D metabolites, can be used as markers of phenotypic maturation during chondrogenesis in vivo and in vitro.

24,25-Dihydroxyvitamin D 3↗

PubMed1996

Identification of a new biological function for the integrin alpha v beta 3: initiation of fibronectin matrix assembly.

Fibronectin matrix assembly is a complex cellular process initiated by specific fibronectin-binding cell surface receptors. Although the integrin alpha 5 beta 1 has been implicated in the assembly of fibronectin matrices, fibroblastic cells derived from alpha 5 integrin null mutant embryos assemble a fibronectin matrix. Thus, alternative receptors must support this process. Although the platelet integrin alpha IIb beta 3 supports fibronectin matrix assembly, its expression is restricted to platelets. We report that alpha v beta 3 integrin, a fibronectin receptor expressed on many cell types provides an alternative pathway for the assembly of soluble fibronectin into the extracellular matrix. This process occurs independent of alpha 5 beta 1, is also modulated by activation, and the resulting matrix is biochemically indistinguishable from that assembled under the control of alpha 5 beta 1. Matrix assembly requires binding to the RGD site in the 10th type III repeat of fibronectin, as well as the participation of the amino-terminal matrix assembly domain. The participation of two distinct integrins in fibronectin matrix assembly suggests a model for the involvement of integrins in a dual system of extracellular matrix assembly and recognition controlled by intracellular activation of extracellular receptors.

Animals↗

PubMed2002

Behavior of fibroblasts on a porous hyaluronic acid incorporated collagen matrix.

A hyaluronic acid (HA) incorporated porous collagen matrix was fabricated at -70 degrees C by lyophilization. The HA incorporated collagen matrix showed increased pore size in comparison with collagen matrix. Biodegradability and mechanical properties of matrices were controllable by varying the ultraviolet (UV) irradiation time for cross-linking collagen molecules. Addition of HA to collagen matrix did not effect ultimate tensile stress after UV irradiation. HA incorporated collagen matrices demonstrated a higher resistance against the collagenase degradation than collagen matrix. In an in vitro investigation of cellular behavior using dermal fibroblasts on the porous matrix, HA incorporated collagen matrix induced increased dermal fibroblast migration and proliferation in comparison with collagen matrix. These results suggest that the HA incorporated collagen porous matrix assumes to enhance dermal fibroblast adaptation and regenerative potential.

Collagen↗

PubMed1999

Vitamin D3 metabolites regulate LTBP1 and latent TGF-beta1 expression and latent TGF-beta1 incorporation in the extracellular matrix of chondrocytes.

Growth plate chondrocytes make TGF-beta1 in latent form (LTGF-beta1) and store it in the extracellular matrix via LTGF-beta1 binding protein (LTBP1). 1,25-(OH)2D3 (1,25) regulates matrix protein production in growth zone (GC) chondrocyte cultures, whereas 24,25-(OH)2D3 (24,25) does so in resting zone (RC) cell cultures. The aim of this study was to determine if 24,25 and 1,25 regulate LTBP1 expression as well as the LTBP1 -mediated storage of TGF-beta1 in the extracellular matrix of RC and GC cells. Expression of LTBP1 and TGF-beta1 in the growth plate and in cultured RC and GC cells was determined by in situ hybridization using sense and antisense oligonucleotide probes based on the published rat LTBP1 and TGF-beta1 cDNA sequences. Fourth passage male rat costochondral RC and GC chondrocytes were treated for 24 h with 10(-7)-10(-9) M 24,25 and 10(-8)-10(-10) M 1,25, respectively. LTBP1 and TGF-beta1 mRNA levels were measured by in situ hybridization; production of LTGF-beta1, LTGF-beta2, and LTBP1 protein in the conditioned media was verified by immunoassays of FPLC-purified fractions. In addition, ELISA assays were used to measure the effect of 1,25 and 24,25 on the level of TGF-beta1 in the media and matrix of the cultures. Matrix-bound LTGF-beta1 was released by digesting isolated matrices with 1 U/ml plasmin for 3 h at 37 degrees C. LTBP1 and TGF-beta1 mRNAs are co-expressed throughout the growth plate, except in the lower hypertrophic area. Cultured GC cells express more LTBP1 and TGF-beta1 mRNAs than RC cells. FPLC purification of the conditioned media confirmed that RC cells produce LTGF-beta1, LTGF-beta2, and LTBP1. GC cells also produce LTGF-beta2, but at lower concentrations. 1,25 dose-dependently increased the number of GC cells with high LTBP1 expression, as seen by in situ hybridization. 24,25 had a similar, but less pronounced, effect on RC cells. 1,25 also caused a dose-dependent increase in the amount of TGF-beta1 protein found in the matrix, significant at 10(-8) and 10(-9) M, and a corresponding decrease in TGF-beta1 in the media. 24,25 had no effect on the level of TGF-beta1 in the matrix or media produced by RC cells. This indicates that 1,25 induces the production of LTBP1 by GC cells and suggests that the TGF-beta1 content of the media is reduced through the formation of latent TGF-beta1 -LTBP1 complexes which mediates storage in the matrix. Although 24,25 induced the expression of LTBP1 by RCs, TGF-beta1 incorporation into the matrix is not regulated by this vitamin D3 metabolite. Thus, vitamin D3 metabolites may play a role in regulating the availability of TGF-beta1 by modulating LTBP1 production.

24,25-Dihydroxyvitamin D 3↗

PubMed2000

[Functional arrangement of genomic DNA and structure of nuclear matrix].

The nuclear matrix (nuclear scaffold), the RNA-protein skeleton of the nucleus, has a role in the organization and function of nuclear DNA. Nuclear processes associated with the nuclear matrix include transcription, replication, repair and splicing. We have purified a nuclear matrix protein, P130, which binds to several matrix attachment regions (MARs). Since the nucleotide sequence of P130 cDNA cloned by us was closely similar to that of matrin 3 cDNA cloned, except for two incorrect nucleotides within the matrin 3 coding region, and since the functions of matrin 3 were unknown, P130, referred to as P130/Mat3, was functionally characterized. The primary structure deduced for P130/Mat3 contained two DNA binding domains with C2H2-type zinc finger motif and two RNA binding domains. In addition, there were a nuclear localization signal and several phosphorylation sites for tyrosine or serine/threonine protein kinases, suggesting its multiple functions. MAR inserted upstream from the SV40 promoter in pMAR/luc assisted luciferase gene transcription in a transient expression system in Ac2F cells. Cotransfection of a plasmid carrying P130/Mat3 cDNA downstream from the CMV promoter into Ac2F cells produced this protein a level 4 times higher than that in wild-type Ac2F, causing 20 times higher luciferase activity from pMAR/luc than that induced by pMAR/luc alone. These findings indicated that MAR functions as a cis-element to which P130/Mat3 binds as one of the possible transactivators. Nuclear matrix proteins, which are tissue- and cell-type-specific, are altered with transformation and state of differentiation. We have shown that an MAR binding protein, P230, is detectable in rat hepatoma cells but not in normal liver, and suggested that this protein is a diagnostic and prognostic marker for liver cancer. It is clear that nuclear matrix proteins hold a considerable promise as diagnostic tools for pathologists. Present evidence, including our data, suggests that nuclear matrix proteins may be useful biomarkers of neoplastic disease in the serum, body fluids, and tissues. Nuclear matrix proteins are also potential candidates for the use as tumor prognostic factors and targets of anticancer drugs through apoptosis. We will discuss screening of drugs that interact with nuclear matrix proteins and influence nuclear events.

Animals↗

PubMed2001

Assembly of high molecular weight kininogen and activation of prekallikrein on cell matrix.

Investigations determined if extracellular matrix of endothelial cells (EC) is a platform for HK assembly and PK activation. In buffers containing bovine serum albumin, biotin-HK binding to ECV304 cells or their matrix requires > or = 50 microM added Zn2+. Ortho-phenanthroline or a HK domain 5 peptide blocks HK binding. Binding to umbilical vein EC or matrix, but not ECV304 cells or matrix, is mediated by cytokeratin 1. Biotin-HK binds to ECV304 cells or matrix with a Kd of 15.8 or 9.0 nM and a Bmax of 2.6 x 10(7) or 2.4 x 10(7) sites/cell, respectively. PK activation on ECV304 cells or matrix is blocked by antipain or SBTI and corn trypsin inhibitor partially inhibits kallikrein formation. PK activation occurs on ECV304 cells or matrix prepared without serum or in human factor XII deficient serum, indicating that the PK activator is not factor XIIa. EC matrix promotes plasminogen activation after the assembly of HK, PK and pro-urokinase. These studies indicate that matrix of various EC has the ability to assemble HK allowing for PK activation and subsequent activities.

Amino Acid Sequence↗

PubMed1992

Density-dependent accumulation of basic fibroblast growth factor in the subendothelial matrix.

Recent evidence indicates that basic fibroblast growth factor (bFGF), which lacks a conventional signal recognition sequence, is a component of the subendothelial matrix. However, the molecular mechanisms regulating its cellular release and subsequent matrix deposition remain equivocal. To examine the cellular and subcellular mechanisms regulating bFGF release and subendothelial sequestration, we generated polyclonal antibodies against a chemically cross-linked bFGF. We then used anti-bFGF IgG in conjunction with 3T3 cell [3H]thymidine incorporation assays, enzyme immunoassays and immunofluorescence to learn whether bFGF accumulation in the subendothelial matrix is dependent upon endothelial cell (EC)-cell contact, which coincides with growth arrest. In contrast to subconfluent cultures, which lacked any detectable extracellular matrix bFGF localization, bovine aortic and microvascular EC plated at confluent densities displayed a punctate extracellular staining pattern that was abolished when EC were pretreated with 10 micrograms/ml cycloheximide. Additionally, when EC were treated with either 1 mM beta-D xyloside, an inhibitor of proteoglycan assembly, or 100 micrograms/ml heparin, there was a 40% reduction in matrix-associated bFGF (quantified by image analysis of antibody stained cultures). 3T3 [3H]thymidine incorporation assays indicated that the beta-D xyloside-induced reduction of matrix-associated bFGF coincided with a significant increase in bFGF activity in the conditioned media. Neither sparsely-plated nor confluent EC cultures possessed specific bFGF localization of the nuclear compartment when cells were fixed using cold methanol; however, when EC were fixed in formaldehyde and lysed in isotonic buffers containing 0.1% Triton X-100 or absolute acetone, there was a marked decrease in anti-bFGF staining of the postconfluent extracellular matrix and a concomitant increase in nuclear fluorescence. Because bFGF-stimulated vascular cell growth has been implicated in controlling neointimal cell proliferation, we screened normal and atherosclerotic coronary blood vessels for bFGF, but we were unable to detect it either in lesioned or normal intima. In contrast, significant bFGF levels were observed in association with the EC and mesangial cells of the renal corpuscle, where heparan sulfate accumulates within the glomerular basement membrane. Our in vitro results suggest that bFGF accumulates within the proteoglycan-containing subendothelial matrix concomitant with the formation of cell-cell contacts. In situ, the composition of the microvascular matrix and the cellular phenotype may facilitate the selective accumulation of bFGF that we observed. This, in turn, may influence vascular morphogenesis and remodeling during angiogenesis.

3T3 Cells↗

PubMed2005

Nuclear matrix proteins and hereditary diseases.

The review summarizes literature data on alterations of structure or expression of different nuclear matrix proteins in hereditary syndromes. From the point of view of involvement of nuclear matrix proteins in etiology and pathogenesis of the disease hereditary pathologies can be classified in pathologies with pathogenesis associated with defects of nuclear matrix proteins and pathologies associated to changes of the nuclear matrix protein spectrum. The first group includes laminopathies, hereditary diseases with abnormal nuclear-matrix associated proteins and triplet extension diseases associated with accumulation of abnormal proteins in the nuclear matrix. Laminopathies are hereditary diseases coupled to structural defects of the nuclear lamina. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Most of them are due to mutations in the lamin A/C gene, one - to mutations in emerin gene, some are associated with mutations in Lamin B receptor gene. In Werner's, Bloom's, Cockayne's syndromes, Fanconi anemia, multiple carboxylase deficiency mutations in nuclear matrix protein or enzyme gene lead to deficient DNA repair, abnormal regulation of cell growth and differentiation or other specific metabolic functions. Proteins with a long polyglutamic tract synthesized in the cells of patients with dentato-rubral and pallido-luysian atrophy, myotonic dystrophy and Huntington disease interfere with transcription on the nuclear matrix. Down's syndrome is a representative of the group of diseases with altered nuclear matrix protein spectrum.

Animals↗

PubMed1992

Partial characterization of nuclear matrix attachment regions from human fibroblast DNA using Alu-polymerase chain reaction.

The proteinaceous nuclear matrix of mammalian cell nuclei has been suggested to be involved in the regulation of chromatin structure, DNA replication, and gene expression. Interaction between cellular DNA and the nuclear matrix is mediated by putative DNA binding sequences, matrix attachment regions (MARs), which may become altered during early events in cellular transformation. Among the cellular changes occurring during the development of neoplasia, all of which may potentially involve the nuclear matrix, are alterations in nuclear structure, loss of control of DNA replication, and significant modifications of cellular gene expression. Therefore, a better understanding of the interaction between DNA and the nuclear matrix is needed. Isolated matrix associated DNA from pulse labeled SV40 transformed human fibroblasts was shown to be enriched in newly replicated DNA, confirming the association of DNA replication with the nuclear matrix as observed by others. Subgenomic fractions of matrix associated DNA enriched in putative MARs sites were prepared from quiescent and logarithmically growing normal human fibroblasts and SV40 transformed human fibroblasts. These fractions of DNA were analyzed by Alu-polymerase chain reaction and agarose gel electrophoresis, revealing complex and unique patterns of DNA products for each cell type investigated. A number of prominent DNA fragments with similar molecular size were found to be present in the amplified DNA products of each DNA source, suggesting that these DNA fragments may represent common DNA sequences which contain MARs sites or which are associated with MARs sites. The application of Alu-polymerase chain reaction to the molecular analysis of nuclear matrix associated DNA may facilitate the isolation and characterization of potentially new human MARs sequences.

DNA↗

PubMed2005

The effect of matrix tension-compression nonlinearity and fixed negative charges on chondrocyte responses in cartilage.

Thorough analyses of the mechano-electrochemical interaction between articular cartilage matrix and the chondrocytes are crucial to understanding of the signal transduction mechanisms that modulate the cell metabolic activities and biosynthesis. Attempts have been made to model the chondrocytes embedded in the collagen-proteoglycan extracellular matrix to determine the distribution of local stress-strain field, fluid pressure and the time-dependent deformation of the cell. To date, these models still have not taken into account a remarkable characteristic of the cartilage extracellular matrix given rise from organization of the collagen fiber architecture, now known as the tension-compression nonlinearity (TCN) of the tissue, as well as the effect of negative charges attached to the proteoglycan molecules, and the cell cytoskeleton that interacts with mobile ions in the interstitial fluid to create osmotic and electro-kinetic events in and around the cells. In this study, we proposed a triphasic, multi-scale, finite element model incorporating the Conewise Linear Elasticity that can describe the various known coupled mechanical, electrical and chemical events, while at the same time representing the TCN of the extracellular matrix. The model was employed to perform a detailed analysis of the chondrocytes' deformational and volume responses, and to quantitatively describe the mechano-electrochemical environment of these cells. Such a model describes contributions of the known detailed micro-structural and composition of articular cartilage. Expectedly, results from model simulations showed substantial effects of the matrix TCN on the cell deformational and volume change response. A low compressive Poisson's ratio of the cartilage matrix exhibiting TCN resulted in dramatic recoiling behavior of the tissue under unconfined compression and induced significant volume change in the cell. The fixed charge density of the chondrocyte and the pericellular matrix were also found to play an important role in both the time-dependent and equilibrium deformation of the cell. The pericellular matrix tended to create a uniform osmolarity around the cell and overall amplified the cell volume change. It is concluded that the proposed model can be a useful tool that allows detailed analysis of the mechano-electrochemical interactions between the chondrocytes and its surrounding extracellular matrix, which leads to more quantitative insights in the cell mechano-transduction.

Animals↗

PubMed1984

The matrix of human breast tumor cells is mitogenic for fibroblasts.

The basis of the scirrhous reaction to human breast carcinoma was investigated. When normal human skin fibroblasts were plated on the preformed extracellular matrix of human breast tumor cells, a remarkable series of changes was observed. The matrix of the tumor cells was mitogenic for the fibroblasts. An increased growth rate and a fourfold increase in cell density was observed. There was also a change in cell morphology and in the pattern in which the cells grew, with an apparent loss of contact inhibition. The spindle-shaped fibroblasts became more elliptical and grew in a series of whorls and dense ridges with spaces between them. These observations were made with the use of newborn foreskin fibroblasts and the matrix of an established line of human breast cancer cells, ZR75-1. No such effect was seen when fibroblasts were plated on their own preformed matrix, on the matrixes of other cell types, on various type-specific collagen gels, or on a combination of collagen and fibronectin or when fibroblasts were grown in media conditioned by the ZR75-1 cells. A floating tumor cell matrix added to the cell media also did not provide the mitogenic stimulus. Apparently, fibroblasts required direct contact with the tumor cell matrix for the mitogenic response to occur. In vivo, the matrix of breast tumor cells may modulate the growth and the morphology of host stromal cells. Collagen is a major synthetic product of fibroblasts. The stimulation of stromal cells to proliferate by adjacent breast tumor matrix may be the basis of the desmoplastic reaction, the intense fibrotic response associated with human breast cancer.

Breast Neoplasms↗

PubMed1995

Chronic renal disease: do metalloproteinase inhibitors have a demonstrable role in extracellular matrix accumulation?

Recent evidence suggests that decreased degradation of the glomerular extracellular matrix may contribute to the matrix accumulation that occurs in the progression of chronic renal disease. The presence of matrix metalloproteinases in cultured glomerular cells and possibly in glomeruli in vivo combined with the ability of these proteinases to degrade extracellular matrix components suggests that these proteinases may play important roles in glomerular extracellular matrix degradation. Decreased activity of these proteinases mediated by upregulation of their inhibitors could theoretically contribute to matrix accumulation. In the limited number of studies that have addressed this issue directly, there is evidence both to support and refute this hypothesis. It is reasonable to suspect, however, that either increased matrix formation, decreased matrix degradation, or both, might contribute to extracellular matrix accumulation in progressive renal disease, depending on the primary etiology.

Animals↗