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PubMed1984

Distribution of bone inductive proteins in mineralized and demineralized extracellular matrix.

Implantation of demineralized extracellular bone matrix results in new bone formation locally. Although the precise molecular mechanisms are not known, the reconstitution of matrix proteins less than 50,000 daltons with collagenous residue results in bone induction. The aim of the present investigation was to ascertain the distribution of the bone inductive protein(s) in various compartments of the tissue. A sequential extraction of mineralized bone matrix was employed: (1) 4 M guanidine HCl to extract proteins that are cell associated and not masked by mineral; (2) 0.5 M EDTA to dissolve the mineral phase; (3) 4 M guanidine HCl to reextract the collagenous matrix-associated proteins under dissociative conditions; (4) 4 M guanidine HCl containing 0.5 M EDTA to release any other residual proteins. This sequential method revealed that about 25% of total biological activity of bone induction is associated with first guanidine extraction, about 15% with the mineral phase and the rest of the activity is tightly associated with the collagenous matrix.

Alkaline Phosphatase↗

PubMed1990

Motility of Lyme disease spirochetes in fluids as viscous as the extracellular matrix.

When properties of extracellular fluids that might regulate the ability of the Lyme disease spirochete to locomote were investigated, the rate of progression correlated with viscoelasticity. Such spirochetes flexed and rotated but did not progress in relatively nonviscous fluids and migrated increasingly rapidly as the viscous characteristics of the medium increased. The viscoelastic properties of various kinds of hyaluronic acid resembled those of a methylcellulose standard. The maximum velocity that spirochetes achieved in such solutions related directly to viscoelasticity rather than to chemical composition. Spirochetes remained motile during 3 h of observation despite 100-fold dilution of the standard nutrient medium. The immobility of Lyme disease spirochetes in media less viscous in character than fixed tissue suggests dissemination via the intercellular ground substance of skin.

Borrelia burgdorferi Group↗

PubMed2004

Extracellular matrix protein gene, EMP1, is required for appressorium formation and pathogenicity of the rice blast fungus, Magnaporthe grisea.

Magnaporthe grisea, the causal fungus of rice blast, forms a specialized infection structure called an appressorium that is crucial for host plant penetration. A cDNA clone of M. grisea, showing strong sequence homology to FEM1 of Fusarium oxysporum and encoding an extracellular matrix protein, was isolated during an expressed sequence tag (EST) analysis of an appressorium cDNA library and named extracellular matrix protein 1 (EMP1). Sequence analysis of the corresponding genomic clone revealed that EMP1 contains an open reading frame of 685 nucleotides encoding 207 amino acids. The estimated molecular weight of the protein product was 20.5 kDa with a pI of 7.84. It contains an 18 amino acid N-terminal secretion signal sequence, as well as four potential N-glycosylation sites. At its C-terminus, the protein contains a 16 amino acid sequence with the characteristics of a glycosylphosphatidylinositol (GPI) anchor addition signal. Northern blot analysis showed that EMP1 transcripts accumulate during appressorium formation but not during vegetative growth. An EMP1 null mutant, emp1, generated by targeted gene disruption, exhibited reduced levels of appressorium formation and pathogenicity but no effect on mycelial growth rate or conidiation ability. These data suggest that EMP1 plays important roles in appressorium formation and the pathogenicity of M. grisea.

Amino Acid Sequence↗

PubMed2003

The extracellular matrix: a new turn-of-the-screw for anti-angiogenic strategies.

Anti-angiogenic therapy is currently one of most active fields in cancer research. The initial strategies, which were aimed at inhibiting tumor vascularization, included upregulation of endogenous inhibitors and blocking of the signals delivered by angiogenic factors. However, interactions between endothelial cells and their surrounding extracellular matrix also play a crucial role in modulation of the angiogenic process. Compounds that target either the integrins implicated in these interactions or the proteases responsible for matrix remodeling have been shown to halt tumor growth in murine models and are now in clinical trials. However, little attention has been paid to integrin ligands, the extracellular matrix components that support endothelial cell survival, movement and reorganization. Here, we summarize the current knowledge about these angiogenesis inhibitors and propose a novel therapeutic approach based on the blocking of crucial binding sites present in the extracellular matrix.

Angiogenesis Inhibitors↗

PubMed1993

Immunohistochemical distribution of extracellular matrix proteins as a diagnostic parameter in healthy and diseased gingiva.

This study showed histopathological findings of the extracellular matrix in healthy, inflamed, and hyperplastic human gingiva with immunohistochemical techniques. The distribution of collagen types V and VI, as well as of glycoprotein fibronectin, shows that they are extracellular matrix structural components which differentiate the tissue pathology. The orientation of the collagen fibers, the intensity of the fluorescent staining, the thickness of the fibrillar component, and the topographical localization of the connective tissue proteins are important parameters for tissue morphology. Therefore, bacterial deposits and the pharmacodynamic properties of drugs associated with gingival hyperplasia lead to an alteration of the matrix compared to the healthy tissues. This may be important in the tissue pathology in cases when the medical history of the patient is not known, as well as in forensic medicine.

Adult↗

PubMed1992

Characterization and localization of large sulfated glycoproteins in the extracellular matrix of the developing asteroid Pisaster ochraceus.

In this study techniques commonly used to extract and purify proteoglycans of vertebrates were applied to the embryo of the asteroid Pisaster ochraceus at the early bipinnaria larva stage, a stage in which extensive cell migration is occurring within the extracellular matrix of the blastocoel. Several large sulfated glycoproteins were isolated and shown to consist of protein cores covalently bound to sulfated polysaccharide chains. The polysaccharide chains consisted primarily of neutral sugars and were not susceptible to glycosaminoglycan-degrading enzymes, suggesting that these were not glycosaminoglycans. The sulfated glycoproteins could be fractionated by electrophoresis on sodium dodecyl sulfate-agarose-acrylamide composite gels. Two types of monoclonal antibodies prepared against isolated extracellular matrix of these embryos reacted with two subsets of bands on Western blots of the composite gels. Staining of sections of the embryos with the antibodies showed that the epitopes that they recognized were located throughout the extracellular matrices of the embryos. That these high molecular weight glycoproteins were located within the extracellular matrix of the embryos suggests that they may be involved in the control of morphogenesis and cellular movement.

Animals↗

PubMed2006

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts.

In order to understand the effect of mechanical strain on scleral extracellular matrix remodeling, human scleral fibroblasts were subjected to equibiaxial stretch in vitro and the expression of proteoglycans, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were evaluated. Isolated human scleral fibroblasts were seeded onto flexible bottom culture plates, and subjected to a cyclic stretch regimen of 15% equibiaxial stretch for 45 s followed by 15s of rest for 6-48 h in the presence of 35SO4. Newly synthesized proteoglycans were measured in the medium by CPC precipitation of radiolabelled glycosaminoglycans. MMP-2 activity and expression levels were measured in the medium by, Western blot, gel zymography and real-time PCR. Steady state levels of TIMP-2 mRNA and membrane-type MMP, MT1-MMP (MMP-14) mRNA were measured in the cell layer using real-time PCR. The predominant gelatinolytic enzyme secreted by scleral fibroblasts was the pro-enzyme form of MMP-2 (ProMMP-2). Mechanical stretch resulted in a significant increase of ProMMP-2 after 12 and 48 h (+76.28%, p<0.05; +19.56%, p<0.01, respectively). Mechanical stretch significantly increased the production of the active form of MMP-2 (ActiveMMP-2) after 48 h (+59.72%, p<0.05) and decreased levels of TIMP-2 mRNA (-22%, p<0.05). The rate of scleral proteoglycan synthesis and the steady state levels of MMP-2 and MMP-14 mRNA were not significantly affected by mechanical stretch. These results suggest that mechanical strain stimulates the activation of MMP-2 by scleral fibroblasts, possibly through increased levels of ProMMP-2 and reduced levels of TIMP-2. Increased levels of ActiveMMP-2 in the sclera would be expected to contribute to scleral extracellular matrix degradation, scleral thinning and possible ocular ectasia.

Adult↗

PubMed1992

Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly.

Cells in culture reveal high levels of protein tyrosine phosphorylation in their focal adhesions, the regions where cells adhere to the underlying substratum. We have examined the tyrosine phosphorylation of proteins in response to plating cells on extracellular matrix substrata. Rat embryo fibroblasts, mouse Balb/c 3T3, and NIH 3T3 cells plated on fibronectin-coated surfaces revealed elevated phosphotyrosine levels in a cluster of proteins between 115 and 130 kD. This increase in tyrosine phosphorylation was also seen when rat embryo fibroblasts were plated on laminin or vitronectin, but not on polylysine or on uncoated plastic. Integrin mediation of this effect was suggested by finding the same pattern of elevated tyrosine phosphorylation in cells plated on the cell-binding fragment of fibronectin and in cells plated on a synthetic polymer containing multiple RGD sequences. We have identified one of the proteins of the 115-130-kD cluster as pp125FAK, a tyrosine kinase recently localized in focal adhesions (Schaller, M. D., C. A. Borgman, B. S. Cobb, R. R. Vines, A. B. Reynolds, and J. T. Parsons. 1992. Proc. Natl. Acad. Sci. USA. 89:5192). A second protein that becomes tyrosine phosphorylated in response to extracellular matrix adhesion is identified as paxillin, a 70-kD protein previously localized to focal adhesions. Treatment of cells with the tyrosine kinase inhibitor herbimycin A diminished the adhesion-induced tyrosine phosphorylation of these proteins and inhibited the formation of focal adhesions and stress fibers. These results suggest a role for integrin-mediated tyrosine phosphorylation in the organization of the cytoskeleton as cells adhere to the extracellular matrix.

3T3 Cells↗

PubMed1990

Lung extracellular matrix: physiology and pathophysiology.

In addition to providing structural support and defining tissue compartments, the lung's extracellular matrix plays an important role in regulating cell behavior. Normal and pathologic interactions between the matrix, or its components, and cells of the lung are examined. Such interactions assume major importance in lung injury and repair.

Basement Membrane↗

PubMed2006

Limitation of cell adhesion by the elasticity of the extracellular matrix.

Cell/matrix adhesions are modulated by cytoskeletal or external stresses and adapt to the mechanical properties of the extracellular matrix. We propose that this mechanosensitivity arises from the activation of a mechanosensor located within the adhesion itself. We show that this mechanism accounts for the observed directional growth of focal adhesions and the reduction or even cessation of their growth when cells adhere to a soft extracellular matrix. We predict quantitatively that both the elasticity and the thickness of the matrix play a key role in the dynamics of focal adhesions. Two different types of dynamics are expected depending on whether the thickness of the matrix is of order of or much larger than the adhesion size. In the latter situation, we predict that the adhesion region reaches a saturation size that can be tuned by the mechanical properties of the matrix.

Cell Adhesion↗

PubMed1989

Interaction of Campylobacter jejuni with extracellular matrix components.

The adhesion of three strains of Campylobacter jejuni to coverslips and microwells coated with isolated extracellular matrix components, fibronectin, laminin and types I, III, IV and V collagens was studied. Fibronectin mediated the adherence of C. jejuni, but there were differences in the binding capacities of the strains. Type I, III and V collagens mediated very strongly the attachment of two strains of C. jejuni. All three strains attached weakly to basement membrane-specific type IV collagen. Laminin was capable of mediating the adhesion only when present at a higher concentration. The observations indicate that extracellular matrix components may serve as anchor molecules for C. jejuni adhesion and that several attachment mechanisms occur simultaneously.

Bacterial Adhesion↗

PubMed1997

Formation of surface reaction products on bioactive glass and their effects on the expression of the osteoblastic phenotype and the deposition of mineralized extracellular matrix.

The objective of the study was to examine the effect of alkali ion release, pH control and buffer capacity on the expression of the osteoblastic phenotype. In addition we determined the importance of modifications of the surface of porous bioactive glass (BG) on the activity of rat calvaria osteoblasts in vitro. We found that at a low tissue culture medium (TCM) volume to BG surface area (Vol/SA) ratio, the products of glass corrosion elevated the pH of the TCM to a value that adversely affected cellular activity; thus, the matrix synthesized by the cells was non-mineralized. On the other hand, when the Vol/SA was high and the buffer capacity of the medium was not exceeded, the cells generated a mineralized extracellular matrix. Addressing the second issue, we observed that modification of the composition of the BG surface markedly influenced osteoblast activity. BG that was coated with either a calcium phosphate-rich layer only or a serum protein layer changed the phenotypic characteristics of the osteoblasts. The presence of either of these surfaces lowered the alkaline phosphatase activity of the attached cells; this finding indicated that the osteoblast phenotype was not conserved. However, when the BG was coated with a bilayer of calcium phosphate and serum proteins, the alkaline phosphatase (AP) activity was elevated and the extracellular matrix contained characteristic bone markers. Our findings indicate that the calcium phosphate-rich layer promotes adsorption and concentration of proteins from the TCM, and it is utilized by the osteoblasts to form the mineralized extracellular matrix.

Adsorption↗

PubMed2001

Knockout mice reveal a contribution of the extracellular matrix molecule tenascin-C to neural precursor proliferation and migration.

The extracellular matrix glycoprotein tenascin-C is widely expressed in the vertebrate central nervous system (CNS) during development and repair. Despite multiple effects of tenascin-C on cell behaviour in culture, no structural abnormalities of the CNS and other organs have been found in adult tenascin-C-null mice, raising the question of whether this glycoprotein has a significant role in vivo. Using a transgenic approach, we have demonstrated that tenascin-C regulates both cell proliferation and migration in oligodendrocyte precursors during development. Knockout mice show increased rates of oligodendrocyte precursor migration along the optic nerve and reduced rates of oligodendrocyte precursor proliferation in different regions of the CNS. Levels of programmed cell death were reduced in areas of myelination at later developmental stages, providing a potential corrective mechanism for any reduction in cell numbers that resulted from the proliferation phenotype. The effects on cell proliferation are mediated via the alphavbeta3 integrin and an interaction with the platelet-derived growth factor-stimulated mitogenic pathway, emphasising the importance of both CNS extracellular matrix and integrin growth factor interactions in the regulation of neural precursor behaviour.

Animals↗

PubMed2026

Desmoplakin loss in alveolar epithelium drives Wnt/β-Catenin-mediated extracellular matrix remodeling and fibrotic signaling in vitro.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by aberrant extracellular matrix (ECM) remodeling, epithelial dysfunction, and limited therapeutic options. Genetic studies implicate Desmoplakin (DSP), a desmosomal adhesion protein, in IPF susceptibility; however, its mechanistic role remains unclear. This study aimed to investigate the role of DSP in regulating fibrotic and ECM remodeling pathways in alveolar epithelial cells. METHODS AND RESULTS: DSP was silenced using siRNA in adenocarcinoma-derived human alveolar epithelial A549 cells. DSP loss induced epithelial-to-mesenchymal transition, enhanced cell migration, and increased epithelial permeability, along with upregulation of fibrotic and ECM-associated genes. Pathway enrichment analysis of DSP interactors (STRING database) identified the Wnt/β-catenin signaling as a potential key pathway. Mechanistic validation using cycloheximide chase assays, qPCR, western blotting, immunofluorescence, and luciferase-reporter assays suggested that DSP loss destabilizes desmosomal complexes, promoting plakoglobin (γ-catenin) degradation while reducing β-catenin turnover. This was associated with increased nuclear accumulation of β-catenin and enhanced TCF/LEF-dependent transcription, leading to elevated expression of ECM-related genes, including COL1A1 and MMP9. DSP overexpression suppressed Wnt/β-catenin signaling and fibrotic gene expression, while pharmacological inhibition of this pathway attenuated DSP-dependent increases in ECM-associated gene expression. CONCLUSION: These findings suggest that DSP may function as a regulator of alveolar epithelial homeostasis and extracellular matrix remodeling in an in vitro epithelial model. Loss of DSP is associated with activation of Wnt/β-catenin-mediated fibrotic signaling, correlating with reduced plakoglobin stability. This study provides mechanistic insight into epithelial-matrix crosstalk in vitro and identifies a candidate pathway that may contribute to ECM dysregulation in IPF, the disease relevance of which will require validation in primary human alveolar epithelial cells and in vivo models.

Humans↗

PubMed2003

Identification and characterization of extracellular matrix metalloproteinase inducer in human endometrium during the menstrual cycle in vivo and in vitro.

Extracellular matrix metalloproteinase inducer (EMMPRIN) participates in the breakdown of the extracellular matrix (ECM) by augmenting matrix metalloproteinase (MMP) expression. In the present study, we identified and characterized the menstrual cycle-dependent expression of EMMPRIN in human endometrium in vivo. At the proliferative phase of the menstrual cycle, EMMPRIN was detected in glandular epithelium of the basal layer in endometrium. In addition, at the superficial region of the functional layer, EMMPRIN was expressed in stroma but not glandular epithelium. At the secretory phase, EMMPRIN was found in both stroma and glandular epithelium of the functional layer and glandular epithelium of the basal layer. Furthermore, EMMPRIN colocalized with MMP-1/collagenase-1 in the glandular epithelium in vivo. Western blot analysis of tissue from the functional layer showed that EMMPRIN species with molecular weights of approximately 35 and 47 kDa were detected at the proliferative phase, whereas approximately 35- and 51-kDa EMMPRIN species were predominantly expressed at the secretory phase. In addition, the variant EMMPRIN molecules were found to differ in glycosylation. On the other hand, EMMPRIN was constitutively produced in primary cultured endometrial stromal and glandular epithelial cells. The production and glycosylation of EMMPRIN in the stromal cells were augmented by progesterone at the posttranscriptional and posttranslational stages, respectively. These results suggest for the first time that EMMPRIN is expressed in human endometrium during the menstrual cycle and that its expression and glycosylation are augmented by progesterone. Moreover, EMMPRIN may be involved in ECM breakdown at the interface between endometrial cells and ECM by using EMMPRIN-bound MMP-1.

Antigens, CD↗

PubMed1987

Monoclonal antibody to fibronectin which inhibits extracellular matrix assembly.

A monoclonal antibody L8 specific to fibronectin was shown to inhibit fibronectin incorporation into the fibroblast extracellular matrix. Antibody L8 could not interact with fibronectin complexed with gelatin. The results suggest the existence of a specific site on the fibronectin molecule playing a critical role in the assembly of the fibronectin extracellular matrix. This site is located near the collagen-binding domain.

Animals↗

PubMed1999

Cyclic strain effects on human monocyte interactions with endothelial cells and extracellular matrix proteins.

Human vascular endothelial cells (ECs) are exposed to various levels of hemodynamic forces, cyclic strain, and shear stress in vivo. Here, we examined the in vitro effects of the various levels (0-6%, 7-16%, and 17-25%) of strain at 60, 30, and 15 cycles per minute (cpm) on human monocyte adherence to endothelial cells and extracellular matrix protein preabsorbed surfaces. Monocyte adhesion to endothelial cells under cyclic strain significantly increased. At both 30 and 60 cpm, ECs under strains of 7-16% and 17-25% showed >52% and >117% higher monocyte adhesion than endothelial cells under static condition when monocytes were added for 0.5 h. This increase in monocyte adhesion to ECs under cyclic strain remained significantly higher even after 24 h of incubation. Human monocyte adhesion to extracellular matrix protein preabsorbed surfaces differed depending on the specific extracellular matrix protein. Monocytes adhered to collagen type I and fibronectin preabsorbed surfaces >50% under 0-6% strain, >23% under 7-16% strain, and >52% under 17-25% strain at 15 and 30 cpm compared to the collagen type V preabsorbed surface. However, when extracellular protein preabsorbed surfaces under cyclic strain were compared to the control static condition, monocyte adhesion did not significantly change on most of other surfaces. These results suggest that cyclic strain may play a role in the regulation of monocyte-endothelial cells/extracellular matrix interactions in vivo.

Cell Adhesion↗

PubMed2000

Time-lapse confocal reflection microscopy of collagen fibrillogenesis and extracellular matrix assembly in vitro.

The development of the next generation of biomaterials for restoration of tissues and organs (i.e., tissue engineering) requires a better understanding of the extracellular matrix (ECM) and its interaction with cells. Extracellular matrix is a macromolecular assembly of natural biopolymers including collagens, glycosaminoglycans (GAGs), proteoglycans (PGs), and glycoproteins. Interestingly, several ECM components have the ability to form three-dimensional (3D), supramolecular matrices (scaffolds) in vitro by a process of self-directed polymerization, "self-assembly". It has been shown previously that 3D matrices with distinct architectural and biological properties can be formed from either purified type I collagen or a complex mixture of interstitial ECM components derived from intestinal submucosa. Unfortunately, many of the imaging and analysis techniques available to study these matrices either are unable to provide insight into 3D preparations or demand efforts that are often prohibitory to observations of living, dynamic systems. This is the first report on the use of reflection imaging at rapid time intervals combined with laser-scanning confocal microscopy for analysis of structural properties and kinetics of collagen and ECM assembly in 3D. We compared time-lapse confocal reflection microscopy (TL-CRM) with a well-established spectrophotometric method for determining the self-assembly properties of both purified type I collagen and soluble interstitial ECM. While both TL-CRM and spectrophotometric techniques provided insight into the kinetics of the polymerization process, only TL-CRM allowed qualitative and quantitative evaluation of the structural parameters (e.g., fibril diameter) and 3D organization (e.g., fibril density) of component fibrils over time. Matrices formed from the complex mixture of soluble interstitial ECM components showed an increased rate of assembly, decreased opacity, decreased fibril diameter, and increased fibril density compared to that of purified type I collagen. These results suggested that the PG/GAG components of soluble interstitial ECM were affecting the polymerization of the component collagens. Therefore, the effects of purified and complex mixtures of PG/GAG components on the assembly properties of type I collagen and interstitial ECM were evaluated. The data confirmed that the presence of PG/GAG components altered the kinetics and the 3D fibril morphology of assembled matrices. In summary, TL-CRM was demonstrated to be a new and useful technique for analysis of the 3D assembly properties of collagen and other natural biopolymers which requires no specimen fixation and/or staining.

Animals↗