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PubMed1994

Neointima formation after acute vascular injury. Role of counteradhesive extracellular matrix proteins.

Restenosis currently limits the long-term beneficial effects of balloon coronary angioplasty. Two important cellular events in the development of clinically significant luminal narrowing after angioplasty are 1) increased production of extracellular matrix proteins and 2) acquisition of a motile phenotype by vascular smooth muscle cells. In this paper, smooth muscle cell responses that produce a fibrocellular neointima after acute vascular injury are reviewed. Particular emphasis is placed on specialized extracellular matrix proteins implicated in cell movement and tissue repair. Tenascin and thrombospondin are large, modular extracellular matrix glycoproteins; they possess both adhesive and counteradhesive domains and are expressed at high levels during smooth muscle cell migration and neointima formation after balloon injury to rat carotid artery. The ability of both tenascin and thrombospondin to down-regulate the assembly and activity of focal adhesions (points of cell-extracellular matrix adhesive interactions) may be important in the conversion of stationary, quiescent smooth muscle cells to cells that are able to move and divide within the strongly adhesive vessel wall. Moreover, tenascin is present in the extracellular matrix as a large 6-armed oligomer (a hexabrachion) that contains both cell-binding and matrix protein-binding domains in each of the hexabrachion arms. The large size and multidomain structure of tenascin and thrombospondin suggest that these proteins may be particularly well suited to form a nascent provisional matrix at sites of 1) neointima formation after acute vascular injury, 2) new growth and expansion within primary atherosclerotic plaques, and 3) intimal repair and luminal narrowing in restenosis after angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1994

Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part IV: Effects on expression of extracellular matrix genes.

Increased deposition of lung extracellular matrix in terminal airways is associated with chronic ozone exposure. In situ hybridization was used to assess whether long-term ozone exposure causes elevated and continued expression of genes coding for connective tissue proteins. Accessory lobes were removed from the animals exposed to 0, 0.12, 0.5, or 1.0 parts per million (ppm)* ozone for 20 months as part of the National Toxicology Program (NTP)/HEI Collaborative Ozone Project. The lungs were perfused fixed under physiologic pressure and processed for in situ hybridization. Sections were hybridized with 35S-labeled probes for messenger RNA (mRNA) coding for various matrix proteins, including collagen types I and III, elastin, and fibronectin, and for interstitial collagenase, a matrix metalloproteinase. Fetal rat lung was used as a positive control for hybridization. No signal for any mRNA was detected in terminal airway stromal cells of lungs from animals exposed to ozone for 20 months or control animals breathing clean air. In all samples from animals exposed to ozone for 20 months and control animals, only a very weak signal was seen in occasional cells within the interstitial spaces around large airways and blood vessels. In contrast, a strong signal for matrix-related mRNA was detected in fetal lung tissue. These findings indicate that active or enhanced matrix production is turned off in the adult animals used in the ozone studies, suggesting that the increase in matrix deposition results from a transient and early fibrotic response. Indeed, signal for type I procollagen and tropoelastin mRNAs was seen in alveolar septal cells in lungs of rats exposed to ozone for two months. No signal was seen in alveolar cells of age-matched control animals. (These animals, exposed for two months, and age-matched controls were from earlier studies supported by the HEI.) These findings indicate that ozone mediates a transient fibrotic response that results in a sustained increase in lung extracellular matrix. Confirmation of this hypothesis would require additional studies using animals exposed to ozone for shorter times.

Administration, Inhalation↗
PubMed1994

[The extracellular matrix: from supporting tissue to regulation of cytokines].

Extracellular matrix is a polymorphic structure composed of at least thirty molecules (collagens, glycoproteins, elastin, and proteoglycans) associated in a complex network. This insoluble structured framework ensures tissue cohesiveness, and allows cells to adhere, migrate and interact. Together with cytokines extracellular matrix is also involved in the control of various aspects of cell activities. Cytokines mediate cell to cell communication. Their broad effect result from their pleiotropic and overlapping activities. Once secreted, these molecules diffuse between cells--i.e. across extracellular matrix--to reach their target cells. An increasing number of cytokines are now known to bind to the extracellular matrix. These interactions change the availability of cytokines on effector cells, activate some growth factors, localize and/or increase the duration of the expected effect. Matrix-cytokines interactions are a new field of investigation which has changed our view on extracellular matrix. First considered as a supporting tissue, extracellular matrix appears now to be critically involved in the regulation of cytokine activities.

Cell Communication↗
PubMed1994

Tumor necrosis factor alpha-induced endothelial tissue factor is located on the cell surface rather than in the subendothelial matrix.

Because there is no consensus regarding the precise distribution of induced endothelial tissue factor (TF), we studied TF activity in and on tumor necrosis factor alpha-stimulated cultured human umbilical vein endothelial cells (ECs) and their underlying matrix. TF was mainly expressed on the cell surface. Only small traces were found on the apical surface suggesting that TF is predominantly located on the basolateral side of the cell membrane. The presence of TF on the cell surface was confirmed by flow cytometry. Subendothelial TF activity appeared to be dependent upon the procedure used to remove the stimulated EC monolayer. Whereas ammonium hydroxide or hypotonic lysis resulted in relatively high levels of matrix-associated TF, virtually no TF was found on the matrix after mild enzymatic detachment of stimulated ECs. Cell removal with EDTA resulted in intermediate levels of matrix-associated TF. Neither the enzymatic treatment nor EDTA degraded or removed this TF activity. Similar patterns were observed for matrix-associated TF antigen and EC surface markers. Electron microscopic analysis showed cell fragments on the matrix after monolayer lysis. The findings strongly suggest that induced endothelial TF associated with the subendothelial matrix actually represents TF on EC remnants.

Antibodies, Monoclonal↗
PubMedDate not supplied

[Biochemical features of protein matrix M1 of the influenza C virus].

Influenza viruses A, B, and C belonging to Orthomyxoviridae comprise an internal ribonucleoprotein (RNP) and an outer lipoprotein envelope with surface spike glycoproteins and the M1 protein matrix. The lipoprotein envelope and spike glycoproteins are solubilized by nonionic detergent treatment in a pH-independent manner. In contrast, disassembly of the M1 protein matrix appears to depend on pH. Treatment of influenza C viruses with nonionic detergent in neutral or alkaline medium (pH 9.0-7.2) results in disintegration of the virion M1 matrix and leads to a significant release of RNP free of the M1 protein. In acidic medium (pH 6.0-5.0) the M1 matrix fails to be removed and the viral core-like complex of RNP along with the M1 matrix cover is released. Since influenza A and B viruses were characterised by acid-dependent disassembly of the virion M1 matrix, influenza C viruses seem to be more resemble the paramyxoviruses, which also show a neutral-alkaline pH dependence of the matrix disintegration. These observations suggest that uncoating of influenza C viruses and paramyxoviruses in target cells may have similar events.

Hydrogen-Ion Concentration↗
PubMed1993

Structural changes of the interphotoreceptor matrix in an inherited retinal degeneration: a lectin cytochemical study of progressive rod-cone degeneration.

PURPOSE: In the retinal disorder progressive rod-cone degeneration (prcd) in miniature poodle dogs, the photoreceptor layer degenerates slowly in the course of 5 to 7 years. Components of the interphotoreceptor matrix form a continuous extracellular lattice around photoreceptors. The purpose was to study the photoreceptor cell-matrix interactions during the disease and degeneration phases. Because degeneration rate was slower in cones, the authors also wanted to investigate whether there was a link between the degeneration and the photoreceptor-specific interphotoreceptor matrix domains. METHODS: Rod- and cone-specific interphotoreceptor matrix domains were examined during two periods: before morphological signs of disease had appeared and during the degenerative stages. Two lectin probes were used; wheat germ agglutinin and peanut agglutinin. By their affinity for terminal carbohydrates, the lectins visually separated the two photoreceptor-specific domains and allowed follow-up of the fate of the rod and cone matrices separately. RESULTS: Before and during the course of disease, the lectin distribution in rod and cone domains remained normal, however, in the degenerative phase of the disease, there were structural changes in the matrix domains. The matrix connections between the individual domains was disrupted and single domains were formed. Cone domains and, to a lesser degree rod domains, were thickened around the inner and outer segments. CONCLUSIONS: The changes occurring in the photoreceptor-specific domains were indicative of structural adaptation to cell death and to degenerative conditions. There was no evidence of an active involvement of the interphotoreceptor matrix components studied in the disease process.

Animals↗
PubMed1993

Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways.

Constitutive overexpression of both urokinase and matrix metalloproteinase (MMP) activity is frequently observed in individual malignant tumors. In this study we describe the combined contribution of these distinct enzyme systems to the invasive phenotype of a highly metastatic human melanoma cell line (M24met). M24met cells were found to secrete a spectrum of MMPs, including interstitial collagenase, type IV collagenases (M(r) 92,000 and 72,000 progelatinases), and stromelysin. Urokinase, but not tissue-type plasminogen activator, was detected in M24met-conditioned media and on cell surfaces. The contribution of these enzymes to extracellular matrix dissolution was determined by exploiting specific inhibitors, namely tissue inhibitor of the metalloproteinases-2 and plasminogen activator inhibitor-2. Due to the coexpression of urokinase and MMP-dependent activity, M24met cells were observed to degrade multiple components of the extracellular matrix and to significantly degrade both interstitial and basement membrane matrices. Urokinase-dependent removal of matrix glycoprotein was observed to precede MMP-dependent collagenolysis as a prerequisite rate-limiting step. We present evidence which suggests that this temporal relationship is imposed by the structural architecture of the matrix such that matrix glycoprotein serves to protect associated collagen from MMP-dependent degradation. In addition to mediating significant collagenolysis, MMP activity was further implicated in the dissolution of matrix tropoelastin. Urokinase/plasmin activity was not found to be required for MMP-zymogen activation.

Amino Acid Sequence↗
PubMed1996

A nuclear matrix acceptor site for the progesterone receptor in the avian c-myc gene promoter.

It has been the goal of this project to determine the location, composition, and biological function of the nuclear acceptor sites (i.e., the nuclear binding sites) for the avian oviduct progesterone (Pg) receptor (PR). Many laboratories have demonstrated a native-(in vivo) like cell-free binding of steroid receptor complexes to specific acceptor sites in nuclei/chromatin in a variety of target tissue systems. These sites appear to involve protein-DNA complexes and some of these have been shown to reside in the nuclear matrix, including the chromatin acceptor sites for the avian oviduct PR. We have purified a nuclear matrix "acceptor protein" for the avian PR. termed receptor binding factor-1 (RBF-1), based on its ability to generate specific, high-affinity PR binding on avian genomic DNA. This 10 kD nuclear matrix protein was found to be unique with minimal homology to a couple of other proteins. Using immunohistochemical techniques and antibodies against the purified RBF-1, the RBF-1 was localized to the nuclei of many avian and rat tissues. Co-localizations of RBF-1 and PR in select cell types in the avian oviduct and rat reproductive organs were also reported. A tissue specificity was found with regard to RBF-1 concentrations. The full length cDNA to RBF-1 has been isolated and used to identify a 0.7 kb mRNA whose levels in various avian tissues reflect the protein levels. Genomic sequences of RBF-1 have been isolated and characterized. Preliminary studies indicate that the over-expression of the RBF in human MCF-7 cells results in an inhibition of the c-myc gene promoter activity which is further inhibited by steroid hormone treatments of the cells. Past studies in our laboratory demonstrated that the c-myc mRNA steady state levels are rapidly (approximately 15 min) reduced by Pg and glucocorticoids in the avian oviduct. Further, partially purified fractions of RBF-1 were shown to generate specific PR binding sites only on the genomic DNAs of certain animal species and on the c-myc gene, but not ovalbumin gene. Using Southwestern blot analyses, the purified RBF-1 was shown to bind specifically to sequences in the 5' end of c-myc, c-jun proto-oncogenes but not to genomic sequences of the ovalbumin gene. A specific DNA binding element in the promoter region of the c-myc proto-oncogene has been identified as AT-rich domain of homopurine/pyrimidine stretches flanked by GC-rich sequences. Southern blot analyses using 200 bp matrix DNA fragments protected by the nuclear matrix structure indicate that the matrix is attached on either side of the RBF-1 binding element. A model is described for a nuclear matrix acceptor site attached to the c-myc promoter which may mediate the Pg-induced down-regulation of the c-myc gene expression.

Animals↗
PubMed1997

Elastin receptor and cell-matrix interactions in heart transplant-associated arteriosclerosis.

Vascular cells, as well as monocytes, neutrophils, and lymphocytes which may infiltrate vascular walls and tissues express a multifunctional 67 kD protein which also serves as a subunit of the cell surface "elastin receptor". This protein differs structurally and functionally from other matrix adhesion molecules. Unlike the integrins or cadherins, it is not a transmembrane molecule, but can be immobilized on the cell surface by association with two other membrane-anchored proteins. Once expressed on the cell surface, it may mediate cell-matrix interaction in a calcium-independent manner. Unlike most integrins, which recognize the linear sequence on the matrix ligands (RGD), it recognizes the secondary structure of the matrix macromolecules and binds to several non identical domains on different matrix components, as long as they form the appropriate hydrophobic conformation. Similarly to the transmembrane selectins, the 67 kD protein has lectin-like properties with the galactosugars' binding specificity. However, binding of galactosugar-bearing ligands interrupts its contacts with matrix proteins and displaces the 67 kD protein from the cell surface. Moreover, the 67 kD protein also serves as an intracellular chaperone which facilitates secretion of tropoelastin and assembly of elastic fibers. In this review I will address the role of this 67 kD protein in mechanisms of mutual interaction between vascular smooth muscle cells, infiltrating leukocytes, and several components of extracellular matrix during the development of heart-transplant associated arteriosclerosis.

Animals↗
PubMed1997

Vasculogenesis and angiogenesis: extracellular matrix remodeling in coronary collateral arteries and the ischemic heart.

Heart failure secondary to ischemic cardiomyopathy is the primary cause of cardiovascular mortality. The promise of the collateral circulation lies in its potential to alter the course of the natural history of coronary heart disease. The collateral circulation of the heart is responsible for supplying blood and oxygen to the myocardium at ischemic risk following severe stenosis and reduced vasoelasticity function of a major coronary artery. In response to flow, stress, and pressure, collateral vessels are restructured and remodeled. Vascular remodeling by its very nature implies synthesis and degradation of extracellular matrix components in the vessel wall. Under normal physiological conditions proteinases that break down the specialized matrix are tightly regulated by antiproteinases. The balance between proteinase and antiproteinase influences is discoordinated during collateral development which leads to adaptive changes in the structure, function, and regulation of extracellular matrix components in the vessel wall. The role of extracellular matrix components in coronary collateral vessel formation in a canine model of chronic coronary artery occlusion has been demonstrated. The role of matrix proteinases and antiproteinases in the collateral vessel play a significant role in the underlying mechanisms of collateral development. This review presents new and significant information regarding the role of extracellular matrix proteinases and antiproteinases in vascular remodeling, function, and collateral development. Such information will have a significant impact on the understanding of the basic biology of the vascular extracellular matrix turnover, remodeling, and function as well as on elucidating potential avenues for pharmacological approaches designed to increase collateral formation and optimize myocardial blood flow in the treatment of ischemic heart disease.

Animals↗
PubMed2004

[Involvement of matrix metalloproteinases (MMPs) in cutaneous melanoma progression].

Among skin cancers, melanoma is probably the most highly invasive and metastasizing, with a poor outcome. During melanoma progression, tumor cells must across the dermal-epidermal junction, and invade the dermis, its principal site of propagation. Therefore, degradation of matrix proteins constituting dermal-epidermal junction and dermis by proteolytic enzymes is an essential step of melanoma invasion. Serines proteinases and Matrix Metalloproteinases (MMPs) families are the main degrading substances involved in this process. Among MMPs, the expression of MMP-1, -2, -3, -9, -14, 15, -16 by melanoma cells was shown in vitro and in vivo, and correlated with the invasive phenotype. In addition to disrupt matrix proteins, MMPs can also cleave non matrix components such as cytokines, and growth factors. The modifications generated by the remodeling of matrix and non-matrix components can influence melanoma cells proliferation, adhesion, vascularization, survival, proteases expression, and migration. Thus, using inhibitors in order to control expression, activation and activity of MMPs could regulate cellular process which led to melanoma progression.

Animals↗
PubMed1995

Quantification of a matrix metalloproteinase-generated aggrecan G1 fragment using monospecific anti-peptide serum.

Several members of the matrix metalloproteinase family have been reported to cleave aggrecan in the interglobular domain between Asn-341 and Phe-342. An antiserum was prepared against a peptide conjugate corresponding to the C-terminal sequence of the matrix metalloproteinase-generated aggrecan G1 fragment (Phe335-Val-Asp-Ile-Pro-Glu-Asn341). A quantitative radioimmunoassay, with a limit of detection of about 80 pM, was developed using this antiserum. This antiserum requires the free carboxyl group of the C-terminal asparagine for optimal recognition. If the C-terminal asparagine is excised from the sequence, replaced with closely related amino acids, or extended across the matrix metalloproteinase cleavage site, there is a 40-10,000-fold loss in detection. Using peptides cleaved from the N-terminus, it was determined that the antiserum requires the entire Phe-Val-Asp-Ile-Pro-Glu-Asn sequence for optimal recognition. The radioimmunoassay detects matrix metalloproteinase-generated G1 fragments with similar sensitivity to the Phe-Val-Asp-Ile-Pro-Glu-Asn peptide, but it does not recognize intact aggrecan. Immunoreactive aggrecan G1 fragments of molecular mass 50 kDa are generated by the matrix metalloproteinases stromelysin and gelatinase A. In contrast, under identical conditions, the closely related metalloproteinases, gelatinase B and collagenase, as well as cathepsin G, cathepsin B and human leucocyte elastase, did not generate a G1 fragment recognized by the antiserum. The anti-Phe-Val-Asp-Ile-Pro-Glu-Asn serum detects stromelysin-generated aggrecan G1 fragments from mouse, guinea pig, rabbit and human, indicating that the detection is not species-specific. This antiserum and radio-immunoassay should be useful for quantifying and characterizing matrix metalloproteinase-generated aggrecan G1 fragments in articular cartilage and synovial fluids from humans and various animal models of articular-cartilage destruction.

Aggrecans↗
PubMed1995

Cytokines regulate gelatinase A and B (matrix metalloproteinase 2 and 9) activity in cultured rat astrocytes.

Under a tightly regulated expression mechanism, matrix metalloproteinases degrade extracellular matrix proteins and are thought to play a role in injury repair and tumor metastasis in peripheral tissues. Little is known about the function of matrix metalloproteinases or agents that regulate their production in adult brain; however, it has been shown that the activity of a calcium-dependent metalloproteinase is elevated in Alzheimer's hippocampus. The goals of this study were to determine whether cultured rat astrocytes produce matrix metalloproteinases and to identify agents that regulate protease activity. Enriched astrocyte cultures were prepared from brains of 1-day-old rat pups, and experiments were performed 13 days later. Gelatinase activity in astrocyte conditioned medium was determined using zymography with gelatin copolymerized with acrylamide in the gel. Under basal conditions after a 24-h incubation, rat astrocytes produce gelatinases of 58 and 66 kDa. On stimulation of astrocytes with lipopolysaccharide, interleukin-1 alpha or -beta, or tumor necrosis factor-alpha for 24 h, a dose-dependent increase in the activity of the 58- and 66-kDa gelatinases and the induction of a 94-kDa gelatinase occurred. All three astrocyte-derived proteases showed maximal activity in the presence of millimolar levels of Ca2+, their activity was inhibited in the presence of 1,10-phenanthroline, and their proenzymes were cleaved and activated after incubation with p-aminophenylmercuric acetate. Using immunoblotting, immunopositive bands at the respective molecular sizes indicated that the 58-kDa gelatinase was gelatinase A (matrix metalloproteinase 2) and the 94-kDa activity was gelatinase B (matrix metalloproteinase 9).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Potential for synthesis and degradation of extracellular matrix proteins by valve interstitial cells seeded onto collagen scaffolds.

Matrix remodeling, which involves proteolytic enzymes, such as the matrix metalloproteinases (MMPs), is of significant importance with respect to tissue engineering a heart valve construct. The ability of valve interstitial cells (ICs) to release these enzymes in biological scaffolds and to synthesize their own matrix has not been adequately studied, and this has important implications for tissue engineering. Cultured human aortic valve ICs were seeded onto a 3-dimensional type I collagen matrix for 28 days, whereby the presence of the remodeling enzymes, MMPs, were determined using immunohistochemistry, and detection of extracellular matrix (ECM) gene expression was performed using in situ hybridization. The collagenases, stromelysins, and membrane-type MMPs were expressed in 1%, 2%, and 5% collagen scaffolds after 28 days, whereas gelatinase expression was not observed. In situ hybridization revealed the presence of the ECM messenger ribonucleic acid (mRNA) in cells cultured in collagen scaffolds however, an increase in all three mRNAs was only detected in the 1% collagen scaffolds. The presence of collagenases, stromelysins, and membrane-type MMPs indicate that human valve ICs have the capacity to remodel type I collagen scaffold and that the genes necessary for synthesizing matrix have been turned on within the cells themselves. Scaffold composition also demonstrated differential effects onMMPexpression. These observations are of relevance with respect to the development of tissue-engineered heart valves.

Aortic Valve↗
PubMed2002

Increased activity and expression of matrix metalloproteinase-9 in a rat model of distal colitis.

Matrix metalloproteinases may play a role in tissue remodelling and destruction associated with inflammation. We investigated activity and expression of matrix metalloproteinases in a rat model of colitis and tested the therapeutic potential of a synthetic inhibitor (CGS-27023-A). Colitis was induced by dextran sulphate sodium (at 5% in drinking water for 5 days) in a group of eight rats, whereas a matched control group received plain water. Activity and expression of matrix metalloproteinases were measured in colonic tissue homogenates using zymography and Western blot on days 3 and 5 after induction of colitis. In another set of experiments, two groups of colitic rats (20 per group) were treated with CGS-27023-A (20 mg/kg) or vehicle, respectively. On days 5 and 14, colonic mucosal lesions were blindly scored by microscopic examination. Induction of colitis led to a significant upregulation of matrix metalloproteinase-9 protein and its activity, but no change in matrix metalloproteinase-2 activity was observed. Treatment with CGS-27023-A significantly decreased the extent and severity of epithelial injury but did not influence mucosal repair. We conclude that increased activity of matrix metalloproteinases may contribute to epithelial damage in this model of colitis.

Animals↗
PubMed2006

Altered expression of matrix-related molecules in the development of chronic Thy1.1 nephritis.

BACKGROUND/AIM: Matrix production and degradation are critically important in chronic nephritis. Our aim was to investigate the precise expression of matrix-related molecules which is essential for understanding the pathogenesis of renal disease. METHODS: Chronic nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. RNA was extracted from renal cortex and isolated glomeruli 4, 7, and 10 weeks after the antibody injection. Matrix-related gene expressions were measured by polymerase chain reaction. The expression of alpha1(IV) and alpha3(IV) collagens was studied by immunohistochemistry. The gelatinolytic activity in the glomeruli was assayed by gelatin zymography. RESULTS: Polymerase chain reaction revealed an increase of alpha1(IV) in both glomeruli and renal cortex from nephritic rats. In contrast, the expression of alpha3(IV), normally a component of the glomerular basement membrane, was decreased in nephritic animals. Immunohistochemistry confirmed the finding that alpha1(IV) and alpha3(IV) were up- and downregulated, respectively, in the glomeruli. Gene expression and activity of matrix metalloproteinase 2 were enhanced, while those of matrix metalloproteinase 9 were clearly suppressed in nephritis. CONCLUSIONS: Downregulation of alpha3(IV) and enhancement of the matrix metalloproteinase-2 activity in the glomeruli may contribute to the glomerular damage by altering the glomerular basement membrane components. Impairment of the glomerular basement membrane integrity may possibly be implicated in irreversible renal dysfunction.

Animals↗
PubMed2000

Matrix metalloproteinase and alphavbeta3 integrin-dependent vascular smooth muscle cell invasion through a type I collagen lattice.

Smooth muscle cell (SMC) migration from the tunica media to the intima is a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. SMCs require not only migratory but also degradative abilities that enable them to migrate through extracellular matrix proteins, which surround and embed these cells. We used a collagen type I lattice as a coating on top of a porous filter as a matrix barrier in a chamber to test the invasive behavior of SMCs in response to a chemoattractant (invasion assay) and compared that behavior with simple SMC migration through collagen type I-coated filters (migration assay). Inhibitors of matrix metalloproteinase, KB-R8301, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), TIMP-2, and peptide 74, attenuated platelet-derived growth factor-BB (PDGF-BB)-directed SMC invasion across the collagen lattice, whereas no effect was seen with these inhibitors on simple SMC migration through collagen-coated filters. RGD peptide inhibited SMC invasion but did not affect SMC migration. Anti-alphavbeta3 integrin antibody attenuated PDGF-BB-directed SMC invasion, whereas other antibodies against RGD-recognizing integrins, namely alphavbeta5 and alpha5, had no effect. None of these antibodies had any effect on simple SMC migration. RGD peptide and anti-alphavbeta3 antibody inhibited the attachment and spreading of SMCs on denatured collagen but not on native collagen. These findings indicate that there is a difference in the mechanisms between simple SMC migration across a collagen-coated filter and SMC invasion through a fibrillar collagen barrier. A proteolytic process is required for SMC invasion, and the degradation of matrix proteins alters the relationship between matrix protein molecules and SMC surface integrins.

Animals↗
PubMed2006

Extracellular matrix in disc degeneration.

The extracellular matrix of the intervertebral disc structures contains many molecules also found in cartilage. The extremely polyanionic proteoglycans play a central role, particularly in the nucleus, by creating an osmotic environment leading to retention of water and ensuing resistance to deformation-important for the resilience of the tissue. Another major structural entity particularly important in the anulus is the network of collagen fibers; fibril-forming collagen 1 is a major constituent. The collagen fibrils in the anulus are largely oriented in sheets around the nucleus. A number of molecules present in the matrix regulate and direct the collagen fibril assembly by interacting with the collagen molecule and also the formed fibril. Several of these molecules bind by one domain to the collagen fiber and present another functional domain to interact either with other fibers or with other matrix constituents. In this manner the collagen fibers are cross-linked into a network that provides tensile strength and distributes load over large parts of the anulus. Diminished function in these cross-bridging molecules will lead to loss of mechanical properties of the collagen network and result in an impaired ability of the anulus to resist forces delivered by compression of the disc and particularly the nucleus. A different network abundant in the disc and in other load-bearing tissues is based on the beaded filaments of collagen 6. The basic building block is a tetramer of two pairs of antiparallel collagen-6 molecules arranged such that two N-terminal ends of collagen 6 are exposed at either end of the unit. Further assembly occurs both by end-to-end and side-to-side associations. This process is catalyzed by both biglycan and decorin, where the combined effect of direct binding of the core protein to the collagen-6 N-terminal globular domain and the presence of the glycosaminoglycan side chain is essential. These ligands are bound at the same site in complexes extracted from the tissue and then also have one bound molecule of matrilin-1, 2, or 3, in turn bound to a collagen fiber, a procollagen molecule, or an aggrecan. Interactions at the cell surface provide signals to the cells with regard to the conditions of the matrix. Such interactions include binding by matrix components to various receptors at the cell surface. Remodeling of the matrix takes place in response to various factors. An early event in disease is degradation of aggrecan by the members of the ADAMTS (a disintegrin-like and metalloprotease with thrombospondin motifs) family and degradation of molecules important in maintaining the collagen network.

Cartilage Oligomeric Matrix Protein↗