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PubMed1997

Matrix and adhesion molecules in kidney pathology: recent observations.

The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) in RNA analysis for matrix; and in developing more effective treatment strategies for patients with kidney disease.

Animals↗
PubMed1998

Collagen subtypes and matrix metalloproteinase in idiopathic restrictive cardiomyopathy.

BACKGROUND: Idiopathic restrictive cardiomyopathy is a rare disease characterized by diastolic dysfunction, and the pathogenesis of the stiff heart remains unclear. The purpose of this study was to analyze the subpopulation of collagen fibers and determine the expression of matrix metalloproteinase in restrictive cardiomyopathy. METHODS AND RESULTS: In endomyocardial biopsy specimens obtained from seven patients with restrictive cardiomyopathy, collagen fiber types I, III, and IV, and matrix metalloproteinase- and two were observed by light and electron microscopy, using monoclonal antibodies. Type I collagen was less prominent in the interstitium, whereas the immunoreactivity for type III collagen was marked. The immunoreactivity against matrix metalloproteinase-1 was observed along with types I and III collagen fibers and in the cytoplasm of some fibrocytes/fibroblasts. The matrix metalloproteinase-1 tended to increase when the reactivity against types I and III collagen was prominent. Both type IV collagen and matrix metalloproteinase-2 were observed along arterial walls and the basement membrane of cardiocytes. CONCLUSIONS: Increased type III collagen may play an important role as the cause of left ventricular stiffness in restrictive cardiomyopathy. The matrix metalloproteinase appeared to be involved in a cascade of collagen synthesis and the remodeling of the heart in patients with restrictive cardiomyopathy.

Adult↗
PubMedDate not supplied

Proteolyzed matrix as a template for the regulation of tumor progression.

Pericellular proteolysis plays a pivotal function in cell invasion, a hallmark of tumor growth and metastasis. The minidegradome constituted of two matrix metalloproteinases (MMP), i.e. MMP-2 and MT1-MMP, associated with tissue inhibitor of metalloprotease-2 (TIMP-2) and integrin (alpha(v)beta(3)) or CD(44), is mainly involved in such invasive program. It catalyzes matrix degradation but, alternatively, proteolytic exposure of matricryptic sites or matrikines liberation by those enzymes regulates either positively or negatively tumor cell migration. That applies to types I and IV collagens, elastin, laminin 5, as described here, but such phenomenon might be extended to other matrix macromolecules. The development of tumors from epithelium origin is related to aging. Senescent fibroblasts are characterized by increased expression of MMPs, (particularly collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)) and deposited matrix by those aged cells was shown to favor cancer cell growth. Thus, compositional variation of matrix-surrounding tumor cells, with formation of matricryptic sites and matrikines, can be considered as one main epigenetic factor contributing to tumor progression. A matrix-directed pharmacological approach in cancer is now emerging.

Animals↗
PubMed1997

Hypochlorous acid disrupts the adhesive properties of subendothelial matrix.

We have investigated whether the cell adhesion-promoting properties of the subendothelial matrix are affected by exposure to neutrophil-derived oxidants. Native subendothelial matrix was exposed to increasing doses of H2O2 in the presence of myeloperoxidase and Cl- or to reagent hypochlorous acid (HOCl). Increasing doses of either oxidant system resulted in progressive loss in the adhesive properties of the matrix, and phase contrast microscopy showed that the cells failed to attach to and spread on the oxidant-treated surface. When cells were replated on the treated matrix in the presence of 20% serum, they did attach, but showed abnormal spreading and morphology in longer-term culture. In a modified ELISA system, binding of antibodies specific to fibronectin, thrombospondin and laminin was also disrupted by prior exposure of the matrix to HOCl. Of these components, the cell-binding region of fibronectin was most affected by HOCl, thrombospondin and laminin were less sensitive, and the collagen-binding region of fibronectin was the most resistant. SDS-PAGE of 35S-labelled subendothelial matrix proteins indicated that there was no major irreversible crosslink formation or fragmentation after exposure to HOCl or the myeloperoxidase system, although formation of disulfides is quite likely.

Cell Adhesion↗
PubMed1989

Interstitial collagenase (MMP-1), gelatinase (MMP-2) and stromelysin (MMP-3) released by human fibroblasts cultured on acellular sarcoid granulomas (sarcoid matrix complex, SMC).

We studied collagenase, gelatinase and stromelysin syntheses by human fibroblasts cultured on three models of tridimensional matrix: native collagen sponge, native collagen complexed with glycosaminoglycans sponge, and acellular sarcoid matrix complex prepared from human sarcoid granulomas. Collagenase and stromelysin biosyntheses were differently stimulated according to culture conditions. Fibroblasts secreted a same amount of collagenase or stromelysin when cultured on collagen and collagen-glycosaminoglycans sponges, while collagenase and stromelysin secretions were widely amplified when cultured on sarcoid matrix complex. In contrast, gelatinase production was equally induced by the three culture conditions. In the different culture conditions on tridimensional matrix, the three matrix metalloproteinases were synthesized in a latent form. Thus, the sarcoid matrix complex stimulated the release of collagenase and stromelysin by fibroblast, but did not stimulate the release of gelatinase. This suggests that collagenase and stromelysin syntheses are co-regulated while gelatinase production is controlled by a distinct mechanism.

Cells, Cultured↗
PubMed1995

Expression of collagens and decorin during aortic arch artery development: implications for matrix pattern formation.

The elastic matrix of the large arteries shows a high level of spatial order. However, the mechanisms by which such order is established and maintained are largely unknown. The embryonic development of the avian heart and great vessels provides an appropriate model to investigate these mechanisms. In control embryos, an elastic matrix with a high level of spatial order develops in the nascent great vessels. But after the normal vascular smooth muscle (VSM) progenitor cells in the great vessels are experimentally replaced by other VSM progenitor cells, the elastic extracellular matrix is congenitally disordered. The present study used this model to test the hypothesis that the proteoglycan decorin was involved in the establishment and maintenance of the normal three-dimensional spatial order of the vascular elastic matrix. The temporospatial expression of decorin was analysed during development of normal vessels and in experimental vessels with surrogate VSM. The results showed the following: (1) the expression of decorin was related in time and space to the establishment of large helical collagen type III fibers that are characteristic of the normal elastic extracellular matrix; (2) in the experimental extracellular matrix there were few helical fibers of collagen type III, but those that were present remained positive for decorin; and (3) in both control and experimental vessels, decorin associated with neither fibers of collagen type I nor fibers of collagen type III in any conformation other than the large helical fibers. These data indicate a previously unrecognized relationship between decorin and the spatial order of the physiologically significant helical fibers of collagen type III.

Animals↗
PubMed1998

Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes.

Cartilage oligomeric matrix protein (COMP) is a large extracellular glycoprotein that is found in the territorial matrix surrounding chondrocytes. Two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are caused by mutations in the calcium binding domains of COMP. In this study, we identified two PSACH mutations and assessed the effect of these mutations on redifferentiated chondrocyte structure and function. We confirmed, in vitro, that COMP is retained in enormous cisternae of the rough endoplasmic reticulum (rER) and relatively absent in the PSACH matrix. The rER accumulation may compromise chondrocyte function, leading to chondrocyte death. Moreover, while COMP appears to be deficient in the PSACH matrix, the matrix appeared to be normal but the over-all quantity was reduced. These results suggest that the abnormality in linear growth in PSACH may result from decreased chondrocyte numbers which would also affect the amount of matrix produced.

Achondroplasia↗
PubMed2002

Matrix-directed regulation of pericellular proteolysis and tumor progression.

The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and alphavbeta3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main 'decryptase'. ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of alpha3 chain of type IV collagen, through alphavbeta3 integrin binding, inhibits both MT1-MMP and alphavbeta3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII beta turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor. ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell-matrix interactions and MMP-2 activation pathway.

Animals↗
PubMed1997

Tissue matrix protein expression in human osteoblasts, osteosarcoma tumors, and osteosarcoma cell lines.

Treatment for osteosarcoma is problematic because there are no prognostic markers. Diagnosis is primarily limited to cytologic grading. Oncogenesis alters cell structure therefore osteoblast tissue matrix proteins (extracellular matrix, cytoskeletal, intermediate filament, and nuclear matrix proteins), components of the cell substructure, are candidates for osteosarcoma markers. Structural proteins of the extracellular matrix, e.g. the collagens, are useful for diagnosis but not for tumors that produce little osteoid. To identify principal cellular tissue matrix proteins that distinguish normal from transformed human osteoblasts, their expression in normal osteoblasts, two osteosarcoma cell lines, and three primary osteosarcoma tumors were compared. The tumors were graded as (i) intermediate, (ii) high, and (iii) high grade recurrent. The 1-D SDS/PAGE profiles of the major components of the nuclear matrix and intermediate filament fractions from normal osteoblasts did not vary with biopsy site, age, or sex of patients. These profiles included known cytoskeletal proteins and OB250, a approximately 250 kD protein(s) observed in the intermediate filament fraction. A loss of protein bands, including OB250, was observed in the osteosarcoma cell lines and tumors. The intermediate and high grade tumors exhibited nearly identical protein profiles including potential tumor-specific proteins and collagen, consistent with the presence of intracellular collagen fibers in osteosarcoma. A microsequence was obtained for OT25, a novel low molecular weight protein observed in osteosarcoma cell lines. Fibrinogen gamma-chain, a protein that mediates cell adhesion was recovered from the high grade recurrent tumor.

Adult↗
PubMed2002

Monocyte-macrophage differentiation in vitro: modulation by extracellular matrix protein substratum.

The influence of extracellular matrix (ECM) on monocyte-macrophage (mo-mphi) differentiation was investigated using an in vitro model with human peripheral blood mononuclear cells (PBMC) maintained on different matrix protein substrata. Macrophage specific markers associated with differentiation studied were, (a) endocytosis of modified proteins; (b) appearance of mphi specific matrix metalloproteinases (MMPs); (c) activities of myeloperoxidase (MPO) and beta-D-glucuronidase; (d) changes in the expression of cell surface antigens. As the duration of monocytes in culture increased, a progressive increase in the rate of differentiation was seen as evidenced by mphi specific functions such as endocytosis of 125[I] acetyl BSA and the appearance of gelatinases A and B. Significantly higher rate of endocytosis and production of MMPs were found in monocytes maintained on fibronectin (FN) and COL I than on COL IV (FN > COL I > COL IV) indicating that cells in contact with stromal components differentiate at a faster rate. FACS analysis done on cells maintained in vitro for phenotypic profile characteristic to mo-mphi differentiation showed downregulation of CD14 occurring in a substratum dependent manner viz, (FN > COL IV > COL I) and upregulation of CD71 was high in cells maintained on COL I and COL IV. Intracellular enzymatic activities such as MPO significantly decreased irrespective of matrix substrata, while beta-D-glucuronidase activity increased in a substratum dependent manner (FN > COL I > COL IV). Pretreatment of cells with genistein significantly decreased the secretion of MMPs, particularly MMP 9 in cells maintained on ECM protein (FN) indicating a phosphorylation dependent signalling process in mediating matrix effect. The results of these in vitro studies on mphi specific markers suggest that apart from the diffusible factors, the microenvironment as provided by various matrix proteins particularly FN can modulate mo-mphi differentiation.

Antigens, Surface↗
PubMed1992

Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1.

Transforming growth factor-beta (TGF-beta) has widespread effects on extracellular matrix production by many cultured cell lines and appears to play a role in the pathological accumulation of extracellular matrix that accompanies inflammatory and fibrotic diseases such as glomerulonephritis. Earlier experiments have shown that mesangial cells respond to TGF-beta 1 with a marked increase in the production of two chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, but their production of other matrix components elevated in glomerulonephritis is not substantially affected by TGF-beta 1. Since the glomerular epithelial cells are also thought to contribute to matrix production in the glomerulus, we examined the ability of these cells to produce some of the nonproteoglycan matrix components in response to TGF-beta 1. Exposure of glomerular epithelial cells to TGF-beta 1 increased the production of fibronectin and type IV collagen, in addition to biglycan. Enhancement of the cell layer accumulation of laminin was also observed. These results show that TGF-beta 1 has a differential effect on extracellular matrix production by epithelial and mesangial cells from glomeruli. TGF-beta 1 released in the glomerulus secondary to injury could thus affect both cell types and lead to increased intraglomerular production of proteoglycans, whereas the increased fibronectin, type IV collagen, and laminin may primarily originate from the epithelial cells.

Animals↗
PubMed1997

Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo.

Mesangial cell proliferation and matrix overproduction characterize many progressive glomerular diseases. Based on currently available data, the role of interleukin-6 (IL-6) in mediating mesangial cell proliferation and matrix production is controversial. The present study attempts to clarify this issue by showing that: (1) IL-6 knock out mice develop a normal glomerular architecture and in particular a normal mesangium. (2) Mesangioproliferative glomerulonephritis induced by Habu snake venom is equally severe in IL-6 knock out mice as in control mice. (3) A continuous seven-day intraperitoneal infusion of 50 micrograms recombinant human IL-6 into rats with a prior minimal (subnephritogenic) injury to mesangial cells does not induce glomerular cell activation, cell proliferation, matrix production, leukocyte influx, platelet influx or proteinuria. (4) A continuous seven-day IL-6 infusion into rats with mesangioproliferative nephritis (anti-Thy 1.1 nephritis) increases matrix protein transcription in the absence of detectable effects on matrix protein accumulation and otherwise has no effect on the natural course of the disease. We conclude from these findings that IL-6 is not an important mediator of mesangial cell proliferation and matrix overproduction in vivo, and that currently little rationale exists to advocate anti-IL-6 therapy in mesangioproliferative disease states.

Animals↗
PubMed2006

Extracellular matrix of the cumulus-oocyte complex.

The mammalian oocyte is surrounded by several layers of cumulus granulosa cells that nurture the oocyte during its development and actively participate in the process of ovulation. After the ovulatory luteinizing hormone surge, a distinctive program of extracellular matrix production is initiated in the cumulus-oocyte complex. This process known as cumulus expansion or mucification involves synthesis of a backbone of long hyaluronan oligosaccharide chains that are cross-linked by a complex of hyaluronan binding cell surface and extracellular matrix proteins and proteoglycans. Active components of the cumulus matrix are synthesized directly by cumulus cells under the control of endocrine- and oocyte-derived factors, secreted by mural granulosa cells, or enter the follicle in blood plasma. Appropriate composition and assembly of the cumulus matrix is essential for ovulation, efficient passage of the oocyte through the oviduct, and for fertilization. This review describes the critical components and their functional roles in the cumulus matrix, as well as the molecular regulation of cumulus matrix gene expression.

Animals↗
PubMed2002

Fluid flow increases mineralized matrix deposition in 3D perfusion culture of marrow stromal osteoblasts in a dose-dependent manner.

Bone is a complex highly structured mechanically active 3D tissue composed of cellular and matrix elements. The true biological environment of a bone cell is thus derived from a dynamic interaction between responsively active cells experiencing mechanical forces and a continuously changing 3D matrix architecture. To investigate this phenomenon in vitro, marrow stromal osteoblasts were cultured on 3D scaffolds under flow perfusion with different rates of flow for an extended period to permit osteoblast differentiation and significant matrix production and mineralization. With all flow conditions, mineralized matrix production was dramatically increased over statically cultured constructs with the total calcium content of the cultured scaffolds increasing with increasing flow rate. Flow perfusion induced de novo tissue modeling with the formation of pore-like structures in the scaffolds and enhanced the distribution of cells and matrix throughout the scaffolds. These results represent reporting of the long-term effects of fluid flow on primary differentiating osteoblasts and indicate that fluid flow has far-reaching effects on osteoblast differentiation and phenotypic expression in vitro. Flow perfusion culture permits the generation and study of a 3D, actively modeled, mineralized matrix and can therefore be a valuable tool for both bone biology and tissue engineering.

Alkaline Phosphatase↗
PubMed1998

Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells.

Matrix metalloproteinases (MMPs) are hypothesized to play a key role in the processes of endothelial cell migration and matrix remodeling during angiogenesis. We utilized an in vitro model of microvascular endothelial cell angiogenesis, cells cultured within a collagen matrix, to investigate the MMP profile of endothelial cells undergoing angiogenesis. We demonstrated by gelatin zymography that monolayer cultures (two-dimensional) of endothelial cells constitutively expressed low levels of latent MMP-2, but that culture in a three-dimensional collagen matrix increased the total amount of MMP-2 mRNA and protein. Furthermore, 51% of total MMP-2 protein was activated in the three-dimensional culture lysates, compared with 3.5% in two-dimensional culture. The mRNA and protein of MT1-MMP, the putative activator of MMP-2, were up-regulated in endothelial cells cultured in three-dimensional as compared with two-dimensional culture. Treatment of cultures with MMP inhibitors blocked activation of MMP-2 and inhibited formation of endothelial cell networks within the collagen gel. Induction of MT1-MMP and MMP-2 appeared to be specific to collagen, inasmuch as culture of the endothelial cells on top of, or within, a Matrigel(R) matrix neither increased total MMP-2 nor increased activation of MMP-2. These results suggest that MT1-MMP activation of MMP-2 occurs in endothelial cells undergoing angiogenesis, that this activation has a functional role in endothelial cell organization, and that specific matrix interactions may be critical for the increased expression of MT1-MMP and MMP-2.

Animals↗
PubMed1999

Extracellular matrix deposition and cell proliferation in a model of chronic glomerulonephritis in the rat.

BACKGROUND: Resident glomerular cell proliferation, matrix deposition and secretion of matrix metalloproteinases play a major role in the progression of chronic glomerular disease. These features were studied in a novel approach in a rat model of chronic glomerulonephritis induced by four injections of an anti-Thy 1.1 antiserum at weekly intervals. METHODS: Chronic immune mediated mesangial injury was induced in male Sprague-Dawley rats by repeated intravenous injection of an anti-Thy 1.1 antiserum. One week after the first and fourth injection of the antiserum proteinuria was evaluated and the kidneys were removed. Immunohistology was performed for proliferating cells, monocytes and collagen type IV. Furthermore, mRNA expression of collagen type IV, TGF-beta and the matrix degrading enzyme MMP-2 as well as MMP-2 protein expression were studied. RESULTS: Urinary protein excretion was dramatically increased after one antiserum injection and stayed elevated at a lower level after the fourth antiserum injection. After the initial induction of nephritis, 7 days following antiserum, resident glomerular cell proliferation was increased whereas with repeated injections of the antiserum cell numbers were not different from controls, as measured 1 week after the fourth injection. In contrast, extracellular matrix accumulation (collagen type IV) increased after the first antiserum injection and further increased after the fourth antiserum injection. The mRNA expression for collagen type IV increased after the first antiserum injection and showed further increase after the fourth antiserum injection. Induction of nephritis also stimulated glomerular mRNA expression of MMP-2 and TGF-beta, both of which remained at a high level after the fourth antiserum injection. Glomerular protein levels of MMP-2 also increased after the first antiserum injection and showed a further slight increase after the fourth injection. CONCLUSION: Increased cellular proliferation is involved in an early stage of this disease, while enhanced expression of glomerular matrix and augmented mRNA and protein expression of the matrix degrading enzyme MMP-2 continue into the chronic phase, and contribute to the extensive structural remodeling process that accompanies this form of glomerular injury.

Animals↗
PubMedDate not supplied

Controlling myocardial matrix remodeling: implications for heart failure.

Progressive congestive heart failure (CHF) is often accompanied by a change in left ventricular geometry and myocardial architecture, commonly referred to as myocardial remodeling. It has been observed that important changes occur within the collagen matrix of the myocardium, potentially contributing to the remodeling process. The myocardial collagen matrix is influenced by 2 fundamental processes: collagen synthesis and collagen degradation. Matrix metalloproteinases are an endogenous family of zinc-dependent enzymes involved in matrix degradation and have been shown to be regulated by a class of proteins called the tissue inhibitors of metalloproteinases. Several studies have identified changes in myocardial matrix metalloproteinase and tissue inhibitors of metalloproteinase expression with the development of CHF. These observations have led to the hypothesis that increased metalloproteinase activity and decreased levels of tissue inhibitors of metalloproteinase result in collagen remodeling that disrupts myocyte alignment and facilitates the left ventricular remodeling process with CHF. Thus, the development of pharmacologic agents that will modulate the activity and expression of myocardial matrix metalloproteinases represents a new and potentially significant therapeutic target for developing CHF.

Animals↗
PubMed2006

Matrix metalloproteinase expression in the spondyloarthropathies.

PURPOSE OF REVIEW: Expression of matrix metalloproteinases and their tissue inhibitors has been an active area of investigation in rheumatoid arthritis and osteoarthritis. Only recently have investigators started to study these factors in spondyloarthropathy. The purpose of this review is to summarize these recent findings. RECENT FINDINGS: Multiple matrix metalloproteinases and their tissue inhibitors are expressed in the synovial fluid as well as serum samples of spondyloarthropathy patients. Their degrees of expression in the synovia correlate with parameters of arthritis activity such as cell infiltration. In the synovial fluids, the factor which is expressed in very high level is matrix metalloproteinase-3. Two separate cohorts demonstrate that serum levels of matrix metalloproteinase-3 correlate with disease activity in ankylosing spondylitis. Their usefulness appears to exceed those of erythrocyte sedimentation rate and C-reactive protein. Multiple studies also indicate that serum levels of matrix metalloproteinase-3 are suppressed when patients are treated with the anti-tumor necrosis factor-alpha antibody infliximab. SUMMARY: New biomarkers are in demand for spondyloarthropathy in deciding whether patients would benefit from treatment with tumor necrosis factoralpha blockers, monitoring response to treatment, or predicting potential of joint damage if untreated. Recent studies show that among the matrix metalloproteinase and their tissue inhibitors, serum MMP-3 is the one with potential usefulness.

Antibodies, Monoclonal↗