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PubMed1993

Specificity in the interactions of extracellular matrix proteins with subpopulations of the glycosaminoglycan heparin.

Many extracellular matrix glycoproteins--including laminin, fibronectin, thrombospondin, type I collagen, and other collagens--bind the glycosaminoglycan heparin, yet little is known about the functional significance of these interactions. It is also not known if heparin-binding extracellular matrix proteins recognize distinct structural elements in heparin, nor whether all extracellular matrix proteins recognize the same or different aspects of heparin structure. If extracellular matrix proteins each recognize distinct features of heparin, such specificity could be of importance in vivo, where structurally distinct heparan sulfate species occur. To investigate specificity in the binding between extracellular matrix proteins and heparin, the method of affinity coelectrophoresis (ACE) was used [Lee, M. K., & Lander, A. D. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2768-2772]. Low M(r) (approximately 6 kDa) 125I-heparin was fractionated by electrophoresis through agarose gel lanes containing extracellular matrix proteins at various concentrations; from heparin migration patterns, binding affinities were calculated. The results indicate that fibronectin, type I collagen, and laminin--but not thrombospondin--each fractionate heparin into subpopulations that differ substantially in binding affinity. From ACE gels containing either fibronectin, type I collagen, or laminin, fractions of heparin were isolated that represent the 25% of molecules most strongly bound and the 25% least strongly bound by each of these proteins. Subsequent ACE analysis of these six fractions showed that (1) for each of fibronectin, type I collagen, and laminin, strongly- and weakly-binding heparin subfractions differ approximately 5-30-fold in Kd; (2) heparin that binds strongly to any one of fibronectin, type I collagen, or laminin also binds strongly to the other two; (3) heparin that binds weakly to any one of fibronectin, type I collagen, or laminin, also binds weakly to the other two; (4) heparin subfractions that differ greatly in affinity for fibronectin, type I collagen, and laminin show little difference in Kd for thrombospondin or for the heparin-binding growth factor basic fibroblast growth factor (bFGF); (5) neither heterogeneity in molecular charge [as measured by diethylaminoethyl (DEAE) chromatography] nor size nor the presence or absence of antithrombin III recognition sequences can account for the selective binding of heparin subpopulations to fibronectin, type I collagen, and laminin. These results suggest that structural elements within heparin can confer preferential binding to extracellular matrix proteins. Sensitivity of some, but not all, extracellular matrix proteins to these structural features suggests that similar features, if present in heparan sulfates or other glycosaminoglycans, may be physiologically relevant in vivo.

Antithrombin III↗
PubMed2003

Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis.

The goal of this study was to discover novel partners for perlecan, a major heparan sulfate proteoglycan of basement membranes, and to examine new interactions through which perlecan may influence cell behavior. We employed the yeast two-hybrid system and used perlecan domain V as bait to screen a human keratinocyte cDNA library. Among the strongest interacting clones, we isolated a approximately 1.6-kb cDNA insert that encoded extracellular matrix protein 1 (ECM1), a secreted glycoprotein involved in bone formation and angiogenesis. The sequencing of the clone revealed the existence of a novel splice variant that we name ECM1c. The interaction was validated by co-immunoprecipitation studies, using both cell-free systems and mammalian cells, and the specific binding site within each molecule was identified employing various deletion mutants. The C terminus of ECM1 interacted specifically with the epidermal growth factor-like modules flanking the LG2 subdomain of perlecan domain V. Perlecan and ECM1 were also co-expressed by a variety of normal and transformed cells, and immunohistochemical studies showed a partial expression overlap, particularly around dermal blood vessels and adnexal epithelia. ECM1 has been shown to regulate endochondral bone formation, stimulate the proliferation of endothelial cells, and induce angiogenesis. Similarly, perlecan plays an important role in chondrogenesis and skeletal development, as well as harboring pro- and anti-angiogenic activities. Thus, a physiological interaction could also occur in vivo during development and in pathological events, including tissue remodeling and tumor progression.

Amino Acid Sequence↗
PubMed1998

VLA-5 is expressed by mouse and human long-term repopulating hematopoietic cells and mediates adhesion to extracellular matrix protein fibronectin.

Fibronectin (FN), an extracellular matrix protein, is involved in the adhesion and migration of hematopoietic cells and has been shown to enhance retroviral gene transfer into primitive hematopoietic cells by co-localization of target cells and retrovirus when used as a substrate in vitro. We have previously found that mouse hematopoietic stem cells could be transduced on a FN fragment that included the recognition sequence Arg-Gly-Asp (RGD), suggesting that stem cells may express the integrin very late antigen (VLA)-5. To address this, we investigated the binding of mouse and human hematopoietic cells to recombinant peptides that contained one or a combination of the three principle cell-binding domains of FN. These domains included the VLA-5- binding sequence RGD, the VLA-4-binding site CS1, and the high affinity heparin-binding domain. Here we show that mouse long-term in vivo repopulating stem cells, as well as primitive human NOD/SCID mouse repopulating cells, can bind extracellular matrix protein FN by using integrin VLA-5 in vitro. This binding is specific and can be inhibited by antibodies to VLA-5. In addition, preincubation of BM cells with peptide CH-296, which contains all three primary FN-binding domains, decreased the engraftment of cells in the bone marrow in vivo, while intravenous injection of the same peptide induced an increase of progenitor cells in the spleen. In summary, our data demonstrate that VLA-5 is expressed on primitive mouse and human hematopoietic cells and suggest that there may be significant cooperation between integrin receptors and proteoglycan molecules in the engraftment of bone marrow cells and hematopoietic cell adhesion in vivo.

Animals↗
PubMed1994

Inhibition of T cell activation by the extracellular matrix protein tenascin.

Tenascin (TN) is an extracellular matrix protein that is expressed widely in the fetus and sparingly in the adult, but reappears at high levels in certain areas of tissue insult such as tumor matrices and sites of wound healing. We show here that soluble TN inhibits proliferation of human T cells in response to alpha CD3 Ab co-immobilized with the extracellular matrix protein fibronectin (FN). TN also inhibits proliferation driven by alpha CD3/IL-2 or by phorbol ester/IL-2, and it prevents high level induction of IL-2R. The presence of TN in culture medium does not detectably alter the pattern of tyrosine phosphorylation resulting from T cell triggering with alpha CD3, but at later time points prevents the appearance of functional NF-AT1 transcription factor complexes in T cell nuclear extracts. These findings are consistent with the postulated role for TN as a natural antagonist to FN action, and suggest that T cell responses occurring at tissue sites in which TN is expressed could be influenced by its presence.

Base Sequence↗
PubMed1995

Extracellular matrix proteins and leukocyte function.

Extracellular matrix (ECM) proteins profoundly affect physiological functioning at the cellular level. Cell growth and differentiation, as well as cell shape and migration via the cytoskeleton, are all affected by ECM proteins. Leukocyte interactions with matrices have recently become an exciting field of research because a number of different leukocyte functions are significantly affected by their binding to ECM proteins. This may be especially important in inflammatory responses where leukocytes are primed for inflammatory mediator and cytokine production by binding to ECM proteins during extravasation. Because activated leukocytes produce potentially damaging substances, the progress of an inflammatory response can be profoundly affected by the ECM proteins encountered by leukocytes during their migration from within the peripheral circulation to sites of inflammation. This review summarizes recent publications describing components of the ECM that influence leukocyte function, the receptors involved in leukocyte binding to ECM proteins, and focuses on the effects of ECM proteins on the production of inflammatory mediators and cytokines by human peripheral blood leukocytes.

Animals↗
PubMed1992

Integrins as receptors for extracellular matrix proteins in human cornea.

Extracellular matrix (ECM) proteins form distinct protein families that play a role during tissue maturation, wound healing and maintenance of tissue architecture. Recent studies show that there are tissue type-specific variations in their expression. ECM proteins function by complexing with each other and also by interacting with their cellular receptors, called integrins. Integrins are heterodimeric membrane glycoproteins that are partly cell type-specifically expressed in human tissues. Like other stratified epithelia, corneal epithelium expresses alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, 4, and alpha v beta 1 integrins that mediate attachment to the basement membrane and cell-cell interactions.

Basement Membrane↗
PubMed1994

Regulatory role of transforming growth factor-beta, bone morphogenetic protein-2, and protein-4 on gene expression of extracellular matrix proteins and differentiation of dental pulp cells.

The expression of developmental stage-specific genes during pulp cell differentiation into preodontoblasts was examined in bovine adult pulp cell culture. When proliferation was down-regulated after 14 days of primary culture, expression of fibronectin and type I and type III collagen mRNAs was increased. Expression of alkaline phosphatase was gradually increased, and mRNA for osteocalcin, a marker of preodontoblast, appeared just before the onset of mineralization. Contrarily, in expanded culture, the expression of mRNA for the extracellular matrix proteins was gradually increased from the beginning of culture up to Day 28. Similarly, mRNA levels of alkaline phosphatase and osteocalcin were also increased gradually. Expression of TGF-beta 1 mRNA disappeared on Day 21 in the primary culture when expression of alkaline phosphatase mRNA was increased. BMP-4 mRNA was expressed on Day 14 when the expression of the extracellular matrix proteins was increased. BMP-2 mRNA was expressed on Day 28 when osteocalcin appeared. Recombinant TGF-beta 1 inhibited alkaline phosphatase activity, while BMP-2 and BMP-4 stimulated it. BMP-4 increased expression of alpha 1(I) collagen mRNA, and BMP-2 increased osteocalcin synthesis. These results demonstrate the regulatory role of these TGF-beta superfamily members on the gene expression of extracellular matrix proteins and the differentiation of pulp cells into preodontoblasts.

Alkaline Phosphatase↗
PubMed1981

Extracellular matrix proteins characterize human tumor cell lines.

Extracellular matrix proteins synthesized and secreted by adherent human tumor cell lines were analyzed using metabolic labelling with glycine and proline in the presence of ascorbate, polypeptide analysis and polyacrylamide gel electrophoresis, affinity chromatography, collagenase digestion, and immunofluorescence staining. The results showed a characteristic pattern of matrix proteins for each tumor cell type. Tumor cell lines of mesenchymal origin produced mostly interstitial types (I and II) of collagen and fibronectin. Carcinoma cell lines secreted only basement membrane proteins, type IV collagen, laminin and fibronectin, but not interstitial collagen. A melanoma and a rhabdomyosarcoma cell line produced type V of procollagen that has not previously been described in cell culture. Neuroblastoma cells were shown to be phenotypically heterogeneous also with respect to matrix protein production. We propose that the analysis of extracellular matrix proteins may serve as an adjunct in the classification of human tumors.

Cell Line↗
PubMedDate not supplied

Puromycin aminonucleoside and adriamycin disturb cytoskeletal and extracellular matrix protein organization, but not protein synthesis of cultured glomerular epithelial cells.

Puromycin aminonucleoside (PA) and Adriamycin (ADR) cause glomerular proteinuria associated with degenerative alterations of glomerular visceral epithelial cells (GVEC) and detachment from the glomerular basement membrane when administered to rats. This in vitro study was performed to define, in detail, the quantitative and qualitative changes of a number of adhesion-associated proteins (cytoskeletal, extracellular matrix and integrin proteins) upon exposure to PA and ADR. By immunofluorescence we observed: (1) dose- and incubation-time-dependent filament pattern changes and decreased staining of the cytoskeletal proteins actin, vimentin, keratin, and beta-tubulin; (2) an altered distribution, and decreased expression of the extracellular matrix proteins laminin and heparan sulfate and (3) a loss of the beta 1-integrin focal adhesions upon exposure to PA and ADR. Using an ELISA, a concentration-dependent decrease was found (a 50% reduction with 50 micrograms/ml PA for 48 h and with 2 micrograms/ml ADR for 24 h) in the production of cytoskeletal and extracellular matrix proteins per cell. These general effects were suggestive of a disturbance of protein synthesis but, by metabolic labelling studies, no reduction in overall protein synthesis was found. Using two-dimensional PAGE on 35S-methionine steady-state labeled cells, no changes were found in intracellular protein patterns of PA- and ADR-treated cells (pH 5-7.5, MW 110-20 kD). We hypothesize that exposure of GVEC in vitro to PA and ADR might result, directly or indirectly, in perturbation of the macromolecular organization of cytoskeletal and extracellular matrix proteins with loss of GVEC adhesion.

Animals↗
PubMed1998

Oxidative modification of low-density lipoprotein enhances mesangial cell protein synthesis and gene expression of extracellular matrix proteins.

The proliferation of intrinsic glomerular cells and the accumulation of extracellular matrix proteins are principal histopathological features seen in glomerular injury. Because of the marked similarity between the cellular and molecular events that occur in both atherosclerosis and glomerulosclerosis and the commonly accepted hypothesis that lipoproteins are implicated in the pathogenesis of glomerulosclerosis, we examined the effect of three atherogenic lipoproteins, low-density lipoprotein (LDL), oxidized (ox)-LDL, and minimally modified (mm)-LDL on the synthesis and secretion of extracellular matrix (ECM) proteins by mesangial cells. The incubation of SV-40 transformed murine mesangial cells with LDL (25-100 microg/ml) increased the synthesis and secretion of both fibronectin and laminin in a dose-dependent manner. Similarly, oxidized forms of LDL (25-100 micro/ml) increased fibronectin and laminin synthesis and secretion dose dependently. However, both oxidatively modified forms of LDL had a greater effect on increasing ECM protein synthesis than their native counterpart. Northern blot analysis showed a dose-dependent increase in mRNA transcripts for fibronectin and laminin in response to the incubation of mesangial cells with LDL, ox-LDL, and mm-LDL. Similar to the ECM protein expression data, the oxidatively modified forms of LDL had more pronounced effects on the gene expression of both fibronectin and laminin. These data show that both LDL and, perhaps more importantly, its oxidatively modified forms stimulate mesangial cells to upregulate both the gene expression and synthesis and secretion of ECM proteins, supporting a role for atherogenic lipoproteins in the pathobiology of glomerular injury.

Animals↗
PubMed1995

Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein.

Relative to other noncollagenous, extracellular matrix proteins in mineralized tissues, colloidal-gold immunocytochemistry has demonstrated that the ultrastructural distribution of osteopontin (OPN) is unique in that this protein preferentially accumulates at mineralized tissue interfaces. In bone, this protein is present as a major component of cell-matrix and matrix-matrix interfacial structures called cement lines and laminae limitantes. In the present article, the implications of this distinct tissue distribution are discussed in terms of the bone remodeling sequence, and a detailed account of the secretion, accumulation and potential role of OPN is presented and related to current theory on the cellular and extracellular matrix events associated with basic multicellular unit (BMU)-based bone remodeling. In this context, a proposal is made describing the production of this protein as one of the earliest, and latest, secretory activities of the osteoblastic lineage, and that this activity manifests itself morphologically as a cement line ('plane') and a lamina limitans, respectively, at bone matrix interfaces. When integrated with other, known functional characteristics of this protein, the present morphological and compositional data indicate that OPN in cement lines and laminae limitantes may participate in initial and late extracellular matrix organization and mineralization, matrix-matrix/mineral adhesion and/or cell adhesion at bone interfaces.

Animals↗
PubMed2004

The role of extracellular matrix protein 1 in human skin.

Extracellular matrix protein 1 (ECM1) was first identified in 1994 as an 85-kDa glycoprotein secreted by a mouse osteogenic stromal cell line. Subsequently, the human homologue has been found to regulate endochondral bone formation, and to stimulate proliferation of endothelial cells and induce angiogenesis. However, a role for ECM1 in skin physiology and homeostasis has also emerged. Specifically, in 2002, loss-of-function mutations in the ECM1 gene were discovered to be the cause of the rare autosomal recessive genodermatosis, lipoid proteinosis. This inherited disorder is characterized clinically by skin and mucosal infiltration and scarring and histologically by disruption/duplication of basement membrane and widespread deposition of hyaline material in the dermis. Moreover, other recent studies have identified circulating autoantibodies against the ECM1 protein in most patients with lichen sclerosus, a common chronic inflammatory condition that shares some clinicopathological features with lipoid proteinosis. ECM1 thus serves as a target antigen in both an inherited and an acquired skin disorder. Within the epidermis, ECM1 has a role in the control of keratinocyte differentiation. Within the dermis, ECM1 binds to the major heparan sulphate proteoglycan, perlecan. In this way, ECM1 may act as a "biological glue" in the dermis, helping to regulate basement membrane and interstitial collagen fibril macro-assembly and growth factor binding. ECM1 may also have a role in other acquired skin disorders and physiological skin changes including scarring, wound healing and skin ageing, although this remains to be determined.

Cell Division↗
PubMed1995

Focal brain injury and upregulation of a developmentally regulated extracellular matrix protein.

Tenascin is an extracellular matrix glycoprotein expressed during both normal development and neoplastic growth in both neural and nonneural tissues. During development of the central nervous system (CNS), tenascin is synthesized by glial cells, in particular by immature astrocytes, and is concentrated in transient boundaries around emerging groups of functionally distinct neurons. In the mature CNS, only low levels of the glycoprotein can be detected. The present study demonstrates that following trauma to the adult human cerebral cortex, discrete populations of reactive astrocytes upregulate their expression of tenascin and dramatically increase their transcription of the tenascin gene. The enhanced expression of tenascin may be involved in CNS wound healing, and may also affect neurite growth within and around a brain lesion.

Adult↗
PubMed2002

Deficiency of a 180-kDa extracellular matrix protein in Fukuyama type congenital muscular dystrophy skeletal muscle.

Abnormalities of the proteins constituting the extracellular matrix have been shown to play important roles in the molecular pathogenesis of muscular dystrophies. In the present study, we have established a monoclonal antibody against a human skeletal muscle extracellular matrix protein. The antibody M1 recognized a single 180-kDa protein (p180) by immunoblot analysis of normal human skeletal muscle and gave a strong and continuous signal along the sarcolemma by immunohistochemical analysis. Furthermore, p180 could be solubilized either under a strong alkaline condition, or in the presence of EDTA or detergents such as Triton X-100, indicating that p180 was an extracellular matrix protein. Interestingly, p180 was deficient in the skeletal muscle of the patients with Fukuyama-type congenital muscular dystrophy (FCMD), but not other muscular diseases, by both immunohistochemical and immunoblot analyses. We presume that the deficiency of p180 in FCMD is caused specifically by the primary deficiency of fukutin, the causative protein of FCMD, and plays an important role in muscle cell degeneration in this disease.

Animals↗
PubMed1991

Common structural motifs in proteins of the extracellular matrix.

Proteins of the extracellular matrix are composed of many structurally and often functionally different autonomous domains which frequently occur as modular units in several different extracellular matrix proteins, but also in proteins of different origin. Some domains serve related assembly functions in different proteins but for domains involved in cell attachment and other cellular activities only a few generalizations are possible.

Animals↗
PubMed2006

[Isolation of human basal keratinocytes by selective adhesion to extracellular matrix proteins].

Epidermal human cells (keratinocytes) differently interact with extracellular matrix proteins of the skin basal membrane depending on the stages of their differentiation. The pool of basal keratinocytes commonly includes stem cells and transient amplifying cells. They directly attach to the skin basal membrane. Keratinocytes change their adhesive properties during differentiation, lose direct interaction with the basal membrane and move to suprabasal epidermal strata. From this, it is suggested that basal and primarily stem cells can be isolated from a heterogenous keratinocyte population due to their selective adhesion to the extracellular matrix proteins. In the current study, we analysed the specificity of interaction between primary keratinocytes and extracellular matrix proteins (collagens of I and IV types, laminin-2/4, fibronectin and matrigel). We have demonstrated that the basal keratinocytes extracted from the skin have different adhesive abilities. The rapidly spreading cells usually interacted with collagen and fibronectin rather that with laminin-2/4 or matrigel. The majority of these cells being represented by basal keratinocytes. Our data demonstrate that the applied method of keratinocyte selection may be directed for precise isolation of skin stem from a common cell population.

Cell Adhesion↗
PubMed2001

Distribution of cytoskeletal proteins, integrins, leukocyte adhesion molecules and extracellular matrix proteins in plastic-embedded human and rat kidneys.

OBJECTIVE: To study the distribution of cytoskeletal proteins (actin, alpha-actinin, vinculin, beta-tubulin, keratin, vimentin, desmin), adhesion molecules for cell-matrix interations (very later antigens [VLA1-61, beta1, beta2 [CD18], vitronectin receptor [alphavbeta3], CD 11b), leukocyte adhesion molecules (ICAM-1) and extracellular matrix proteins (collagen IV, fibronectin, laminin, vitronectin) in human and rat kidneys by using a superior processing and immunohistochemical staining technique. STUDY DESIGN: Human and rat kidneys were fixed in 2% paraformaldehyde, dehydrated in acetone and processed in a new, low-toxic glycol, methacrylate mixture, especially developed for immunohistochemistry. Both the glomeruli and the interstitial areas were carefully examined and scored semiquantitatively. RESULTS: Immunostained plastic sections showed excellent morphology combined with remarkably well preserved antigenicity. CONCLUSION: The above mentioned provides an excellent tool for the accurate localization of a wide variety of antigens at the light microscopic level.

Animals↗