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PubMed2006

[Effect of jiangu granule on levels of urinary deoxypyridinoline and osseous intigrin beta1 mRNA expression in Ovariectomized osteoporosis model rats].

OBJECTIVE: To investigate the regulatory effect of Jiangu Granule (JGG) on osteoblast and its effect on bone absorption on the molecular level and from aspect of bone metabolism. METHODS: Osteoporosis model SD rats established by ovariectomy were interfered by drug. Levels of urinary deoxypyridinoline (D-Pyr) and osseous integrin beta1 (Itgbeta1) mRNA expression were detected by ELISA and in situ hybridization, respectively. RESULTS: Level of urinary D-Pyr increased (P < 0.01) and osseous Itgbeta1 mRNA expression decreased significantly in the model rats. After treatment with JGG for 12 weeks, the D-Pyr levels in them decreased significantly (P < 0.05), while the quantity of osteoblasts and the expression of Itgbeta1 mRNA in bone tissue increased obviously. Conclusion JGG can not only decrease the catabolism of collagen fiber type I in bone matrix, but also promote the osteogenic activity of osteoblast. So, it can improve or reverse the pathological tendency of osteogenesis shortage caused by E2 reduction to play its action in strengthening bone.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Cell type-dependent collagen-type recognition by cell receptors.

Affinity chromatography of a number of cell types on collagens I and III reveals three proteins with M(R)of 250, 170 and 140 kDa. These proteins are able to discriminate between types I and III, but not types III and IV. Collagen-type recognition is therefore characteristic for cells of connective tissue origin. Polyclonal antibodies (Ab) raised against 170 and 140 kDa polypeptides and used in immunofluorescence show membrane localisation for both, with their distribution being similar to each other and to the distribution of the integrin beta1 chain. Ab p140 and commercial monoclonal antibodies against alpha(2)chain stain a band of the same molecular mass as from purified collagen binding proteins from liver cells, indicating that the 140 kDa protein is probably the alpha(2)integrin chain. The alpha(2)chain containing integrins are therefore able to discriminate collagen types I and III and collagen type recognition by this receptor is cell-type dependent.

Animals↗
PubMed2004

Rewiring cell adhesion.

The adhesion of cells is mediated by the binding of several cell-surface receptors to ligands found in the extracellular matrix. These receptors often have overlapping specificities for the peptide ligands, making it difficult to understand the roles for discrete receptors in cell adhesion, migration, and differentiation as well as to direct the selective adhesion of cell types in tissue-engineering applications. To overcome these limitations, we developed a strategy to rewire the receptor-ligand interactions between a cell and substrate to ensure that adhesion is mediated by a single receptor with unique specificity. The strategy combines a genetic approach to engineer the cell surface with a chimeric integrin receptor having a unique ligand binding domain with a surface chemistry approach to prepare substrates that present ligands that are bound by the new binding domain. We show that Chinese hamster ovary cells that are engineered with a chimeric beta1 integrin adhere, signal, and even migrate on a synthetic matrix.

Animals↗
PubMed2005

Inhibition of pathologic retinal neovascularization by alpha-defensins.

Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that alpha-defensins interfere with alpha5beta1-FN interactions and dependent endothelial cell functions. Here, alpha-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, alpha-defensins specifically inhibited alpha5beta1-integrin-dependent migration of bovine retinal endothelial cells (BRECs) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in 3-dimensional fibrin-matrices. An up-regulation of beta1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of alpha-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of alpha5beta1-blocking antibody. alpha-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that alpha-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.

Animals↗
PubMed2002

Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins.

Mast cells are inflammatory and immunoregulatory cells resident in tissues. They develop from bone marrow-derived progenitor cells that enter the tissue through the blood circulation. The specific localization and migration of mast cells in tissues is dependent on their interaction with extracellular matrix (ECM) proteins. Adhesion of human mast cells isolated from intestinal mucosa and cultured in the presence of stem cell factor (SCF) to ECM proteins is analyzed. It was observed that SCF is a unique cytokine enhancing mast cell adhesion to all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI, XIV) up to 5-fold, particularly to fibronectin (54% +/- 12% of mast cells) and to denatured collagens (40% +/- 12% on cyanogen bromide-cleaved peptides of collagen I). Most noteworthy, preculture of mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their potency to adhere to ECM proteins to one third compared to mast cells cultured with SCF alone. Mast cell adhesion was preferentially mediated by beta1 integrins, and most cells expressed the ECM-binding integrins alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, and alphaVbeta3. SCF-induced mast cell adhesion was totally blocked by wortmannin and apigenin, indicating an involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, and it was related to an up-regulation of the HUTS-21 beta1 epitope, which is associated with an activated conformation of beta1. In conclusion, these data indicate that SCF induces the adhesion of cultured mast cells to ECM proteins, whereas IL-4 may promote detachment from the ECM.

Cell Adhesion↗
PubMed1997

Neuronal differentiation in SH-SY5Y human neuroblastoma cells induces synthesis and secretion of tenascin and upregulation of alpha(v) integrin receptors.

Human SH-SY5Y neuroblastoma cells were induced to neuronal differentiation by using 12-0-tetradecanoylphorbol-13-acetate (TPA) and retinoic acid (RA). Both treatments rapidly induced long neurites and increased the content of neurofilaments as shown by immunocytochemistry and immunoblotting. Immunoprecipitation and immunoblotting of the culture medium with monoclonal antibodies demonstrated a rapid onset of synthesis and secretion of Mr 280,000 tenascin (Tn) polypeptide with TPA and both Mr 280,000 and 190,000 Tn polypeptides with RA and an increased secretion of extradomain A cellular fibronectin (EDA-Fn) upon both treatments. Upon RA treatment both Tn polypeptides were also found in extracellular matrix preparations of the differentiated cells. A diffuse extracellular Tn immunoreactivity and a distinct cytoplasmic reaction were seen in differentiated cells especially after exposure to monensin to inhibit cellular secretion. Instead, immunoprecipitation experiments suggested that laminin was synthesized by the cells but was not upregulated upon differentiation. Experiments with purified Tn, used to coat the culture substratum, demonstrated that the undifferentiated cells were unable to adhere or spread on Tn but rapidly acquired the spreading capacity upon differentiation with the inducing agents. In immunofluorescence and immunoblotting the undifferentiated cells presented only a faint heterogenous reaction for beta1 integrin (Int) subunit, whereas cells exposed to RA presented a strong reaction for the Int alpha1 and beta1 subunits, hence suggestive of Int alpha1beta1, and for Int alpha(v) subunit. Cells exposed to TPA showed an enhanced immunoreaction for Int alpha2 and beta1 subunits, suggestive of Int alpha2beta1, and for Int alpha(v) subunit. Immunoreactivity for Int alpha(v) located to distinct punctate plaques in the differentiated cells after both inducing agents. The results suggest that Tn is produced by cultured neuronally differentiating cells, and it is accompanied by the acquitance of an adhesion receptor for Tn.

Antigens, CD↗
PubMed2005

Reelin, integrin and DAB1 interactions during embryonic cerebral cortical development.

Extracellular matrix-like molecule reelin and cell surface adhesion receptors such as alpha3beta1 integrin can regulate neuronal migration and position in the developing cerebral cortex. Here we show that alpha3beta1 integrin binds to the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with other reelin receptors such as VLDLR/ApoER2. Furthermore, Dab1, a member of the reelin signaling pathway, can complex with the cytoplasmic region of beta1 integrin in a reelin-dependent manner. Thus, alpha3beta1 integrin-reelin interactions may contribute to appropriate neuronal placement in the developing cerebral cortex.

Animals↗
PubMedDate not supplied

Cell adhesion molecules, leukocyte trafficking, and strategies to reduce leukocyte infiltration.

Leukocyte-endothelial cell interactions are mediated by various cell adhesion molecules. These interactions are important for leukocyte extravasation and trafficking in all domestic animal species. An initial slowing of leukocytes on the vascular endothelium is mediated by selectins. This event is followed by (1) activation of beta2 integrins after leukocyte exposure to cytokines and pro-inflammatory mediators, (2) adherence of leukocyte beta2 integrins to vascular endothelial ligands (eg, intercellular adhesion molecule-1 [ICAM-1]), (3) extravasation of leukocytes into tissues through tight junctions of endothelial cells mediated by platelet and endothelial cell adhesion molecule-1 (PECAM-1), and (4) perivascular migration through the extracellular matrix via beta1 integrins. Inhibiting excessive leukocyte egress and subsequent free radical-mediated damage caused by leukocyte components may attenuate or eliminate tissue damage. Several methods have been used to modify leukocyte infiltration in various animal models. These methods include nonspecific inhibition of pro-inflammatory mediators and adhesion molecules by nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, inhibition of cytokines and cytokine receptors, and inhibition of specific types of cell adhesion molecules, with inhibitors such as peptides and antibodies to beta2 integrins, and inhibitors of selectins, ICAMs, and vascular cell adhesion molecule-1 (VCAM-1). By understanding the cellular and molecular events in leukocyte-endothelial cell interactions, therapeutic strategies are being developed in several animal models and diseases in domestic animal species. Such therapies may have clinical benefit in the future to overcome tissue damage induced by excessive leukocyte infiltration.

Animal Diseases↗
PubMed1997

The role of conserved amino acid motifs within the integrin beta3 cytoplasmic domain in triggering focal adhesion kinase phosphorylation.

Integrin-mediated adhesion of cells to extracellular matrix proteins triggers a variety of intracellular signaling pathways including a cascade of tyrosine phosphorylations. In many cell types, the cytoplasmic focal adhesion tyrosine kinase, FAK, appears to be the initial protein that becomes tyrosine-phosphorylated in response to adhesion; however, the molecular mechanisms regulating integrin-triggered FAK phosphorylation are not understood. Previous studies have shown that the integrin beta1, beta3, and beta5 subunit cytoplasmic domains all contain sufficient information to trigger FAK phosphorylation when expressed in single-subunit chimeric receptors connected to an extracellular reporter. In the present study, beta3 cytoplasmic domain deletion and substitution mutants were constructed to identify amino acids within the integrin beta3 cytoplasmic domain that regulate its ability to trigger FAK phosphorylation. Cells transiently expressing chimeric receptors containing these mutant cytoplasmic domains were magnetically sorted and assayed for the tyrosine phosphorylation of FAK. Analysis of these mutants indicated that structural information in both the membrane-proximal and C-terminal segments of the beta3 cytoplasmic domain is important for triggering FAK phosphorylation. In the C-terminal segment of the beta3 cytoplasmic domain, the highly conserved NPXY motif was found to be required for the beta3 cytoplasmic domain to trigger FAK phosphorylation. However, the putative FAK binding domain within the N-terminal segment of the beta3 cytoplasmic domain was found to be neither required nor sufficient for this signaling event. We also demonstrate that the serine 752 to proline mutation, known to cause a variant of Glanzmann's thrombasthenia, inhibits the ability of the beta3 cytoplasmic domain to signal FAK phosphorylation, suggesting that a single mutation in the beta3 cytoplasmic domain can inhibit both "inside-out" and "outside-in" integrin signaling.

Amino Acid Sequence↗
PubMed2004

Adhesion and signaling by B cell-derived exosomes: the role of integrins.

Exosomes are nanometer-sized vesicles secreted by various cells, with potentially diverse roles in physiology. Although emphasis has been placed on their involvement in immune modulation, their potential for more wide-ranging biological effects has not been appreciated. A common exosome feature is the expression of adhesion molecules, which include the integrin family. We have for the first time addressed the possible function of B cell-derived exosome-integrins by examining adhesive interactions of exosomes (immobilized onto beads) with extracellular matrix (ECM) components and cytokine-treated fibroblasts. Integrin (beta1 and beta2) expression was demonstrated by Western blotting and flow cytometry. Binding studies (with blocking antibodies) demonstrated their function in adhesion to collagen-I, fibronectin, and tumor necrosis factor (TNF)-alpha-activated fibroblasts. Exosome adhesion to TNF-alpha-activated fibroblasts also triggered integrin-dependent changes in cytosolic calcium, measured by single cell imaging. Thus, B cell-derived exosomes express functional integrins, which are capable of mediating anchorage to ECM and cell-surface adhesion molecules, and may be a novel mode of delivering adhesion signals at distances beyond that of direct cell-cell contact during inflammation.

B-Lymphocytes↗
PubMed2000

Modes of regulation of laminin-5 production by rat astrocytes.

Astrocytes have a prominent role in central nervous system-specific microvascular growth and function. Extracellular matrix molecules (ECMs) bind to specific adhesion molecules - integrins. These adhesion complexes are responsible for tissue integrity and cellular signalling. We have examined astrocyte-endothelial cell interactions in relation to expression of the ECM laminin-5. Astrocytes produce laminin-5 in cell culture. The production is enhanced by endothelial cells. Direct cellular contact possibly involving a beta1 integrin or an insoluble matrix compound detected by the astrocytes is responsible for the induction of astrocytic laminin production by endothelial cells. Hypoxia also influences ECM production. The described regulation goes in concert with the known effects of astrocyte-endothelial cell interaction and stresses its importance for microvascular integrity.

Animals↗
PubMed2002

Regulation of melanoma cell migration and invasion by laminin-5 and alpha3beta1 integrin (VLA-3).

We evaluated the role of soluble factors produced from epidermal cells in melanoma cell motility by using the Boyden chamber chemoinvasion system. The migration of two melanoma cell lines, A375 and Mewo, was potentiated by conditioned media of A431 epidermoid cells in a concentration-dependent manner. The enhancement of A375 melanoma cell motility induced by the conditioned medium was blocked by antibodies against either alpha3 or beta1 integrin subunit. The motility-stimulating activity was recovered in the same fraction as the alpha3 integrin-dependent adhesion-promoting activity in a high-molecular-weight (>200 kDa) fraction on Superose 12 gel chromatography, and adsorbed with an anti-laminin-5 antibody. Purified laminin-5 was capable of potentiating melanoma cell migration as measured in either the chemotaxis assay with a soluble form of laminin-5 or the haptotaxis assay with membranes coated with a mixture of laminin-5 and Matrigel. Furthermore, immobilized laminin-5 induced A375 melanoma cells to secrete matrix metalloproteinase-9 (type IV collagenase) into the culture medium. These results strongly suggest that the interaction of laminin-5 produced in the epidermis with alpha3beta1 integrin on melanoma cells is involved in cell migration, invasion, and degradation of extracellular matrix proteins.

Cell Adhesion Molecules↗
PubMed2006

Increased transcriptional response to mechanical strain in keloid fibroblasts due to increased focal adhesion complex formation.

Clinicians have observed that keloids preferentially form in body areas subject to increased skin tension. We hypothesized a difference exists in the transcriptional response of keloid fibroblasts to mechanical strain compared with normal fibroblasts. Normal and keloid fibroblasts were seeded in a device calibrated to deliver a known level of equibiaxial strain. We examined the transcriptional response of TGF-beta isoforms and collagen Ialpha, genes differentially expressed in keloids. Keloid fibroblasts produced more mRNA for TGF-beta1, TGF-beta2, and collagen Ialpha after mechanical strain compared to normals, and this was correlated with protein production. Inhibiting the major mechanical signal transduction pathway with the ERK inhibitor, U0126, blocked upregulation of gene expression. In addition, keloid fibroblasts formed more focal adhesion complexes as measured by immunofluorescence for focal adhesion kinase, integrin beta1, and vinculin. Finally, there is increased activation of focal adhesion kinase when we detected the phosphorylated form of focal adhesion kinase with immunofluorescence and immunoblotting. In summary, keloid fibroblasts have an exaggerated response to mechanical strain compared to normal fibroblasts leading to increased production of pro-fibrotic growth factors. This may be one molecular mechanism for the development of keloids.

Adolescent↗
PubMed2001

Osteoblast integrin adhesion and signaling regulate mineralization.

Integrin adhesion and signaling events may contribute to the progressive differentiation of the osteoblast and to the initiation of a mineralized matrix. The purpose of our study was to begin to analyze the role of integrin receptors, in particular alpha2beta1, alpha5beta1, and alphaVbeta3, regarding mediation of the initiation of a mineralized matrix. Integrin-perturbation assays were conducted in microdot cultures of UMR-106-01 Bone Sialoprotein (BSP) osteoblast cells. For phenotypic analysis, we performed bright-field microscopy and Aliziran Red S staining to analyze effects on mineralization initiation. Mineralization was reduced significantly (P < 0.001) following the addition of alpha5- or beta1-integrin subunit antibody by approximately 20% and 45%, respectively--alphaVbeta3 integrin by nearly 65%, and alpha2beta1 integrin by nearly 95%. This effect was reversible following the removal of the antiintegrin antibody. These results suggest that integrin adhesion and signaling events may contribute to the ability of this cell line to mediate the initiation of the mineralization phenotype biologically.

Analysis of Variance↗
PubMed2002

Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway.

PURPOSE: To investigate myofibroblast differentiation and signal transduction induced by TGF-beta family members activin A and bone morphogenetic protein (BMP)-7. METHODS: Transcription of activin and receptors (ActR) for activin A and BMP-7 was detected by RT-PCR. Levels of marker proteins for differentiation and phosphorylation of similar to mothers against decapentaplegics (Smads) were quantified by Western blot analysis in response to BMP-7, activin A and follistatin. Transfection with antisense Smad2/3 was performed to evaluate signal transduction. RESULTS: Activin A and receptors (ActR-I, ActR-IB, ActR-II) are transcribed in corneal fibroblasts. Compared with TGF-beta1 or serum, activin A but not BMP-7 increased alpha-smooth muscle (SM) actin and actin-binding proteins such as SM myosin, alpha-actinin, and vinculin. Talin, paxillin, and desmin were not induced and vimentin was downregulated by activin. Activin also induced extracellular matrix proteins fibronectin and integrin beta1. Activin-dependent accumulation of proteins was blocked by follistatin. Regarding signal transduction, activin A induced phosphorylation of Smad 2, and BMP-7 induced Smad 1, both of which were inhibited by follistatin. Transfection with antisense Smad 2/3 prevented activin-induced expression and accumulation of alpha-SM actin. CONCLUSIONS: TGF-beta proteins have different functions in the cornea. Activin A and TGF-beta1, but not BMP-7, are regulators of corneal keratocyte differentiation and may play a role during myofibroblast transdifferentiation. Smad 2/3 signal transduction seems to be important in the regulation of muscle-specific genes. Further investigation of Smad signaling may help to better understand the function of TGF-beta family members in the cornea.

Activins↗
PubMed1999

Functional expression of beta1 and beta2 integrins on tumor infiltrating lymphocytes (TILs) in colorectal cancer.

Integrins play an important role in various lymphocyte functions. In this study, tumor-infiltrating lymphocytes (TIL) were isolated from colorectal cancer tissues and the expression of beta1 and beta2 integrins on the TIL was quantitatively examined with two-color flow cytometry. In comparison with peripheral blood lymphocytes (PBL), TIL expressed a lower level of common beta1 chain (CD29) in both CD4 and CD8 subpopulations. Among the associated alpha chains, the expressions of alpha1 (CD49a) and alpha2 (CD49b) were slightly higher in TIL than in PBL, whereas alpha4 (CD49d) and alpha6 (CD49f) were markedly downregulated in TIL. Both alphaL (CD11a) and beta2 (CD18) were reduced in CD8(+) TIL but not in CD4(+) TIL. TIL with the CD8(+) cytotoxic phenotype showed significantly decreased binding to purified intracellular adhesion molecules (ICAM)-1, and vascular adhesion cell molecule (VCAM)-1, and HT29 colon cancer cells, compared with the in counterparts in PBL. The peculiar expression pattern and functional down regulation of these integrins may explain why TIL in colorectal cancer cannot eradicate the malignant cells.

Aged↗
PubMed2005

Rigidity sensing at the leading edge through alphavbeta3 integrins and RPTPalpha.

Cells require optimal substrate stiffness for normal function and differentiation. The mechanisms for sensing matrix rigidity and durotaxis, however, are not clear. Here we showed that control, Shp2-/-, integrin beta1-/-, and talin1-/- cell lines all spread to a threefold greater area on fibronectin (FN)-coated rigid polyacrylamide surfaces than soft. In contrast, RPTPalpha-/- cells spread to the same area irrespective of rigidity on FN surfaces but spread 3x greater on rigid collagen IV-coated surfaces than soft. RPTPalpha and alphavbeta3 integrins were shown previously to be colocalized at leading edges and antibodies to alphavbeta3 blocked FN rigidity sensing. When FN beads were held with a rigid laser trap at the leading edge, stronger bonds to the cytoskeleton formed than when held with a soft trap; whereas back from the leading edge and in RPTPalpha-/- cells, weaker bonds were formed with both rigid and soft laser traps. From the rigidity of the trap, we calculate that a force of 10 pN generated in 1 s is sufficient to activate the rigidity response. We suggest that RPTPalpha and alphavbeta3 at the leading edge are critical elements for sensing FN matrix rigidity possibly through SFK activation at the edge and downstream signaling.

Animals↗
PubMed1999

Fibroblast expression of collagen integrin receptors alpha1beta1 and alpha2beta1 is not changed in systemic scleroderma.

The skin of patients with systemic scleroderma (SSc) is characterized by excessive extracellular matrix deposition in the dermis. As collagens represent the major structural component, we used fluorescence-activated cell sorter analysis to study the levels of collagen receptors expressed at the surface of fibroblasts derived from involved skin areas. In contrast to previous reports, no differences in the expression of alpha1, alpha2 or beta1 integrin subunits, which constitute the major collagen receptors on fibroblasts, were detected on SSc fibroblasts as compared with normal control fibroblasts. Variation of cell culture conditions, e. g. passage number (from 2 to 10), seeding density, cell cycle or serum concentration, did not change this result. These observations indicate that any abnormal response of SSc fibroblasts to their matrix environment is not controlled at the level of receptor expression.

Adult↗