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PubMed1996

Platelet adhesion to collagen type IV under flow conditions.

Collagen type IV is a sheet-forming collagen and a major constituent of the vessel wall. To find out which conditions are important for platelet adhesion to collagen type IV, we performed perfusion studies with anticoagulated blood in parallel plate perfusion chambers. The role of divalent cations was investigated by using plasmas with variable concentrations of Mg2+ and Ca2+ ions. When Mg2+ concentration was decreased from 2.00 mmol/L to 0.25 mmol/L at a fixed Ca2+ concentration of 1.25 mmol/L, platelet coverage on the collagen type IV surface decreased from 22.8% +/- 1.8% (n = 4) to 4.6% +/- 0.6% (n = 4) at a shear rate of 1,600 s-1. Also, platelet aggregate formation on collagen type IV was strongly impaired. A monoclonal antibody against the glycoprotein (Gp) Ib receptor and von Willebrand factor (vWF)-depleted plasma reduced the platelet coverage to collagen type IV to, respectively, 10% and 45% of the control value. Electron microscopy showed that vWF was only present between platelets and between the platelet and the collagen type IV surface, but did not bind elsewhere to collagen type IV. These data indicate that collagen type IV is a reactive collagen for platelets. Differences in physiologic plasma magnesium concentrations may in part explain the differences in platelet reactivity to collagen type IV between individuals, and perhaps contribute to differences in the risk for thrombosis.

Calcium↗
PubMed1992

Significance of serum type-IV collagen levels in various liver diseases. Measurement with a one-step sandwich enzyme immunoassay using monoclonal antibodies with specificity for pepsin-solubilized type-IV collagen.

Serum type-IV collagen levels determined with a one-step sandwich enzyme immunoassay (EIA) using monoclonal antibodies with specificity for pepsin-solubilized type-IV collagen were compared with histologic changes in liver biopsy specimens from 107 patients with various liver diseases. Serum type-IV collagen levels were increased in the groups with liver diseases compared with controls. The serum type-IV collagen levels in the group with alcoholic cirrhosis showed significantly higher values than the other groups (P less than 0.05). A significant positive correlation was found between the serum type-IV collagen level and the degree of fibrosis or cell infiltration in 107 patients. Immunolocalization of type-IV collagen was observed around blood vessels and bile ducts increased in number in the portal tracts, with cell infiltration and fibrosis, increased around vessels in fibrous septa, and sinusoidal walls of areas with cell infiltration or necrosis in hepatic lobules, and along the boundary between fibrous septa and hepatocytes. The present data indicate that serum type-IV collagen may be a sensitive marker for active fibrosis and that the elevation of serum type-IV collagen level primarily reflects the enhancement of type-IV collagen synthesis and deposition in the liver tissue at the stage of active fibrosis in liver disease.

Adolescent↗
PubMed1993

Elongational flow studies on type IV collagen: comparison with type I.

Elongation flow techniques have been used to investigate the birefringent response of monodisperse type IV collagen in dilute solution and the results compared with type I collagen. A four-roll mill apparatus was used to characterize the solutions at low strain rates, epsilon < or = 300 s-1. The birefringence is nonlocalized and rises gradually to a plateau value, in accordance with rigid-rod behavior. The gradients of the tangent to the curves at zero strain rate are estimated for types IV and I collagen. The concentrations of the solutions used were in the dilute to semidilute regimes. Using a value of 300 nm for the length of type I collagen, values of 364-408 nm were calculated for the length of the type IV collagen molecule, depending on the concentration regime chosen, which is consistent with biochemical predictions based on a rigid molecule. The results imply that the behavior of type IV collagen molecules in solution is similar to type I collagen, despite the presence of several sequence interruptions in the type IV helix.

Chemistry, Physical↗
PubMed1986

Alpha 1 type IV collagen gene evolved differently from fibrillar collagen genes.

Type IV collagen is a major structural component in basement membranes. It is considerably different from the fibrillar collagens, types I-III. For example, unlike fibrillar collagens, the triple helical domain of type IV collagen is frequently interrupted by nonhelical regions. In this report, we demonstrate several overlapping genomic clones which cover most of the mouse alpha 1(IV) chain. Electron microscopic analysis of R-loops revealed that there were at least 28 exons within 35 kilobases of the gene segment. The sizes of six exons were determined by DNA sequence analysis to be 81, 178, 134, 73, 129, and 213 base pairs. These sizes do not appear to be related to the 54-base pair coding unit which is characteristic of fibrillar collagen exons, suggesting that the alpha 1 type IV collagen gene evolved differently from the fibrillar collagen genes.

Actin Cytoskeleton↗
PubMed1987

Cellular events associated with lung branching morphogenesis including the deposition of collagen type IV.

In this study mouse lung development was examined using an in vitro model system. The culture system permitted examination of a morphogenic process that eventually led to the formation of presumptive alveoli (terminal sacs). The observations included changes in epithelial cell morphology (transition from a columnar to a spindle shape), and evidence for motile activity on the part of primitive airway epithelial cells. The importance of Type IV collagen to the cellular events associated with branching morphogenesis was investigated by immunolocalization. In addition, we assessed the similarity of normal lung development to in vitro development by comparing cultured lungs with equivalent stages of embryonic and fetal mouse lungs. The results show that cultured embryonic lung explants proceed along a morphogenic pathway that parallels normal lung development; that primitive pulmonary epithelial cells engage in motile activity and transiently acquire an extended cell shape both in vitro and in vivo; that, as suggested by others, the pattern of late branching morphogenesis is not dichotomous, but irregular; and that short wisplike fibers of Type IV collagen are present in developing embryonic and fetal lung mesenchyme. Taken together, the results show that early and late lung branching patterns differ significantly, and suggest that later stages of lung branching involve distinct epithelial cell shape transitions. The immunofluorescence data suggest that fibrous Type IV collagen may be the extracellular matrix scaffold within which early epithelial cells accomplish lung branching morphogenesis.

Animals↗
PubMed1980

Immunohistochemical evidence for the intracellular formation of basement membrane collagen (type IV) in developing tissues.

Antibodies to type IV collagen obtained from the basement membrane of the mouse EHS tumor were incubated with sections of rat incisor teeth and other tissues for immunostaining by direct or indirect methods. In all locations, the immunostaining was pronounced in basement membranes in which it was restricted to the "basal lamina" layer, from which "bridges" often extended to nearby basal laminae. Usually no immunostaining was detectable in the cells associated with the basement membranes. However, examination of the capillaries at the posterior extremity of the rat incisor tooth, where tissues are at an early stage of development, showed immunostaining not only of the basement membrane, but also of the endothelial cells. The staining was localized in rough endoplasmic reticulum cisternae, some Golgi saccules and their peripheral distensions, and structures believed to be secretory granules. These findings suggest that the synthesis of type IV collagen proceeds along the classical secretory pathways through rough endoplasmic reticulum and Golgi apparatus. At the same time, immunostaining was usually lacking in the cells of the capillaries that had migrated about 2 mm away from the posterior end of the incisor tooth and also in the cells of most other tissues examined, even though the associated basal laminae were reactive. It is, therefore, presumed that the production of type IV collagen may be high in cells at an early stage of development and that any later production and turnover of basement membrane collagen can only be minimal.

Animals↗
PubMed1991

Use of the polymerase chain reaction to clone and sequence a cDNA encoding the bovine alpha 3 chain of type IV collagen.

A novel type IV collagen, alpha 3(IV), has previously been isolated from a collagenase digest of bovine and human glomerular and lens basement membranes. The cloning and sequencing of a cDNA encoding the alpha 3(IV) chain is described here. Using the polymerase chain reaction, with primers derived from the known 27-residue bovine alpha 3(IV) amino acid sequence, a 68-base pair bovine genomic fragment (KEM68) which encodes the known peptide sequence, was synthesized. KEM68 was then used to screen a bovine lens cDNA library and a 1.5-kilobase partial cDNA clone obtained, encoding 471 residues of the bovine alpha 3(IV) chain: 238 residues from the triple helical collagenous domain and all 233 residues of the noncollagenous domain. The collagenous repeat sequence has three interruptions, coinciding with those in the alpha 1(IV) chain. The noncollagenous domain has 12 cysteine residues in identical positions to those of other type IV collagens and 71, 61, and 70% overall similarity with the human alpha 1(IV), alpha 2(IV), and alpha 5(IV) chains. The noncollagenous domain of alpha 3(IV) is of particular interest as it appears to be the component of glomerular basement membrane that reacts maximally with the Goodpasture antibody. Furthermore, such antigenicity is absent from collagenase digests of the glomerular basement membrane of some patients with Alport syndrome. The alpha 3(IV) cDNA clone described here now permits study of the molecular pathology of COL4A3 in Alport syndrome.

Amino Acid Sequence↗
PubMed1985

Immunolocalization of type IV collagen and laminin in nonbasement membrane structures of murine corneal stroma. A light and electron microscopic study.

The extracellular matrix of adult vertebrate corneal stroma is composed primarily of the interstitial collagen type I and smaller amounts of types III and V collagen. These collagens are organized into overlapping lamellae of striated filaments. In addition to these lamellar structures, the corneal stroma also contains 100- to 250-nm bundles of nonstriated 8- to 11-nm microfibrils. By immunofluorescent localization and electron microscopic immunolocalization, these microfibril bundles in the mouse are associated with type III collagen, type IV collagen, and laminin. By immunologic and histochemical criteria, these bundles do not contain either type I collagen, type V collagen, elastin, or oxytalan microfibrils. The cellular source, composition, and possible functions of these microfibril bundles are discussed.

Animals↗
PubMed2000

Assembly of type IV collagen. Insights from alpha3(IV) collagen-deficient mice.

Type IV collagen includes six genetically distinct polypeptides named alpha1(IV) through alpha6(IV). These isoforms are speculated to organize themselves into unique networks providing mammalian basement membranes specificity and inequality. Recent studies using bovine and human glomerular and testis basement membranes have shown that unique networks of collagen comprising either alpha1 and alpha2 chains or alpha3, alpha4, and alpha5 chains can be identified. These studies have suggested that assembly of alpha5 chain into type IV collagen network is dependent on alpha3 expression where both chains are normally present in the tissue. In the present study, we show that in the lens and inner ear of normal mice, expression of alpha1, alpha2, alpha3, alpha4, and alpha5 chains of type IV collagen can be detected using alpha chain-specific antibodies. In the alpha3(IV) collagen-deficient mice, only the expression of alpha1, alpha2, and alpha5 chains of type IV collagen was detectable. The non-collagenous 1 domain of alpha5 chain was associated with alpha1 in the non-collagenous 1 domain hexamer structure, suggesting that network incorporation of alpha5 is possible in the absence of the alpha3 chain in these tissues. The present study proves that expression of alpha5 is not dependent on the expression of alpha3 chain in these tissues and that alpha5 chain can assemble into basement membranes in the absence of alpha3 chain. These findings support the notion that type IV collagen assembly may be regulated by tissue-specific factors.

Animals↗
PubMed1989

Distribution of familial nephritis antigen in normal tissue and renal basement membranes of patients with homozygous and heterozygous Alport familial nephritis. Relationship of familial nephritis and Goodpasture antigens to novel collagen chains and type IV collagen.

The glomerular basement membranes (GBM) of Alport familial nephritis (FN) are laminated and split and fail to bind Goodpasture autoantibodies by indirect immunofluorescence. The Goodpasture antigen has been localized to multiple peptides of the noncollagenous C terminal (NC1) domain of type IV collagen. The principal target antigen is a 28-kDa peptide (M28) that coisolates with type IV collagen NC1 and which is derived from a larger collagenous molecule. We have shown that two novel 28-kDa peptides found in normal GBM (M28M28+) are absent from collagenase digests of X-linked dominant Alport FN GBM and that monoclonal antibodies specific for these collagen chains fail to bind to Alport GBM. In normal tissue these chains have a distribution restricted to specific basement membranes of kidney, eye, inner ear, lung, and brain, the former three of which are affected in Alport FN. Epitopes on a 26-kDa NC1 peptide identified by an antibody from a transplanted Alport patient (FN antibody) colocalized with the 28-kDa components in these tissues. The FN antibody did not bind to the GBM of homozygous Alport males. Antibodies to the 28-kDa peptides and the FN antibody colocalized in a segmental pattern in heterozygous Alport GBM by indirect immunofluorescence and were unrelated to the normal distribution of type IV collagen. Three of eight homozygous Alport FN tissues showed the presence of the 28-kDa components in Bowman's capsule in a focal distribution, and in four of eight tissues reactive antigen was present in the cytoplasm of some parietal and visceral epithelial cells. These observations support the hypothesis that the genetic abnormality in Alport FN is a defective parent chain of the 26-kDa peptide, which results in failure of normal 28-kDa collagen chain integration.

Antibodies, Monoclonal↗
PubMed1988

An immunohistochemical study of laminin, type-IV collagen and type-III pN-collagen with relation to reticular fibres in Hodgkin's disease.

The distribution of aminoterminal propeptides of type-III procollagen (indicating the presence of type-III pN-collagen, i.e., type-III collagen molecule with a non-cleaved aminoterminal propeptide), laminin and type-IV collagen was studied by immunohistochemical methods. The results were compared with the distribution of reticular fibres using Gomori's reticulin stain. Lymph nodes from 20 cases of Hodgkin's disease (HD) and 3 spleens affected by nodular sclerosis HD were studied. The reticular fibres stained for all the antigens investigated, the strongest reaction being for pN type-III collagen. Thick fibres stained mainly for type-III pN-collagen, the BM proteins being located in a fragmented rim on the surface. The distribution and composition of fibres was similar in both nodal and extranodal infiltrations. The morphological alterations noted in the fibres comprised (1) compression between nodules in the nodular type of lymphocyte-predominant HD, and (2) fragmentation, present in collections of histiocytes in lymphocyte-predominant HD. BM proteins and type-III pN-collagen were present in the walls of the sinuses and vessels. The marginal sinuses were often partially spared in spite of extracapsular invasion. Our results suggest that laminin, type-IV collagen and type-III pN-collagen are important components of reticular fibres in HD and that the composition of the fibres is similar to that seen in the normal lymph node.

Adult↗
PubMed1992

Recombinant human bone morphogenetic protein 2B stimulates PC12 cell differentiation: potentiation and binding to type IV collagen.

Bone morphogenetic protein 2B (BMP 2B, also known as BMP 4) induces cartilage and bone morphogenesis in ectopic extraskeletal sites. BMP 2B is one of several bone morphogenetic proteins which along with activins and inhibins are members of the transforming growth factor-beta (TGF-beta) family. Both BMP 2B and activin A, but not TGF-beta 1, induce rat pheochromocytoma PC12 neuronal cell differentiation and expression of VGF, a nervous system-specific mRNA. PC12 cells exhibited approximately 2,500 receptors per cell for BMP 2B with an apparent dissociation constant of 19 pM. Extracellular matrix components, including fibronectin, laminin, and collagen type IV potentiated the activity of BMP and activin A, with the latter being the most active. Direct experiments demonstrated that radioiodinated BMP 2B bound to collagen type IV better than to either laminin or fibronectin. These data demonstrate a common neurotrophic activity of both BMP 2B and activin A, and suggest that these regulatory molecules alone and in conjunction with extracellular matrix components may play a role in both the development and repair of nervous tissue.

Activins↗
PubMed1988

The anticonvulsant sodium valproate specifically induces the expression of a rat glial heat shock protein which is identified as the collagen type IV receptor.

A potential mechanism for valproate (VPA)-induced increases in glial cell-substratum adhesivity has been demonstrated. Metabolically labelled glioma (C6) and primary astrocytes showed a statistically significant accumulation of protein when cultured in the presence of therapeutic concentrations of VPA (1 mM). This was mainly accounted for by a 10-fold increase in the production of a single polypeptide of 43 kDa molecular weight. Fractionation studies and metabolic labelling with N-acetyl-D-mannosamine showed this to be a sialoglycoprotein which was plasma membrane-bound. VPA-induction of the polypeptide was apparently specific to glioma and primary astrocytes and was not observed in neuroblastoma (neuro-2a), fibroblasts (3T3), pituicytes (GH3) and epithelial cells (NCTC). The 43 kDa component of glia was demonstrated to be the receptor for type IV collagen by binding metabolically labelled and solubilised cells to Sepharose beads which had been individually coated with laminin, fibronectin and type IV collagen. The protein has also been shown to be a heat shock product as metabolically labelled glioma showed a 10-fold increase in its expression when cultured at 42 degrees C. This heat shock induced expression was transient and was in marked contrast to that seen with VPA where it increased with time and was sustained. The expression of 43 kDa is suggested to arise by VPA and heat shock induced delays in cell cycle progression and this is discussed in relation to teratogenic action.

Anticonvulsants↗
PubMed1993

Heterogeneity of antibodies in Goodpasture syndrome reacting with type IV collagen.

Sera from patients with antiglomerular basement membrane (anti-GBM) antibodies associated with Goodpasture syndrome (GP) or glomerulonephritis were tested by ELISA and electroimmunoblot against whole basement membrane collagen (type IV) isolated from bovine anterior lens capsule (ALC) and bacterial collagenase resistant domains of the collagen molecule, that is, the NC-1 and 7-S domains isolated from either ALC or bovine and human glomerular basement membrane (GBM). Reactivity was high with the NC-1 domain by both the ELISA and the electroimmunoblot techniques. Some of the anti-GBM sera reacted with both the NC-1 and 7-S domains of both human and bovine type IV collagen. At a time when the patients' sera reacted weakly with a collagenase digest of human GBM using a radioimmunoassay, the reactivity with the NC-1 domain was also low, but some of the sera continued to react with the 7-S domain. The data suggest that there may be heterogeneity in the nature of autoantibodies with respect to collagen type IV domain reactivity in the sera of patients with anti-GBM antibody disease.

Animals↗
PubMed1986

The role of the main noncollagenous domain (NC1) in type IV collagen self-assembly.

Type IV collagen incubated at elevated temperatures in physiologic buffers self-associates (a) via its carboxy-terminal (NC1) domain, (b) via its amino-terminal (7S) domain, and (c) laterally; and it forms a network. When examined with the technique of rotary shadowing, isolated domain NC1 was found to bind along the length of type IV collagen to four distinct sites located at intervals of approximately 100 nm each. The same 100-nm distance was observed in domain NC1 of intact type IV collagen bound along the length of the collagen molecules during initial steps of network formation and in complete networks. The presence of anti-NC1 Fab fragments in type IV collagen solutions inhibited lateral association and network formation in rotary shadow images. During the process of self-association type IV collagen develops turbidity; addition of isolated domain NC1 inhibited the development of turbidity in a concentration-dependent manner. These findings indicate that domain NC1 of type IV collagen plays an important role in the process of self-association and suggest that alterations in the structure of NC1 may be partially responsible for impaired functions of basement membranes in certain pathological conditions.

Animals↗
PubMed1997

A cell binding domain from the alpha3 chain of type IV collagen inhibits proliferation of melanoma cells.

Our previous studies have shown that a peptide corresponding to the residue sequence 185-203 of the NC1 domain of the alpha3 chain of basement membrane collagen (type IV) inhibits the activation of polymorphonuclear leukocytes. Peptides from the same region of the alpha1, alpha2, alpha4, and alpha5(IV) chains did not exhibit this property. Because of the intimate relationship between metastasizing neoplastic cells and vascular as well as epithelial basement membranes, we measured the cell adhesion-promoting activity of peptides from the NC1 domain of type IV collagen and their effect on proliferation of human melanoma cells. We found that peptide alpha3(IV)185-203 (CNYYSNSYSFWLASLNPER) not only promotes adhesion of human melanoma cells but also inhibits their proliferation. Adhesion increased by 50-60% over control. Melanoma cell proliferation was inhibited by 40% when cells were grown in a medium containing 5 microg/ml peptide for 5 days. Studies showed that replacement of serine in position 189 or 191 by alanine resulted in significantly reduced adhesion. Similarly, serine replacement resulted in reduced ability to inhibit proliferation. Our data suggest that a region of the NC1 domain of the alpha3(IV) chain, contained within the sequence 185-203, not only specifically promotes adhesion but also inhibits proliferation of melanoma cells. These properties appear to be dependent on the presence of the triplet sequence -SNS- (residues 189-191), which is unique to the alpha3 chain and may represent an important functional epitope.

Amino Acid Sequence↗
PubMed2005

Synthesis of prolyl 4-hydroxylase alpha subunit and type IV collagen in hemocytic granular cells of silkworm, Bombyx mori: Involvement of type IV collagen in self-defense reaction and metamorphosis.

The present study shows that hemocytic granular cells synthesize and secrete type IV collagen (ColIV) in the silkworm Bombyx mori (B. mori) and suggests that these cells play roles in the formation of basement membrane, the encapsulation of foreign bodies, and the metamorphic remodeling of the gut. The full- and partial-length cDNA of B. mori prolyl 4-hydroxylase alpha subunit (BmP4Halpha) and B. mori ColIV (BmColIV) were cloned, respectively. In situ hybridization and immunocytochemistry on larval tissues and cells identified hemocytic granular cells as the cells that express mRNAs and proteins of both BmP4Halpha and BmColIV. Immunohistochemistry and immunocytochemistry demonstrated that BmColIV was present in the basement membrane and in the secretory granules of granular cells, respectively. Granular cells in culture secreted BmColIV without accompanying the degranulation and discharged it from the granules when the cells were degranulated. Nylon threads were inserted into the hemocoel of larvae. Granular cells concentrated around the nylon threads and encapsulated them as a self-defense reaction. BmColIV was found to be a component of the capsules. Furthermore, the present study showed that actively BmColIV-expressing granular cells accumulated around the midgut epithelium and formed BmColIV-rich thick basal lamina-like structures there in larval to pupal metamorphosis.

Amino Acid Sequence↗
PubMed2003

Differential recruitment of alpha2beta1 and alpha4beta1 integrins to lipid rafts in Jurkat T lymphocytes exposed to collagen type IV and fibronectin.

Collagen type IV (CnIV) and fibronectin (Fn) were used as ligands to study the distribution of alpha(2)beta(1) and alpha(4)beta(1) integrins in low-density, detergent-resistant microdomains (DRM) of Jurkat lymphocytes. CnIV-coated microspheres induced (optical trapping) the redistribution of GM(1)-associated fluorescence from the cell periphery to the area of contact. This was not observed in cells treated with beta-methyl cyclodextrin (MCD). Fn- or bovine serum albumin-coated microspheres did not modify the peripheral distribution of fluorescence. These observations were confirmed by confocal microscopy. Western blot analysis of cells exposed to surfaces coated with CnIV revealed that the alpha(2)-subunit was initially present at low levels in DRM, became strongly associated after 40 min, and returned to basal levels after 75 min. Fn induced a slight recruitment of the beta(1)-integrin alpha(4)-subunit in DRM after 5 and 10 min, followed by a return to basal levels. Neither CnIV nor Fn triggered significant changes in the distribution of the beta(1)-subunit in DRM. Fn- and CnIV-coated microspheres or surfaces coated with these ligands triggered a MCD-sensitive mobilization of Ca(2)(+). MCD did not alter the state of the Ca(2)(+) reserves. The differential distributions of the alpha(2)beta(1) and alpha(4)beta(1) integrins in DRM may provide one additional step in the regulation of outside-in signaling involving these integrins.

Calcium↗