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PubMed1990

Appearance of laminin, heparan sulphate proteoglycan and collagen type IV during initial stages of vascularisation of the neuroepithelium of the mouse embryo.

The appearance of the basement membrane components laminin, heparan sulphate proteoglycan and Type IV collagen was investigated by indirect immunofluorescence during the onset of vascularisation of the neuroepithelium of mouse embryos (Days 10, 11 and 12 of development). All three basement membrane components could initially be seen in the embryonic CNS anlage along with the appearance of capillaries in the neuroepithelial cell layer. From this direct correlation between vascularisation and appearance of basement membrane components in the embryonic anlage one can assume that the basement membrane components laminin, heparan sulphate proteoglycan and collagen Type IV are involved in the initial vascularisation of the CNS anlage of 10 to 12 day old mouse embryos.

Animals↗
PubMed1996

The Goodpasture autoantigen. Structural delineation of two immunologically privileged epitopes on alpha3(IV) chain of type IV collagen.

The family of type IV collagen comprises six chains numbered alpha1 through alpha6. The alpha3(IV) NC1 domain is the primary target antigen for autoantibodies from patients with anti-basement membrane disease and Goodpasture syndrome. Earlier peptide studies suggested that the last 36 amino acids of the alpha3 NC1 domain probably contains one recognition site for Goodpasture autoantibodies, and an algorithm analysis of secondary structure from a later study predicted a second possible upstream epitope near the triple helix junction. We have used several analytic approaches to evaluate the likelihood of two immunologic epitopes for the Goodpasture antigen. In our first set of studies, peptide antibodies directed against these two putative regions co-inhibited Goodpasture autoantibodies binding to denatured human alpha3(IV) NC1 monomer by nearly 80%, with the helix-junction region of the alpha3 NC1 domain contributing 26% of the binding sites and the C-terminal region contributing the remaining 50%. Second, both of these candidate regions are normally sequestered within the associated alpha3(IV) NC1 hexamer but become more visible for binding by anti-peptide antibodies upon their dissociation, a property that is shared by the Goodpasture autoantibodies. Third, segment deletions of recombinant alpha3 NC1 domain further confirmed the presence of two serologic binding sites. Finally, we looked more closely at the C-terminal binding region of the alpha3(IV) NC1 domain. Since the lysines in that region have been previously advanced as possible contact sites, we created several substitutions within the C-terminal epitope of the alpha3 NC1 domain. Substitution of lysines to alanines revealed lysines 219 and 229 as essential for antibody binding to this distal site; no lysines were present in the NC1 part of the helix-NC1 junction region. Substitutions involving arginine and cysteines to alanines in the same C-terminal region did not produce significant reductions in antibody binding. In summary, our findings characterize two Goodpasture epitopes confined to each end of the alpha3 NC1 domain; one is lysine-dependent, and the other is not. We propose, as a hypothetical model, that these two immunologically privileged regions fold to form an optimal pathogenic structure within the NC1 domain of the alpha3 chain. These sites are subsequently concealed by NC1 hexamer assembly of type IV collagen.

Anti-Glomerular Basement Membrane Disease↗
PubMed1995

Identification and characterization of a novel transcriptional silencer in the human collagen type IV gene COL4A2.

Collagen type IV [alpha 1(IV)2 alpha 2(IV)] is the basic structural component of all basement membranes. The two subunit genes COL4A1 and COL4A2 are found closely linked in the human and murine genomes and are transcribed divergently from a common promoter. Previously, activating elements had been detected within both genes which are indispensable for efficient transcription. An additional negative regulatory element has now been identified within the third intron of the COL4A2 gene which is able to inhibit transcription of both COL4 genes from their shared promoter, as well as the nonrelated herpes simplex virus thymidine kinase promoter. The element exerts its inhibitory effect largely independently from its relative orientation and distance from the initiation site of transcription. Therefore, the element represents a silencer which is named the "COL4 silencer." The minimal functional silencer could be narrowed down by deletion mapping to a sequence element located within intron 3 of the COL4A2 gene. This motif is specifically recognized by a nuclear protein, named "SILBF," and the binding site of which was determined by footprinting assays. Mutation studies and deletion analysis proved that the presence of this sequence element and its interaction with SILBF is not only essential but also sufficient for the silencing function. We assume that the COL4 silencer plays an important role in the control of overall expression and the balance of divergent transcription of both COL4 genes.

Animals↗
PubMed1991

Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen.

A novel type IV collagen, alpha 3(IV), has recently been identified in human and bovine basement membranes. Here we describe the cloning and sequencing of a cDNA encoding 218 residues of the NC1 domain of the human alpha 3(IV) chain. Of interest is the possible role of abnormalities of the alpha 3(IV) chain in Alport syndrome, as suggested by the failure to detect the NC1 domain of alpha 3(IV) in the basement membranes of some Alport syndrome patients. To determine whether the alpha 3(IV) gene (COL4A3) may be mutated in Alport syndrome, we localized it, by somatic cell hybrid analysis and in situ hybridization of metaphase chromosomes, to chromosome 2q35-2q37. Mutations in alpha 3(IV) cannot therefore be responsible for the vast majority of cases of Alport syndrome, which have been shown to be X linked. One explanation for the immunochemical data implicating alpha 3(IV) in Alport syndrome pathogenesis is that mutations of the alpha 5(IV) chain, which has been localized to Xq22 and found to be mutated in at least three kindreds with Alport syndrome, lead to failure to incorporate the alpha 3(IV) chains into the multimeric structure of glomerular basement membrane in a stable fashion.

Amino Acid Sequence↗
PubMed2001

Loss of collagen type IV in rheumatoid synovia and cytokine effect on the collagen type-IV gene expression in fibroblast-like synoviocytes from rheumatoid arthritis.

Collagen type IV is a structural matrix protein which contributes to the structural organization of the synovia. In order to characterize the distribution of this protein in synovia with chronic synovitis, collagen type IV was detected by immunochemistry in normal synovia and in synovia from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). A decrease of collagen type IV was observed in synovial layers of rheumatoid synovia, which statistically correlated with the grade of inflammation and with the thickness of the synovial layer. In vitro, we found no differences in the gene expression of collagen type IV in cultures of fibroblast-like synoviocytes (FLS) derived from OA and RA using a reverse-transcriptase polymerase chain reaction. Nevertheless, we observed a downregulating effect of tumor necrosis factor-alpha and interleukin (IL)-1beta on the gene expression of collagen type IV only in FLS isolated from patients with RA. The effect of IL-1beta was dose dependent. In summary, we observed an inflammation-associated decrease of collagen type IV in the synovial layer of rheumatoid synovia. Inflammatory cytokines may play a role in regulating the synthesis of collagen type IV in the rheumatoid process in vivo.

Arthritis, Rheumatoid↗
PubMed1992

Simultaneous expression of 70 kilodalton type IV collagenase and type IV collagen alpha 1 (IV) chain genes by cells of early human placenta and gestational endometrium.

BACKGROUND: In this study we used in situ hybridization to investigate the expression of the genes 70 kilodalton (kd) collagenase and the alpha 1(IV) collagen chain of type IV collagen in cells of early human placenta and gestational endometrium. EXPERIMENTAL DESIGN: The aim was to study the spatial distribution of these gene expressions within a developing tissue which possesses physiologic invasive potential. The results obtained for the 70 kd type IV collagenase mRNA expression were also compared with the immunohistochemical distribution of the corresponding antigen. RESULTS: Expression of mRNAs for these proteins was found in cells of trophoblastic columns, stromal cells of villi and in cells of decidua and endometrial stroma. The only differences between the expressions was the lower level of signals for 70 kd type IV collagenase in fibroblastic stromal cells and endothelial cells of villi and in the pericytic cells of spiral arteries. Otherwise the results for both types of mRNA were comparable. We also studied the immunohistochemical distribution of the 70 kd type IV collagenase using specific monoclonal antibodies against the enzyme. Immunohistochemistry supported well the findings obtained by in situ hybridization. CONCLUSIONS: The results indicate that the genes for the 70 kd type IV collagenase and for the alpha 1(IV) collagen chain are simultaneously active in cells of placenta and gestational endometrium and the same cells which produce type IV collagen also can produce the cleaving enzyme, the 70 kd type IV collagenase. The results also show that the cytotrophoblastic cells, which during early pregnancy invade the extracellular matrix and spiral arteries of uterine wall contain significant amount of mRNA for the 70 kd type IV collagenase. This finding supports the concept that the 70 kd type IV collagenase would be important for invasion, and in the case of this study, also for the physiologic invasion of placental cytotrophoblasts.

Amino Acid Sequence↗
PubMed1995

Extracellular matrix binding properties of recombinant fibronectin type II-like modules of human 72-kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen.

72-kDa gelatinase/type IV collagenase is an important matrix metalloproteinase in the degradation of basement membranes and denatured collagens (gelatin). These proteolytic processes are required for pathologic tissue destruction and physiologic tissue remodeling. To investigate the molecular determinants of substrate specificity of this enzyme, a 21-kDa domain of 72-kDa gelatinase, consisting of three tandem fibronectin type II-like modules, was expressed in Escherichia coli. Similar to full-length 72-kDa gelatinase and the type II modules in fibronectin, the recombinant (r) fibronectin-like domain of this proteinase bound denatured type I collagen with an apparent Kd in the micromolar range. This domain, designated the collagen-binding domain (rCBD123), possesses at least two collagen-binding sites that can each be simultaneously occupied. rCBD123 also avidly bound elastin and denatured types IV and V collagens, but neither native types IV and V collagens nor fibronectin, all of which are substrates of the enzyme. Although 72-kDa gelatinase is involved in basement membrane degradation, rCBD123 also did not bind reconstituted basement membrane, laminin, or SPARC. Native type I collagen, which is not degraded by 72-kDa gelatinase, competed with gelatin for a shared binding site on rCBD123. rCBD123 also displaced full-length 72-kDa gelatinase bound to native type I collagen, further demonstrating that the collagen binding properties of the recombinant domain closely mimicked those of the full-length enzyme. Since rCBD123 showed reduced binding to pepsin-cleaved type I collagen, either or both of the collagen telopeptide ends contain recognition sites for the 72-kDa gelatinase fibronectin-like domain. This was confirmed by the avid binding of rCBD123 to the alpha 1(I) collagen cyanogen bromide fragment CB2 from the NH2-terminal telopeptide. rCBD123 also bound alpha 1(I)-CB7, which encompasses the fibronectin-binding site, and to alpha 1(I)-CB8, a fragment not bound by fibronectin. Thus, type I collagen contains multiple binding sites for rCBD123 which are partially masked by the triple helical conformation of native collagen and fully exposed upon unfolding of the triple helix. The potential of the fibronectin-like collagen binding domain of 72-kDa gelatinase to bind extracellular matrix proteins may facilitate enzyme localization in connective tissue matrices.

Base Sequence↗
PubMed1996

Serum type IV collagen in various liver diseases in comparison with serum 7S collagen, laminin, and type III procollagen peptide.

The clinical significance of the immunoreactive triple helical domain of type IV collagen in serum was evaluated in 73 healthy controls and 161 patients with various biopsy-proven liver diseases. Although serum levels of type III procollagen peptide were increased in all liver diseases, those of type IV collagen, 7S collagen, and laminin were principally increased in chronic liver diseases associated with hepatic fibrogenesis/fibrosis. In both non-alcoholic and alcoholic liver diseases, 7S collagen was increased in serum, while type IV collagen and laminin in serum were particularly increased in alcoholic liver diseases and in hepatocellular carcinoma, in which latter the sensitivity was greater for type IV collagen than for laminin. Gel filtration analysis in Sephacryl S-400 revealed type IV collagen in serum to be a single molecular form with a molecular weight that correspond to type IV collagen, whereas 7S collagen was recognized as several heterogeneous macromolecules. These findings indicate that serum type IV collagen is derived from the type IV protocollagen pool, and is a sensitive marker for the fibrogenetic process in hepatic basement membranes.

Adult↗
PubMed1996

The function of type IV collagen during Drosophila muscle development.

Type IV collagen forms a network that provides the major structural support for basement membranes. Basement membranes are specialized forms of extracellular matrix with important functions in development. One collagen gene (Dcg1) was characterized in Drosophila melanogaster and shown to encode a collagen chain related to vertebrate basement membrane type IV collagen chains. Therefore, to access the functional importance of type IV collagen during Drosophila myogenesis, we adopted two different approaches to decrease the Dcg1 gene expression in Drosophila embryos. We describe, here, that the decrease in Dcg1 gene expression causes, in particular, defective muscle attachments. These mutant phenotypes suggest that type IV collagen acts to stabilize cell-matrix interactions.

Animals↗
PubMed2000

Enterococcus faecalis adhesin, ace, mediates attachment to extracellular matrix proteins collagen type IV and laminin as well as collagen type I.

Adhesin-mediated binding to extracellular matrix (ECM) proteins is thought to be a crucial step in the pathogenic process of many bacterial infections. We have previously reported conditional adherence of most Enterococcus faecalis isolates, after growth at 46 degrees C, to ECM proteins collagen types I and IV and laminin; identified an E. faecalis-specific gene, ace, whose encoded protein has characteristics of a bacterial adhesin; and implicated Ace in binding to collagen type I. In this study, we constructed an ace disruption mutant from E. faecalis strain OG1RF that showed marked reduction in adherence to collagen types I and IV and laminin when compared to the parental OG1RF strain after growth at 46 degrees C. Polyclonal immune serum raised against the OG1RF-derived recombinant Ace A domain reacted with a single approximately 105-kDa band of mutanolysin extracts from OG1RF grown at 46 degrees C, while no band was detected in extracts from OG1RF grown at 37 degrees C, nor from the OG1RF ace mutant grown at 37 or 46 degrees C. IgGs purified from the anti-Ace A immune serum inhibited adherence of 46 degrees C-grown E. faecalis OG1RF to immobilized collagen type IV and laminin as well as collagen type I, at a concentration as low as 1 microg/ml, and also inhibited the 46 degrees C-evoked adherence of two clinical isolates tested. We also showed in vitro interaction of collagen type IV with Ace from OG1RF mutanolysin extracts on a far-Western blot. Binding of recombinant Ace A to immobilized collagen types I and IV and laminin was demonstrated in an enzyme-linked immunosorbent assay and was shown to be concentration dependent. These results indicate that Ace A mediates the conditional binding of E. faecalis OG1RF to collagen type IV and laminin in addition to collagen type I.

Animals↗
PubMed1999

Absence of the alpha6(IV) chain of collagen type IV in Alport syndrome is related to a failure at the protein assembly level and does not result in diffuse leiomyomatosis.

X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the alpha3-alpha6 chains of collagen type IV, although each is coded by a separate gene. The molecular basis for this loss remains unclear. In canine X-linked hereditary nephritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the alpha3, alpha4, and alpha5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of alpha6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canine COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp. These two regions are >/= 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the alpha6 mRNA level remained normal in affected male dog smooth muscle while the alpha5 mRNA level was markedly reduced. However, both alpha5 and alpha6 chains were absent at the protein level. Our results suggest that production of the alpha6 chain is under a control mechanism separate from that coordinating the alpha3-alpha5 chains and that the lack of the alpha6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the alpha5 and alpha6 chains are present in the same network. The lack of the alpha6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes.

Animals↗
PubMed1989

Characterization of two possible forms of type IV collagen from human kidney cortex.

Type IV collagen was isolated from human kidney cortex according to the purification of mouse kidney type IV collagen (MKIVC) with minor modifications as described previously [Oikawa, T., et al. (1986) Chem. Pharm. Bull. 34, 789-797]. Chromatography of human kidney type IV collagen (HKIVC) on a column of DEAE-cellulose resulted in its separation into two fractions, i.e., one (HKIVC-1) passed through and the other (HKIVC-2) adsorbed to the column, similar to MKIVC. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Bio-Gel A-5m chromatography revealed that both HKIVC-1 and -2 differed from each other in the ratios of major and minor components. Amino acid analyses also demonstrated that there was a significant difference in the contents of several amino acid residues between both type IV collagens and their 80-kDa components, one of the major ones. These results indicate the possibility that there exist two forms of type IV collagen in human kidney.

Amino Acids↗
PubMed1990

Type I and type IV collagen promote adherence and spreading of human type II pneumocytes in vitro.

Human lung tissue was enzymatically digested with dispase and type II pneumocytes were subsequently separated on a discontinuous metrizamide gradient. In primary adherence assays with freshly isolated cells, mean adherence values of 21.7, 19.6, 13.4, 6.8 and 7.0% were obtained after 48 hours on type I collagen (CI), type IV collagen (CIV), fibronectin (FN), laminin (LM) and tissue culture plastic, respectively. Secondly, readherence and spreading assays were performed with type II pneumocytes, previously cultured on CI, FN, matrix of murine EHS cells, and culture plastic. After a culture period of 48 to 72 hours, the cells were replated and tested on CI, CIV, FN, LM, CI + FN, CI + LM, CIV + FN and CIV + LM substrata in order to find out whether preculture substrata can modulate the adherence response of these cells. Readherence values, 1 hour after replating, were 3.3- to 8.6-fold higher than primary adherence values after 48 hours. The highest readherence values were always obtained on collagen-containing substrata after preculture on fibronectin. Spreading values after replating ranged between 35.4 and 6.6% on collagen-containing substrata, the highest values were again obtained after preculture on FN. Less than 6.9% and 0.5% of the cells spread on pure FN and pure LM, respectively. The data of the present investigation indicate that human type II pneumocytes adhere and spread preferentially on collagenous substrata rather than on other components of the extracellular matrix. This might be important in helping us to understand the functional in vivo activity of these cells, especially as regards re-epithelialization of the injured pulmonary alveolus.

Cell Adhesion↗
PubMed1999

A peptide of the alpha3 chain of type IV collagen protects basement membrane against damage by PMN.

We have shown that basement membrane (BM) collagen (type IV), and specifically the peptide CNYYSNSYSFWLASLNPER (a.a. 185-203), from the non-collagenous domain of the alpha3 chain inhibits PMN. We examined the role of this peptide on PMN damage to BM in a vessel wall model. The presence of the endothelial monolayer as well as treatment of PMN with the alpha3(IV) 185-203 peptide reduced damage to BM by non-activated but not by activated PMN. The damage inhibition is unique to the alpha3(IV) peptide and not exhibited by comparable alpha1(IV) and alpha2(IV) chain peptides. A shorter peptide alpha3(IV) 185-191, containing the -SNS- triplet, reduced damage, whereas the one lacking the triplet, residues 194-203, was not effective. The CD47-alphavbeta3 integrin complex is the receptor for the alpha3(IV) peptide. Incubation of PMN with CD47 reactive mAb followed by the alpha3(IV) peptide abolished its protective effect on BM damage.

Amino Acid Sequence↗
PubMed1989

Radioimmunoassay for immunoreactive non-collagenous domain of type IV collagen (NC1) in serum: normal pregnancy and preeclampsia.

The use of a magnetic separation agent in a modified radioimmunoassay for the non-collagenous cross-linked region (NC1) of basement membrane collagen is described. The rabbit anti-NC1 serum employed in the assay revealed a binding behaviour similar to that reported recently (Mark et al. (1985) Eur. J. Biochem. 146, 555-562; Schuppan et al. (1986) J. Clin. Invest. 78, 241-248) with respect to the integrity of NC1-disulphide bridges, affinity to NC1 subunits and lack of reactivity with other determinants of type IV collagen. Immunoreactive serum NC1, which increased towards the end of gestation, showed a broad peak during the second trimester of pregnancy. In preeclampsia, immunoreactive serum-NC1 was slightly elevated.

Blotting, Western↗
PubMed1986

Immunohistochemical distribution of collagens types IV, V, and VI and of pro-collagens types I and III in human alveolar bone and dentine.

The aim of the present study was to characterize the composition of the organic matrix in alveolar jaw bone and dentine using antibodies against pro-collagens Types I and III and collagens Types IV, V, and VI. After demineralization of oral hard tissues in 0.2 N HCl, antigenicity was well preserved and the distribution of the pro-collagens and collagens could be demonstrated. Staining for pro-collagen Type I was prominent around osteoblasts and in pre-dentine, indicating active de novo synthesis of Type I pro-collagen. Pro-collagen Type I was ubiquitous but was less abundant in bone and dentine, whereas pro-collagen Type III was seen only in areas of bone remodeling, in peritubular spaces, and in pre-dentine. Type IV collagen was limited to the basement membranes of vessels in osteons and bone marrow. Type V collagen was detected neither in pre-dentine nor in bone. In contrast, Type VI collagen was found in dentine and bone, showing a faint but homogeneous staining which, similarly to pro-collagen Type III, was pronounced around osteoblasts and in pre-dentine, areas of active bone and dentine formation. This study showed that the organic matrix of dentine and bone contains Type VI as well as Type I collagen. Pro-collagen Type III (and to a lesser extent collagen Type VI) is transiently produced during new formation and remodeling of oral hard tissues, and disappears once the matrix calcifies. Type I pro-collagen qualifies as a general marker protein for increased osteoblastic activity. We conclude that immunostaining for the different collagen/pro-collagen types can be used to assess normal or abnormal stages of bone/dentine formation.

Adolescent↗
PubMed1988

Serum concentrations of the N-terminal propeptide of type III procollagen and two type IV collagen fragments and gene expression of the respective collagen types in liver in rats with dimethylnitrosamine-induced hepatic fibrosis.

Dimethylnitrosamine (DMN)-induced liver fibrosis was used as an experimental model to study the relationship between serum concentrations of the N-terminal propeptide of type III procollagen [S-Pro(III)-N-P] and the N-terminal (S-7S) and C-terminal (S-NC1) domains of type IV collagen and hepatic concentrations of type III and IV collagen mRNAs. Increases in S-Pro(III)-N-P, and especially in the two type IV collagen-related antigens, were found to be early events in the formation of DMN-induced hepatic fibrosis. The mean concentration of S-Pro(III)-N-P was 120% of the control mean on day 7 of DMN treatment, 230% on day 14 and 250% on day 21. The corresponding values for S-7S were 260, 950 and 1100% and, for S-NC1, 310, 820 and 1000%. All these changes were very similar to those found in the hepatic concentrations of the respective mRNAs. These data support a previous suggestion that an enhanced production of basement-membrane (type IV) collagen is an early event in the development of the DMN-induced hepatic fibrosis. The results also indicate that S-7S and S-NC1 are very sensitive indicators of changes in type IV collagen metabolism. Data obtained in gel-filtration experiments for these three serum antigens were consistent with the suggestion that all three antigens are mainly derived from the synthesis of the respective collagens.

Animals↗