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Results for “Collagens”

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At least 127 records · Page 7Linked to original sources

PubMed1992

Inhibition of human platelet adenylate cyclase by collagen fibres. Effect of collagen is additive with that of adrenaline, but interactive with that of thrombin.

Collagen fibres in suspension have been shown to inhibit adenylate cyclase in human platelet preparations. Direct inhibition by collagen fibres was observed when intact platelets were used, although secondary events such as ADP secretion or prostanoid formation were important contributors to the inhibition of adenylate cyclase after treatment of platelets with collagen. The nature of the direct inhibition caused by collagen has been investigated in platelet membrane preparations, with the following results. (1) Collagen fibres inhibit platelet membrane adenylate cyclase in a dose-dependent manner. (2) Inhibition of adenylate cyclase by thrombin, adrenaline or collagen fibres could be abolished in the presence of guanosine 5'-[beta-thio]diphosphate; half-maximal inhibition was obtained at about 100 microM for the inhibitory action of thrombin, and at about 500 microM for that of either adrenaline or collagen. (3) The action of each ligand was blocked to a similar extent by pertussis-toxin treatment of the platelet membranes. Taken together, these results indicate that the action of collagen, like that of thrombin and adrenaline, is G-protein-dependent. (4) inhibition of adenylate cyclase by collagen fibres was additive with that caused by adrenaline, but co-operative with that caused by thrombin, suggesting that inhibitory pathways exists for collagen and adrenaline which are distinct from, but interactive with, that for thrombin. (5) Modification of the collagen fibres by pepsin treatment attenuated the effects of collagen, whereas heat-denaturation of the collagen fibres completely abolished their effects. These data suggest that the effects of collagen are specific, and depend on the detailed structure of the collagen fibres.

Adenylyl Cyclase Inhibitors↗

PubMed1995

The mRNAs for the three chains of human collagen type XI are widely distributed but not necessarily co-expressed: implications for homotrimeric, heterotrimeric and heterotypic collagen molecules.

In cartilage collagen type XI exists as heterotrimeric molecules composed of alpha 1(XI), alpha 2(XI) and alpha 3(XI) subunits. Messenger RNAs for some of the alpha chains of collagen type XI have also been found in non-chondrogenic tissues but the chain composition of the molecule in these sites is not known. Some non-chondrogenic tissues also contain heterotrimers containing collagen alpha 2(V) and alpha 1(XI) chains. We have explored the possibility that collagen type XI could exist in differing trimeric forms in non-chondrogenic tissues and aimed to predict the subunit composition of this collagen in those tissues. The distribution and relative levels of expression of collagen alpha 1(XI), alpha 2(XI) and alpha 3(XI)/alpha 1(II) mRNAs in different human fetal tissues were studied. Expression of mRNAs for all three genes of collagen type XI is not restricted to cartilage but is widespread. However, in some non-chondrogenic tissues, the mRNAs for all three alpha chains of collagen type XI were not co-expressed, but collagen alpha 1(XI) and alpha 2(XI) mRNAs were found either singly or without collagen alpha 3(XI) transcripts. Collagen type XI may therefore exist as homotrimers and/or heterotrimers composed of two collagen alpha(XI) chains in some tissues. The distribution of mRNAs for collagen alpha 2(V) and alpha 1(I) were also studied. Co-expression of collagen type XI, alpha 2(V) and alpha 1(I) mRNAs was found for many tissues. These findings have implications for the possibility of additional chain associations for collagen types XI and V in cross-type heterotrimers within heterotypic fibrils.

Cartilage↗

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

Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I.

The specific binding of the amyloid precursor protein (APP) to extracellular matrix molecules suggests that APP regulates cell interactions and has a function as a cell adhesion molecule and/or substrate adhesion molecule. On the molecular level APP has binding sites for collagen, laminin, and glycosaminoglycans which is a characteristic feature of cell adhesion molecules. We have examined the interactions between the APP and collagen types I and IV and identified the corresponding binding sites on APP and collagen type I. We show that APP bound most efficiently to collagen type I in a concentration-dependent and specific manner in the native and heat-denatured states, suggesting an involvement of a contiguous binding site on collagen. This binding site was identified on the cyanogen bromide fragment alpha 1(I)CB6 of collagen type I, which also binds heparin. APP did not bind to collagen type I-heparin complexes, which suggests that there are overlapping binding sites for heparin and APP on collagen. We localized the site of APP that mediates collagen binding within residues 448-465 of APP695, which are encoded by the ubiquitously expressed APP exon 12, whereas the high affinity heparin binding site of APP is located in exon 9. Since a peptide encompassing this region binds to collagen type I and inhibits APP-collagen type I binding in nanomolar concentrations, this region may comprise the major part of the collagen type I binding site of APP. Moreover, our data also indicate that the collagen binding site is involved in APP-APP interaction that can be modulated by Zn(II) and heparin. Taken together, the data suggest that the regulation of APP binding to collagen type I by heparin occurs through the competitive binding of heparin and APP to collagen.

Amino Acid Sequence↗

PubMed2003

Covalent and non-covalent interactions of betaig-h3 with collagen VI. Beta ig-h3 is covalently attached to the amino-terminal region of collagen VI in tissue microfibrils.

Transforming growth factor-beta induced gene-h3 (betaig-h3) was found to co-purify with collagen VI microfibrils, extracted from developing fetal ligament, after equilibrium density gradient centrifugation under both nondenaturing and denaturing conditions. Analysis of the collagen VI fraction from the non-denaturing gradient by gel electrophoresis under non-reducing conditions revealed the present of a single high molecular weight band that immunostained for both collagen VI and betaig-h3. When the fraction was analyzed under reducing conditions, collagen VI alpha chains and betaig-h3 were the only species evident. The results indicated that betaig-h3 is associated with collagen VI in tissues by reducible covalent bonding, presumably disulfide bridges. Rotary shadowing and immunogold staining of the collagen VI microfibrils and isolated tetramers indicated that betaig-h3 was specifically and periodically associated with the double-beaded region of many of the microfibrils and that this covalent binding site was located in or near the amino-terminal globular domain of the collagen VI molecule. Using solid phase and co-immunoprecipitation assays, recombinant betaig-h3 was found to bind both native and pepsin-treated collagen VI but not individual pepsin-collagen VI alpha chains. Blocking experiments indicated that the major in vitro betaig-h3 binding site was located in the pepsin-resistant region of collagen VI. In contrast to the tissue situation, the in vitro interaction had the characteristics of a reversible non-covalent interaction, and the Kd was measured as 1.63 x 10(-8) m. Rotary shadowing of immunogold-labeled complexes of recombinant betaig-h3 and pepsin-collagen VI indicated that the in vitro betaig-h3 binding site was located close to the amino-terminal end of the collagen VI triple helix. The evidence indicates that collagen VI may contain distinct covalent and non-covalent binding sites for betaig-h3, although the possibility that both interactions use the same binding region is discussed. Overall the study supports the concept that betaig-h3 is extensively associated with collagen VI in some tissues and that it plays an important modulating role in collagen VI microfibril function.

Animals↗

PubMed1993

Increased collagen synthesis and increased content of type VI collagen in myocardium of tight skin mice.

OBJECTIVE: The tight skin mouse (TSK) is a mutant strain characterised by excessive collagen accumulation in skin and some internal organs such as the heart. The aims of this study were (1) to examine in vitro collagen synthesis in TSK myocardium; (2) to determine myocardial content of type VI collagen in the same model; and (3) to examine the expression of one of the genes for type VI collagen in cultured TSK myocardial fibroblasts. METHODS: Individual hearts from 8 month old heterozygous male TSK and normal sex and age matched mice were incubated with 14C proline. Total 14C protein and 14C collagen synthesis by myocardial tissues were determined with collagenase digestion and SDS gel electrophoresis. For determination of type VI collagen, hearts from 10 month old male TSK and normal mice were subjected to guanidine extraction followed by pepsin digestion, salt fractionation, and western blotting. Expression of the alpha 2(VI) collagen gene was determined in myocardial fibroblasts cultured from TSK and normal mice, employing northern and dot blot hybridizations with a murine specific cDNA. RESULTS: TSK hearts had up to twofold greater protein and collagen biosynthesis and 2.5-fold greater type VI collagen content (400 micrograms v 156 micrograms). Fibroblasts cultured from TSK mice hearts displayed up to threefold higher steady state concentrations of alpha 2(VI) collagen mRNA than normal myocardial fibroblasts. CONCLUSIONS: Hearts from TSK mice showed increased protein and collagen biosynthesis and increased myocardial content of type VI collagen compared with hearts from age matched normal mice. Also, fibroblast cultures from TSK mice myocardium showed increased expression of the alpha 2(VI) collagen gene, indicating that increased transcription of type VI collagen genes may be responsible for the accumulation of this collagen in myocardium from TSK mice.

Animals↗

PubMed1999

Interaction of collagen molecules from the aspect of fibril formation: acid-soluble, alkali-treated, and MMP1-digested fragments of type I collagen.

Collagen type I extracted with acid or digested with pepsin forms fibrils under physiological conditions, but this ability is lost when the collagen is treated with alkaline solution or digested with matrix metalloproteinase 1 (MMP1). When acid-soluble collagen was incubated with alkali-treated collagen, the fibril formation of acid-soluble collagen was inhibited. At 37 degrees C, at which alkali-treated collagen is denatured, the lag time was prolonged but the growth rate of fibrils was not affected. At 30 degrees C, at which the triple helical conformation of alkali-treated collagen is retained, the lag time was prolonged and the growth rate reduced. Heat-denatured alkali-treated collagen and MMP1-digested fragments have no inhibitory effect on the fibril formation of acid-soluble collagen. This means that the triple helical conformation and the molecular length are important factors in the interaction of collagen molecules and that alkali-treated collagen acts as a competitive inhibitor for fibril formation of collagen. We found that alkali-treated collagen and MMP1-digested fragments form fibrils that lack the D periodic banding pattern and twisted morphology under acidic conditions at the appropriate ionic strength. We also calculated the relative strengths of hydrophobic and electrostatic interactions between collagen molecules. When the hydrophobic interaction between linear collagen molecules was considered, we found a pattern of periodic maximization of the interactive force including the D period. On the other hand, the electrostatic interaction did not show the periodic pattern, but the overall interaction score affected fibril formation.

Acids↗

PubMed1986

Preparation of [3H]collagen for studies of the biologic fate of xenogenic collagen implants in vivo.

Reduction of a commercially available, pepsin-solubilized, bovine dermal collagen (Vitrogen 100) with sodium [3H]borohydride provided radiolabeled collagen preparations with specific activities ranging from 7.1-12.0 muCi/mg collagen. These specific activities were 2-3 times greater than those obtained by reduction of intact rat tail tendon collagen under similar conditions. The alpha, beta, and higher aggregate components of type I collagen were radiolabeled as well as the alpha component of a small amount of type III collagen present in the samples. Fractionation of cyanogen bromide peptides showed that alpha 1(I)CB7, alpha 1(I)CB8, and alpha 2(I)CB3,5 were the predominant peptides labeled by this procedure. Amino acid analysis indicated that the majority of the radioactivity was in reducible cross-links, precursors of these cross-links, and in hexosyllysine residues. Reconstitution experiments comparing this radiolabeled collagen with nonlabeled collagen showed them to be indistinguishable. Bacterial collagenase digestion of this reconstituted fibrillar collagen in both a lightly cross-linked (glutaraldehyde 0.0075%) and noncross-linked form provided evidence that digestion of labeled and nonlabeled collagens proceeded at similar rates. Thus, labeling did not change the properties of the collagen. Cross-linking made the preparation refractory to proteolytic degradation. Injection of fibrillar collagen preparations, spiked with radiolabeled collagen, into the guinea pig dermis followed by quantitation of the amount of radioactivity recovered from implant sites as a function of time, indicated that the lightly cross-linked samples also were more resistant to degradation in vivo than the noncross-linked preparation. The half-life of noncross-linked collagen was about 4 days while that of the cross-linked collagen was about 25 days. These degradation rates were much faster than observed for similar, nonlabeled samples injected into the dermis of humans, presumably due to a higher metabolic activity in the guinea pig dermis.

Animals↗

PubMed1985

Adoptive transfer of suppression of arthritis in the mouse model of collagen-induced arthritis. Evidence for a type II collagen-specific suppressor T cell.

This study details the suppressive mechanism involved in the antigen-specific suppression of collagen-induced arthritis. Intravenous injection of 500 micrograms of soluble native type II collagen 3 d before immunization with native type II collagen emulsified in complete Freund's adjuvant resulted in animals with decreased in vitro cellular and humoral immune response to native and denatured type II collagen compared with control groups. Control groups were composed of animals preinoculated with saline and type I collagen and established the antigen-specific nature of the observed suppression. Mice with reduced immune responses to type II collagen also were observed to portray little or no erythema and edema associated with collagen-induced arthritis. Adoptive transfer experiments established the requirement of T cells for the suppression of collagen-induced arthritis. Analysis of the phenotype of responding splenic cells in chronic immunotherapeutically suppressed mice in vitro revealed that responding cells were Ly1-2+ (suppressor/cytotoxic) T cells. On the other hand, the cellular phenotype of T cells responding to type II collagen in nonsuppressed collagen-induced arthritic mice was Ly1+2- (helper/inducer T cells). The data indicate that type II collagen-specific T cells are generated on intravenous inoculation of soluble native type II collagen. These cells are observed in type II collagen-immune animals, which are nonarthritic and portray reduced humoral and in vitro cellular immune response to type II collagen. This study suggests that specific suppression of immune responses to type II collagen by T-suppressor cells can be immunotherapeutic in certain forms of arthritis.

Animals↗

PubMed1995

Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to TGF-beta.

Transforming growth factor-beta, a potent modulator of cell function, induces fibroblasts cultured on plastic to increase collagen synthesis. In 5- and 7-day porcine skin wounds, which have minimal to moderate collagen matrix, respectively, transforming growth factor-beta and type I procollagen were coordinately expressed throughout the granulation tissue. However, in 10-day collagen-rich granulation tissue type I procollagen expression diminished despite persistence of transforming growth factor-beta. To investigate whether collagen matrix attenuates the collagen-synthetic response of fibroblasts to transforming growth factor-beta, we cultured human dermal fibroblasts in conditions that simulate collagen-rich granulation tissue. Therefore, human dermal fibroblasts were suspended in attached collagen gels and collagen and noncollagen production was assayed in the absence and presence of transforming growth factor-beta. Although transforming growth factor-beta stimulated collagen synthesis by fibroblasts cultured in the collagen gels, these fibroblasts consistently produced less collagen than similarly treated fibroblasts cultured on plastic. This phenomenon was not secondary to nonspecific binding of transforming growth factor-beta to the collagen matrix. Fibroblasts cultured in a fibrin gel responded to transforming growth factor-beta similarly to fibroblasts cultured on plastic. Using immunofluorescence probes to type I procollagen, we observed that transforming growth factor-beta increased type I procollagen expression in most fibroblasts cultured on plastic, but only in occasional fibroblasts cultured in collagen gels. From these data we conclude that collagen matrices attenuate the collagen synthetic response of fibroblast to transforming growth factor-beta in vitro and possibly in vivo.

Animals↗

PubMed1992

Copolymerization of normal type I collagen with three mutated type I collagens containing substitutions of cysteine at different glycine positions in the alpha 1 (I) chain.

Previous observations with type I collagen from a proband with lethal osteogenesis imperfecta demonstrated that type I collagen containing a substitution of cysteine for glycine alpha 1-748 copolymerized with normal type I collagen (Kadler, K. E., Torre-Blanco, A., Adachi, E., Vogel, B. E., Hojima, Y., and Prockop, D. J. (1991) Biochemistry 30, 5081-5088). Here, three preparations containing normal type I procollagen and type I procollagen with a substitution of cysteine for glycine alpha 1-175, glycine alpha 1-691, or glycine alpha 1-988 were purified from cultured skin fibroblasts from probands with osteogenesis imperfecta. The procollagens were then used as substrates in a system for assaying the self-assembly of type I collagen into fibrils. The cysteine-substituted collagens in all three preparations were incorporated into fibrils. The cysteine alpha 1-175 and cysteine alpha 1-691 collagens were shown to increase the lag time and decrease the propagation rate constant for fibril assembly. All three preparations containing cysteine-substituted collagens formed fibrils with diameters that were two to four times the diameter of fibrils formed under the same conditions by normal type I collagen. Also, the three preparations containing cysteine substituted collagens had higher solubilities than normal type I collagen. The results, therefore, demonstrated that the three cysteine-substituted collagens copolymerized with normal type I collagen. The effects of the mutated collagens on fibril assembly can be understood in terms of a recently proposed model of fibril growth from symmetrical tips by assuming that the mutated monomers partially inhibit tip growth but not lateral growth of the fibrils. Of special interest was the observation that the Cys alpha 1-175 collagen from a proband with a non-lethal variant of osteogenesis imperfecta had quantitatively less effect on several parameters of fibril assembly at 37 degrees C than cysteine-substituted collagens from three probands with lethal variants of the disease.

Adult↗

PubMed1994

Type XI collagen-induced arthritis in the Lewis rat. Characterization of cellular and humoral immune responses to native types XI, V, and II collagen and constituent alpha-chains.

Autoimmune arthritis can be induced in rats by immunization with cartilage-specific types II and XI collagen. Type XI collagen is composed of alpha 1(XI), alpha 2(XI), and alpha 3(XI) chains, in which alpha 3(XI) is essentially identical to alpha 1(II) of type II, and alpha 1(XI) and alpha 2(XI) are similar to alpha 1(V) and alpha 2(V) of type V collagen. To characterize the immune response to type XI collagen, Lewis rats were injected with bovine type XI collagen, and the cellular and humoral responses were compared with those of rats injected with types V and II collagen. Arthritis, IgG deposits in cartilage, and joint destruction were seen in rats immunized with types XI and II collagen. Type XI elicited strong cellular responses to rat types XI, V, and II; conversely, types II and V collagen elicited strong responses to rat type XI. Antitype XI Abs reacted with rat type XI, moderately with rat type V, but poorly with rat type II. Direct and inhibition ELISA showed that cross-reactions between types XI and V collagen resulted from recognition of determinants shared by their respective alpha 2(XI) and alpha 1(V) chains. Abs eluted from joints of rats immunized with type XI collagen, however, reacted only with native rat type XI collagen. These data demonstrate that type XI collagen induces diverse populations of Abs differing in collagen-type specificity, and suggest that only those Abs to native rat type XI collagen are central to the pathogenesis of type XI collagen-induced arthritis.

Animals↗

PubMedDate not supplied

Imbalance in the synthesis of collagen type I and collagen type III in smooth muscle cells derived from human varicose veins.

Varicose veins have a thickening wall. Their smooth muscle cells are disorganized as regards proliferation and production of extracellular matrix protein. An imbalance between the synthesis of collagen type I protein (collagen I) and collagen type III protein (collagen III) could explain the lack of elasticity of varicose veins. Therefore, collagen synthesis was compared in the media and in cultured smooth muscle cells derived from human control and varicose saphenous veins. An increase in total collagen synthesis was observed in the media and in smooth muscle cells derived from varicose veins. This augmentation was due to an overproduction of collagen I in cultured cells from varicose veins consistent with an increase in the release of collagen I metabolites in the media. A concomitant decrease in collagen III was observed in cultures of smooth muscle cells from varicose veins. The increase in the synthesis of collagen I in cells from varicose veins was correlated with an overexpression of the gene since mRNAs for collagen I were augmented without change in mRNA-half-life. This augmentation in the synthesis of collagen I was reduced by the addition of exogenous collagen III in cultures from varicose veins. These findings suggest a dysregulation of the synthesis of collagen I and III in smooth muscle cells derived from varicose veins.

Aged↗

PubMed2003

Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen.

The functional integrity of articular cartilage is dependent on the maintenance of the extracellular matrix (ECM), a process which is controlled by chondrocytes. The regulation of ECM biosynthesis is complex and a variety of substances have been found to influence chondrocyte metabolism. In the present study we have investigated the effect of degraded collagen on the formation of type II collagen by mature bovine chondrocytes in a cell culture model. The culture medium was supplemented with collagen hydrolysate (CH) and biosynthesis of type II collagen by chondrocytes was compared to control cells treated with native type I and type II collagen and a collagen-free protein hydrolysate. The quantification of type II collagen by means of an ELISA technique was confirmed by immunocytochemical detection as well as by the incorporation of (14)C-proline in the ECM after a 48 h incubation. Chondrocytes in the control group were maintained in the basal medium for 11 days. The presence of extracellular CH led to a dose-dependent increase in type II collagen secretion. However, native collagens as well as a collagen-free hydrolysate of wheat proteins failed to stimulate the production of type II collagen in chondrocytes. These results clearly indicate a stimulatory effect of degraded collagen on the type II collagen biosynthesis of chondrocytes and suggest a possible feedback mechanism for the regulation of collagen turnover in cartilage tissue.

Animals↗

PubMed2006

Collagen type V enhances matrix contraction by human periodontal ligament fibroblasts seeded in three-dimensional collagen gels.

Extracellular matrix components play an important role in modulating cellular activity. To study such capacities of the matrix, fibroblasts are frequently cultured in a three-dimensional gel and contraction is assessed as a measure of cellular activity. Since a connective tissue contains several types of collagen, we investigated the effect of gels composed of collagen I alone or in combination with 10% collagen III and/or 5% collagen V on contraction by human periodontal ligament fibroblasts. Gels containing collagen V contracted much faster than those without this type of collagen. Blocking of the integrin beta1-subunit with an activity-blocking antibody delayed (gels with collagen V) or almost completely blocked (gels without collagen V) contraction. Use of an antibody directed against integrin alpha2beta1 resulted in delay of gel contraction for gels both with and without collagen V. Anti-integrin alpha v beta3 or RGD peptides partially blocked contraction of gels containing collagen V, but had no effect on gels consisting of collagen I alone. The beta1-containing integrins are involved in the basal contraction by fibroblasts that bind to collagens I and III. The enhanced contraction, stimulated by collagen V, appears to be mediated by integrin alpha v beta3. We conclude that collagen V may play an important modulating role in connective tissue contraction. Such a modulation may occur during the initial stages of wound healing and/or tissue regeneration.

Adult↗

PubMed1996

The A-domain of integrin alpha 2 binds specifically to a range of collagens but is not a general receptor for the collagenous motif.

Integrin alpha 2 beta 1 is a major cellular receptor for collagens, but the molecular basis of its function is unknown. The alpha 2 subunit contains a von Willebrand factor A-domain (I-domain) in its N-terminal region, and it has been demonstrated recently that this domain binds specifically to collagen I. This interaction requires divalent cations (e.g., Mg2+) and native collagen conformation, as does binding of the parent integrin to collagen. The alpha 2 A-domain therefore has a number of functional similarities to the parent integrin, alpha 2 beta 1. However, while sequence specificity has been demonstrated for the parent integrin, no such observations have been made for the A-domain. In particular, it is not known whether the A-domain is responsible for sequence-specific recognition of collagens or whether it binds to the genetic collagenous motif. To investigate the ligand specificity of the alpha 2 A-domain, its binding to a range of collagenous ligands has been studied, with cation dependence, collagen triple-helicity, and inhibition by function-blocking antibodies as criteria for specificity. Binding of the parent integrin was examined for comparison. The alpha 2 A-domain was found to bind specifically to collagens I, II, IV and XI. The complement component C1q has a collagenous domain but this was unable to support specific binding of alpha 2 A-domain or alpha 2 beta 1. Furthermore, synthetic triple-helical collagenous peptides failed to act as specific ligands. In conclusion, the alpha 2 A-domain binds specifically to a range of extracellular matrix collagens, but it is not a receptor for all collagenous triple helices. By inference, these findings indicate the existence of an integrin-specific sequence motif within collagenous ligands recognised by the alpha 2 A-domain.

Antigens, CD↗

PubMed2001

Collagens and collagen-related diseases.

The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than 20 collagen types with altogether at least 38 distinct polypeptide chains, and more than 15 additional proteins that have collagen-like domains. Most collagens form polymeric assemblies, such as fibrils, networks and filaments, and the superfamily can be divided into several families based on these assemblies and other features. All collagens also contain noncollagenous domains, and many of these have important functions that are distinct from those of the collagen domains. Major interest has been focused on endostatin, a fragment released from type XVIII collagen, which potently inhibits angiogenesis and tumour growth. Collagen synthesis requires eight specific post-translational enzymes, some of which are attractive targets for the development of drugs to inhibit collagen accumulation in fibrotic diseases. The critical roles of collagens have been clearly illustrated by the wide spectrum of diseases caused by the more than 1,000 mutations that have thus far been identified in 22 genes for 12 out of the more than 20 collagen types. These diseases include osteogenesis imperfecta, many chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, Alport syndrome, Bethlem myopathy, certain subtypes of epidermolysis bullosa, Knobloch syndrome and also some cases of osteoporosis, arterial aneurysms, osteoarthrosis, and intervertebral disc disease. The characterization of mutations in additional collagen genes will probably add further diseases to this list. Mice with genetically engineered collagen mutations have proved valuable for defining the functions of various collagens and for studying many aspects of the related diseases.

Animals↗

PubMed2004

Increased collagen turnover is only partly associated with collagen fiber deposition in the arterial response to injury.

OBJECTIVE: In the arterial response to injury, collagen breakdown has been studied extensively, but little is known on collagen synthesis and fiber formation. Here, we studied in vivo collagen synthesis and collagen fiber content in relation to collagen breakdown following arterial balloon injury. METHODS AND RESULTS: Twenty-five New Zealand White rabbits were balloon dilated in femoral and iliac arteries and terminated at 2, 7, 14 and 28 days. From day 7, both constrictive arterial remodeling and intimal hyperplasia were observed. Collagen degradation, synthesis and fiber content were studied using zymography, quantitative Polymerase Chain Reaction, Western blotting and picrosirius red staining. Collagen synthesis, reflected by procollagen I and heat shock protein 47 (Hsp47) expression, increased at day 2 with a maximum at day 14 and was accompanied by increased collagen breakdown as reflected by matrix metalloproteinase-1 and -2 levels. Collagen content in media and adventitia only increased between days 2 and 7 after balloon injury. CONCLUSIONS: In the first week after arterial injury, increased collagen content is associated with increased collagen synthesis and degradation. However, after 1 week, collagen turnover remains high in contrast to increased collagen fiber content. This suggests that after 1 week, collagen turnover is used for other processes like cell migration and arterial remodeling.

Angioplasty, Balloon↗