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PubMed1992

The modular architecture of vertebrate collagens.

Collagens are typical mosaic proteins containing a number of shuffled domains. These domains have been classified by sequence similarity in order to characterize their structural and functional relationships to other proteins. This analysis provides an overview of homologies of collagen domains. It also reveals two new relationships: (i) a module common to type V, IX, XI, and XII collagens was found to be homologous to the heparin binding domain of thrombospondin; (ii) the modular architecture of a human type VII collagen fragment was identified. Its N-terminal globular domain contains fibronectin type III repeats located adjacent to a Von Willebrand factor type A module. The proposed structural similarities point to analogous subfunctions of the respective domains in otherwise distinct proteins.

Amino Acid Sequence↗
PubMed1994

The triple-helical region of human type XIX collagen consists of multiple collagenous subdomains and exhibits limited sequence homology to alpha 1(XVI).

We previously isolated a clone from a human rhabdomyosarcoma (RH) cDNA library coding for a collagen chain different from those constituting the 18 reported types (Myers, J. C., Sun, M. J., D'Ippolito, J. A., Jabs, E. W., Neilson, E. G., and Dion, A. S. (1993) Gene (Amst.) 123, 211-217). The sequence translated to a 186-amino acid noncollagenous region, a 524-residue three-subdomain collagenous region, and a presumed 8-amino acid COOH-terminal peptide. To further elucidate the primary structure of this collagen, we have now determined the sequence of additional cDNA clones. Overlapping 3' clones, found to diverge exactly where the noncollagenous 8-residue COOH sequence began, encode two additional collagenous subdomains of 168 and 70 residues and a 19-residue COOH-terminal peptide. Analysis of genomic DNA spanning the region in question revealed several 45- and 51-base pair exons linked by 4 introns totaling over 5 kilobases (kb). A 2-kb intron, absent from the clones coding for the extended collagenous region, was used in Northern blot hybridization to detect an apparently prevalent splicing intermediate 2 kb larger than the major 12.4-kb RH transcript. Therefore, the triple-helical region of this collagen chain is likely to be composed of 832 amino acids divided into five collagenous subdomains separated by 20-44 residue interruptions. Two interruptions are similar in sequence and position to those located in the type XVI chain. Furthermore, the arrangement of 2 cysteines near the COOH terminus and two imperfections in collagenous subdomain 1 are conserved in the related subclass composed of type IX, XII, XIV, and XVI collagens. However, in contrast to the COOH-terminal interchain bridging in this latter collagen group, molecular modeling strongly predicts that the cysteines in RH collagen participate in intrachain disulfide bonds. Taken together, the data clearly show that RH collagen does not represent another chain of one of the known collagen types. We propose that it be designated the alpha 1 chain of type XIX collagen.

Amino Acid Sequence↗
PubMed2003

BMP2 initiates chondrogenic lineage development of adult human mesenchymal stem cells in high-density culture.

Human bone marrow-derived mesenchymal stem cells (MSCs) have been shown to differentiate into distinct mesenchymal tissues including bone and cartilage. The capacity of MSCs to replicate undifferentiated and to mature into cartilaginous tissues suggests these cells as an attractive cell source for cartilage tissue engineering. Here we show that the stimulation of human bone marrow-derived MSCs with recombinant bone morphogenetic protein-2 (BMP2) results in chondrogenic lineage development under serum-free conditions. Histological staining of proteoglycan with Alcian blue and immunohistochemical staining of cartilage-specific type II collagen revealed the deposition of typical cartilage extracellular matrix components. Semi-quantitative real-time gene expression analysis of characteristic chondrocytic matrix genes, such as cartilage link protein, cartilage oligomeric matrix protein, aggrecan, and types I, II, and IX collagen, confirmed the induction of the chondrocytic phenotype in high-density culture upon stimulation with BMP2 and transforming growth factor-beta3 (TGFbeta3). Histologic staining of mineralized extracellular matrix with von Kossa, immunostaining of type X collagen (typical for hypertrophic chondrocytes), and gene expression analysis of osteocalcin and adipocyte-specific fatty acid binding protein (aP2) further documented that BMP2 induced chondrogenic lineage development and not osteogenesis and/or adipogenesis in human MSCs. These results suggest BMP2 as a promising candidate for tissue engineering approaches regenerating articular cartilage on the basis of mesenchymal progenitors from bone marrow.

Adult↗
PubMed1997

Incomplete processing of type II procollagen by a rat chondrosarcoma cell line.

The Swarm rat chondrosarcoma cell line, RCS-LTC, deposits an extracellular matrix that contains the typical type II, IX, and XI collagen phenotype of hyaline cartilage, but the fibrils appear abnormally thin. By N-terminal sequence analysis, the type II collagen from the matrix was shown to have retained its N-propeptides with no evidence of normal processing to type II collagen. Amplification and sequencing of cDNA prepared from the pro alpha1(II) mRNA of these cells showed a normal N-propeptide cleavage site. Furthermore, the type II N-procollagen could be processed to type II collagen by incubation with culture medium from normal chondrocytes. The findings indicate that the RCS-LTC cell line fails to express an active type II procollagen N-proteinase and, therefore, offers a useful culture system in which to study the role of N-propeptide removal in fibrillogenesis.

Amino Acid Sequence↗
PubMed1996

Identification of the endothelial cell binding site for factor IX.

We previously demonstrated that the primary region of factor IX and IXa responsible for saturable specific binding to bovine aortic endothelial cells resides in residues 3-11 at the amino terminus of factor IX. We also demonstrated that mutations of lysine to alanine at residue 5, factor IX K5A, or valine to lysine at residue 10, factor IX V10K, resulted in a molecule unable to bind to endothelial cells. Moreover, a mutation with lysine to arginine at residue 5, factor IX K5R, resulted in a factor IX molecule with increased affinity for the endothelial cell binding site. In this paper we report that collagen IV is a strong candidate for the factor IX binding site on endothelial cells. Factor IX and factor IX K5R compete with 125I-labeled factor IX for binding to tetrameric collagen IV immobilized on microtiter plates, while factor X, factor VII, and factor IX K5A or V10K fail to compete. The Kd for wild-type factor IX binding to collagen IV in the presence of heparin was 6.8 +/- 2 nM, and the Kd for factor IX K5R was 1.1 +/- 0.2 nM, which agrees well with our previously published Kd values of 7.4 and 2.4 nM for binding of the same proteins to endothelial cells. Our working assumption is that we have identified the endothelial cell binding site and that it is collagen IV. Its physiological relevance remains to be determined.

Animals↗
PubMed1997

The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction.

Recombinant human procollagenase-3 and a C-terminal truncated form (Delta249-451 procollagenase-3) have been stably expressed in myeloma cells and purified. The truncated proenzyme could be processed by aminophenylmercuric acetate via a short-lived intermediate form (N-terminal Leu58) to the final active form (N-terminal Tyr85). The kinetics of activation were not affected by removal of the hemopexin-like C-terminal domain. The specific activities of both collagenase-3 and Delta249-451 collagenase-3 were found to be similar using two quenched fluorescent substrates, but Delta249-451 collagenase-3 failed to cleave native triple helical collagens (types I and II) into characteristic one- and three-quarter fragments. It was noted, however, that the beta1,2(I) chains of type I collagen were susceptible to Delta249-451 collagenase-3, which indicates that the catalytic domain displays telopeptidase activity, thereby generating alpha1,2(I) chains that are slightly shorter than those in native type I collagen. It can be concluded that the C-terminal domain is only essential for the triple helicase activity of collagenase-3. Binding of procollagenase-3 and active collagenase-3 to type I collagen is mediated by the C-terminal domain. Both collagenase-3 and Delta249-451 collagenase-3 hydrolyzed the large tenascin C isoform, fibronectin, recombinant fibronectin fragments, and type IV, IX, X, and XIV collagens; thus, these events were independent from C-terminal domain interactions. In contrast, the minor cartilage type XI collagen was resistant to cleavage. Kinetic analysis of the mechanism of inhibition of wild-type and Delta249-451 collagenase-3 by wild-type and mutant tissue inhibitors of metalloproteinase (TIMPs) revealed that the association rates for complex formation were influenced by both N- and C-terminal domain interactions. The C-terminal domain of wild-type collagenase-3 promoted increased association rates with the full-length inhibitors TIMP-1 and TIMP-3 and the hybrid N.TIMP-2/C.TIMP-1 by a factor of up to 33. In contrast, the association rates for complex formation with TIMP-2 and N.TIMP-1/C.TIMP-2 were only marginally affected by C-terminal domain interactions.

Amino Acid Sequence↗
PubMedDate not supplied

Cellular, biochemical and molecular characterization of the bovine temporomandibular joint disc.

The cellular and collagenous components of the bovine temporomandibular joint (TMJ) disc have been isolated and analysed. In the central regions of the disc, significant amounts of type I, II, IX and XII collagen were found. The identity of these molecules was verified with collagenase digestions, Western blot analysis and Northern blot analysis (for type II collagen). Cells isolated from the TMJ disc synthesized alkaline phosphatase, proteoglycans and collagen in culture; however, the basal rate of synthesis for these molecules was lower than that for isolated osteoblasts, articular and growthplate chondrocytes. The TMJ disc cells proliferated more rapidly in culture than osteoblasts or chondrocytes. Transforming growth factor-beta stimulated proliferation by 250%, whereas prostaglandin E2 had no effect.

Alkaline Phosphatase↗
PubMed1990

Binding of the J1 adhesion molecules to extracellular matrix constituents.

The J1 glycoproteins can be obtained in multiple forms in the soluble fraction of developing and adult mouse brain tissue. They are recovered as two forms of apparent molecular weights of 160,000 and 180,000 (J1-160) from adult mouse brain and as forms of apparent molecular weights of 200,000 and 220,000 (J1-220) from developing brain. J1-160 and J1-220 share common epitopes but are considered as separate entities, with J1-220 being immunochemically closely related if not identical to tenascin. Based on the observation that J1 immunoreactivity appears on basement membrane and interstitial collagens after denervation of the neuromuscular junction in adult rodents, we became interested in investigating the binding properties of J1 glycoproteins to extracellular matrix constituents in vitro. Both J1-160 and J1-220 bound to collagens type I-VI and IX but not to laminin, fibronectin, bovine serum albumin, or gelatin under hypotonic buffer conditions. Under isotonic buffer conditions, J1-220 bound to all collagen types, whereas J1-160 bound only to collagen types V and VI with values that could be examined by Scatchard analysis. Binding of J1-220 to collagens displayed two binding constants (KD) between 1.5 and 4.4 X 10(-9) and 1.8 and 5.5 X 10(-8) M, respectively, under hypotonic buffer conditions and a single KD of 2.1-8.0 X 10(-8) M under isotonic buffer conditions. Binding of J1-160 to collagens had an apparent KD of 1.9-8.0 X 10(-9) M under hypotonic buffer conditions. Under isotonic buffer conditions, binding constants of J1-160 to collagen types V and VI were approximately 2 X 10(-8) M. Binding of J1-220 to collagen type I could be inhibited by J1-220, J1-160, and collagen type VI but not by fibronectin or gelatin. Conversely, binding of J1-160 was inhibited by J1-220, J1-160, and collagen type VI (in order of decreasing efficacy of competition). J1-160 and J1-220 were retained on a heparin-agarose column and eluted in a salt gradient at approximately 0.5 M NaCl. The formation of the J1-heparin complexes was inhibited 100-fold more efficiently by heparin than by chondroitin sulfate. These experiments show that J1 glycoproteins resemble in many respects the extracellular matrix constituents fibronectin, laminin, vitronectin, and von Willebrand factor.

Animals↗
PubMed1998

Immunolocalisation of collagens in the developing rat molar tooth.

This study identifies different types of collagens during tooth development, maturation and ageing. Tissues from the rat first molar (from animals ranging in age from E14 to 104 wk postnatally) were immunostained using a panel of mono- and polyclonal antibodies against types I, II, III, IV, VI, IX and X collagen, fibronectin and laminin. During tooth development, types I and III collagens were expressed in the dental papilla at all stages but were also unexpectedly observed in the stellate reticulum of the enamel organ. Transient expression of type II collagen was also observed in the stellate reticulum during the late bell stage. Types IV and VI collagens, with laminin and fibronectin, were located within the basement membranes of the tooth germ. Collagen types I and III were observed within the developing follicle/periodontal ligament, type III predominating where collagen fibres were inserting into the alveolar bone and cementum. The pattern of types I and III collagen labelling within the periodontal ligament and the dental pulp did not change with age. Thus, some unusual collagen localisations were observed in the tooth germ, particularly within the stellate reticulum.

Animals↗
PubMed2005

Osteoarthritis development in novel experimental mouse models induced by knee joint instability.

OBJECTIVE: Although osteoarthritis (OA) is induced by accumulated mechanical stress to joints, little is known about the underlying molecular mechanism. To apply approaches from mouse genomics, this study created experimental mouse OA models by producing instability in the knee joints. METHODS: The models were of four types: severe, moderate, mild, and medial, depending on the severity and direction of instability imposed by combinations of ligament transection and menisectomy. OA development was evaluated by X-ray and histology by Safranin-O staining, and quantified using our original gradings. Expressions of type II, IX and X collagens and matrix metalloproteinase (MMP)-2, -3, -9 and -13 were further examined by immunohistochemistry and in situ hybridization (ISH). RESULTS: The severe, moderate and mild models exhibited OA development in the posterior tibial cartilage. The severe model showed cartilage destruction at 2 weeks and osteophyte formation at 4-8 weeks after surgery; however, the mild model showed only a partial cartilage destruction at 8 weeks. The grading confirmed that the OA disorders progressed depending on the severity of joint instability. In the medial model, the OA development in the medial tibial cartilage was similar to that in the posterior cartilage of the mild model. Among the collagens and MMPs, type X collagen and MMP-13 were markedly induced and colocalized in the early stage OA cartilage. CONCLUSION: We established four types of mouse models exhibiting various speeds of OA progression. By applying a mouse genomics approach to the models, molecular backgrounds in various stages of OA development can be clarified.

Animals↗
PubMed2001

The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis.

OBJECTIVE: Relapsing polychondritis (RP) is an inflammatory disease that mainly affects cartilage tissue in the auricle, nose, and lower respiratory tract. When tracheolaryngeal cartilage is involved, the disease is occasionally fatal. Matrilin 1 is a cartilage-specific protein most prominently expressed in tracheal cartilage, but not in joint cartilage. Immunization with the protein in rats and mice induces respiratory distress and nasal destruction, as seen in RP. We investigated the response to matrilin 1 and other cartilage proteins in sera from patients with RP, 4 additional groups of patients with other major connective tissue diseases, and healthy control subjects. METHODS: Sera were analyzed by enzyme-linked immunosorbent assay (ELISA) for antibody responses to matrilin 1, types II, IX, and XI collagen, and cartilage oligomeric matrix protein (COMP). Titers above the mean + 3SD of controls were considered positive. Specificity of matrilin 1 recognition was further investigated by the capacity of high-titer sera to block the binding of a matrilin 1-specific monoclonal antibody in inhibition ELISAs. In vivo reactivity and specificity were tested by injecting sera into neonatal mice, and antibody binding was detected by immunohistochemical staining. RESULTS: Serum antibodies from RP patients bound tracheolaryngeal and nasal cartilage in vivo and inhibited the binding of anti-matrilin 1-specific monoclonal antibodies. Thirteen of the 97 RP patients had increased titers of matrilin 1 antibody. Positive titers correlated with respiratory symptoms in 69% of the cases. Significant responses to type II collagen and COMP were also detected. CONCLUSION: Antibodies to matrilin 1 bind tracheolaryngeal cartilage in vivo and are correlated with an inflammatory attack on tracheolaryngeal cartilage that is often seen in RP.

Adult↗
PubMed1993

Alterations of collagen mRNA expression during retinoic acid induced chondrocyte modulation: absence of untranslated alpha 1(I) mRNA in hyaline chondrocytes.

Retinoic acid (RA) has been shown to rapidly modulate the collagen expression pattern of chondrocytes in vitro at doses of 1-10 microM. Embryonic chicken sternal chondrocytes stop synthesizing the cartilage-specific type II collagen within 2-4 days of RA treatment and turn on the synthesis of types I and III collagen and fibronectin. While suppression of type II collagen synthesis and onset of type III collagen and fibronectin synthesis have been shown to be regulated at the transcriptional level, conflicting data are available on a possible post-translational regulation of alpha 1(I) collagen gene expression. In this study we demonstrate by comparing a commonly used alpha 1(I) cDNA probe from the 3' end of the alpha 1(I) mRNA with a newly prepared alpha 1(I) cDNA probe from the 5' end (p1E1) that--in contrast to previous reports--chicken sternal chondrocytes do not contain untranslated alpha 1(I) mRNA which may become translatable after RA treatment. By in situ hybridization we show the absence of cytoplasmic alpha 1(I) mRNA from chondrocytes and its presence in the perichondrium of sternal cartilage. Perichondral cells might have contaminated sternal chondrocyte preparations, explaining low levels of alpha 1(I) mRNA seen by Northern hybridization and RNase protection assays of chicken sternal cartilage mRNA even with the p1E1 probe. We show by Northern hybridization and metabolic labeling with 3H-proline followed by SDS-gel electrophoresis that retinoic acid at 3 microM suppresses type II, IX, and X collagen gene expression within 2 days both at the mRNA and protein level and induces the onset of alpha 1(I), alpha 2(I), and alpha 1(III) expression within 3 days. No expression of CRABP, the cellular retinoic acid binding protein, was seen in RA-treated or control chondrocytes, indicating that CRABP protein is not involved in the RA-induced modulation of the chondrocytes.

Animals↗
PubMed1985

Morphology of the pericellular capsule in articular cartilage revealed by hyaluronidase digestion.

To allow a more valid comparison between our previous ultrastructural data and the immunolocalization of type IX and other minor collagen species in cryosectioned cartilage, we examined both normal and testicular hyaluronidase-digested canine tibial cartilage by electron microscopy. Removal of matrix proteoglycans caused the pericellular capsule to collapse against the cell surface, suggesting that its normal anatomical position is mediated by pericellular matrix hydration. Detailed examination of the pericellular capsule and pericellular channel revealed fine, faintly banded fibrils and an amorphous component somewhat similar in structure to basement membrane collagens. Matrix vesicles and the electron-dense material of the interterritorial matrix were only partially digested by hyaluronidase. We propose that the pericellular capsule is composed of a "felt-like" network of minor collagen species which act synergistically to maintain both the composition of the pericellular matrix and the integrity of the chondrocyte/pericellular matrix complex during compressive loading.

Animals↗
PubMed1993

Expression of simian virus 40 large T (tumor) oncogene in mouse chondrocytes induces cell proliferation without loss of the differentiated phenotype.

We have infected primary embryonic mouse limb chondrocytes with a retrovirus carrying simian virus 40 early regions and have obtained a monoclonal mouse chondrocyte line, MC615, that was able to grow on culture dishes for at least 7 months and 20 passages. MC615 cells show expression of simian virus 40 large T (tumor) antigen and express markers characteristic of cartilage in vivo, such as types II, IX, and XI collagen, as well as cartilage aggrecan and link protein. These data show that cell growth induced by large T oncogene expression does not prevent the maintenance of the chondrocytic phenotype.

Animals↗
PubMed1992

[Proteolytic and collagenolytic activities of the bovine vitreous body].

The vitreous contains collagen and soluble non-collagen proteins. The degeneration of collagen takes place in a different manner than in the other proteins. It has been detected that the cattle vitreous does not show any collagenolytic activity against the basic types of collagen (I, II, IX, and XI). The vitreous digests haemoglobin only in the acidic section of pH (optimum 3.5-4.5). No proteolytic activity towards Hb in physiological pH has been found.

Animals↗
PubMed1989

Binding properties of the neural cell adhesion molecule to different components of the extracellular matrix.

A soluble form of the neural cell adhesion molecule (N-CAM) was obtained from 100,000-g supernatants of crude brain membrane fractions by incubation for 2 h at 37 degrees C. The isolated N-CAM, consisting of one polypeptide chain with a molecular mass of 110 kilodaltons (N-CAM 110), was studied for its binding specificity to different components of the extracellular matrix (ECM). N-CAM 110 bound to different types of collagen (collagen types I-VI and IX). The binding efficiency was dependent on salt concentration and could be called specific according to the following criteria: (a) Binding showed substrate specificity (binding to collagens, but not to other ECM components, such as laminin or fibronectin). (b) Binding of N-CAM 110 to heat-denatured collagens was absent or substantially reduced. (c) Binding was saturable (Scatchard plot analyses were linear with KD values in the range of 9.3-2.0 X 10(-9) M, depending on the collagen type and buffer conditions). Binding of N-CAM 110 to collagens could be prevented in a concentration-dependent manner by the glycosaminoglycans heparin and chondroitin sulfate. N-CAM 110 also interacted with immobilized heparin, and this interaction could be prevented by heparin and chondroitin sulfate. Thus, in addition to its role in cell-cell adhesion, N-CAM is a binding partner for different ECM components, an observation suggesting that it also serves as a substrate adhesion molecule in vivo.

Animals↗
PubMed1991

Collagen family of proteins.

Collagen molecules are structural macro-molecules of the extracellular matrix that include in their structure one or several domains that have a characteristic triple helical conformation. They have been classified by types that define distinct sets of polypeptide chains that can form homo- and heterotrimeric assemblies. All the collagen molecules participate in supramolecular aggregates that are stabilized in part by interactions between triple helical domains. Fourteen collagen types have been defined so far. They form a wide range of structures. Most notable are 1) fibrils that are found in most connective tissues and are made by alloys of fibrillar collagens (types I, II, III, V, and XI) and 2) sheets constituting basement membranes (type IV collagen), Descemet's membrane (type VIII collagen), worm cuticle, and organic exoskeleton of sponges. Other collagens, present in smaller quantities in tissues, play the role of connecting elements between these major structures and other tissue components. The fibril-associated collagens with interrupted triple helices (FACITs) (types IX, XII, and XIV) appear to connect fibrils to other matrix elements. Type VII collagen assemble into anchoring fibrils that bind epithelial basement membranes and entrap collagen fibrils from the underlying stroma to glue the two structures together. Type VI collagen forms thin-beaded filaments that may interact with fibrils and cells.

Amino Acid Sequence↗
PubMed1989

Inherited disorders of collagen gene structure and expression.

As a result of investigations completed during the last 15 years, the molecular bases of most form of osteogenesis imperfecta (OI) and of some forms of the Ehlers-Danlos syndrome (EDS) are now known. Most forms of OI result from point mutations in the genes (COL1A1 and COL1A2) that encode the chains of type I procollagen or mutations that affect the expression of these genes. Less frequently, mutations that affect the size of the chain can also result in these phenotypes. The phenotypic presentation appears to be determined by the nature of the mutation, the chain in which it occurs, and, for point mutations, the position of the substitution and the nature of the substituting amino acid in the protein product. Similar mutations in the gene (COL3A1) that encodes the chains of type III procollagen result in the EDS type IV phenotype. Mutations which result in deletion of the cleavage site for the aminoterminal procollagen protease result in the EDS type VII phenotype and other mutations which affect the structure of the triple-helical domain by deletions and alter the conformation of the substrate at the site of proteolytic conversion can produce mixed phenotypes. Alterations in post-translational processing of collagenous proteins can result in the EDS type VI and EDS type IX phenotypes. Linkage analysis and study of type II collagen proteins from individuals with a variety of skeletal dysplasias suggest that similar mutations in these genes also result in clinically apparent phenotypes. Mutations in the majority of the 20 known collagen genes have not yet been identified.

Chromosome Mapping↗