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PubMed1993

Immunohistochemical localization of collagenous proteins in cartilaginous tumors: characteristic distribution of type IX collagen.

The distinctive tissue localization of collagen types, particularly of type IX collagen in human cartilaginous tumors (10 cases of enchondroma and 15 cases of chondrosarcoma including 3 cases of secondary chondrosarcoma) was examined immunohistochemically using affinity-purified antibodies against types I, II, III, V, VI, and IX collagen, in comparison with that in human fetal cartilage. In fetal cartilage matrix, types II and IX collagen were diffusely distributed, while types I, III, and V collagens were not present. In the matrices of enchondromas and primary chondrosarcomas, types II and IX collagens were also diffusely distributed, but with some areas of irregular type IX collagen deposits. The secondary chondrosarcoma simulated normal fetal cartilage in the distribution pattern of types II and IX collagen, unlike the pattern in primary chondrosarcoma, where types II and IX collagen were decreased and poorly immunostained, whereas non-cartilaginous interstitial collagens (I, III, and V) appeared diffusely in the matrix, increasing with the grade of malignancy. These findings suggest that neoplastic cartilage is characterized initially by an uneven distribution of type IX collagen, prior to any alteration of other types of collagen; the diverse expressions of intercellular components in cartilaginous tumors may be one indicator for malignancy.

Adolescent↗
PubMed2000

Two-dimensional peptide mapping of cross-linked type IX collagen in human cartilage.

Type IX collagen is a quantitatively minor component of hyaline cartilage that is essential for the normal structural integrity of the tissue. Purification and analysis are difficult because the mature protein is insoluble as a cross-linked integral component of the fibrillar matrix. In order to view a peptide map of the total pool of type IX collagen in a cartilage sample, a selective method based on Western blot analysis was developed for displaying collagen IX peptides in a cyanogen bromide digest of tissue. Digests were partially resolved by reverse-phase HPLC, individual fractions were run on SDS-PAGE and then transblotted to membrane, and the collagen IX fragments were revealed using an anti-collagen IX rabbit antiserum. All major CB-peptides from alpha1(IX), alpha2(IX), and alpha3(IX) chains in the resulting two-dimensional display were identified by amino-terminal sequence analysis. Cross-linked peptides originating from sites of covalent interaction between collagen types IX and II and between IX and IX were also defined. By comparison with an analysis of soluble type IX collagen from chondrocyte culture medium, the results showed that the pool of type IX collagen molecules in fetal and adult human cartilage is extensively cross-linked intermolecularly at sites previously revealed by other methods using purified protein. This sensitive, direct method has the potential to screen for abnormalities in the content and properties of type IX collagen in tissue samples, for example, in the study of heritable chondrodysplasia syndromes and the pathogenesis of cartilage destruction in osteoarthritis.

Adult↗
PubMed1992

Occurrence of collagen and proteoglycan forms of type IX collagen in chick embryo cartilage. Production and characterization of a collagen form-specific antibody.

Type IX collagen from chick embryonic cartilage is a proteoglycan bearing a single chondroitin sulfate chain covalently linked to the alpha 2(IX) polypeptide chain. We have isolated type IX collagen metabolically labeled with [3H]proline using an antibody to type IX collagen and have found that the molecule is synthesized in two forms, a collagen form (COLIX) and a proteoglycan form (PGIX). In cultured chondrocytes, the two forms of type IX collagen showed a different ability to be deposited in the matrix. We have suggested the possibility that both forms may arise from an alternative substitution of a chondroitin sulfate chain to the NC3 domain of the alpha 2(IX) chain. Based on the reported amino acid sequence at the NC3 domain of alpha 2(IX), we have synthesized undecapeptides containing the sequence around the glycosaminoglycan attachment site of the alpha 2(IX) chain. Antibody against the peptide, which was raised in rabbit, only recognized COLIX and made it possible to distinguish COLIX from PGIX. Evidence shows that this could be due to a difference in antigenicity of the NC3 domain of the alpha 2(IX) chain between COLIX and PGIX caused by the substitution of a chondroitin sulfate chain to the serine residue in this domain. Therefore, this antibody may be useful as a probe for studies on the functions of glycosaminoglycan substitution in type IX collagen.

Amino Acid Sequence↗
PubMed1992

Hypothesis: can type IX collagen "glue" together intersecting type II fibers in articular cartilage matrix? A proposed mechanism.

Type IX collagen is crosslinked to the surface of type II collagen molecules, and has been proposed as the glue that binds the collagen network of cartilage matrix. However, there is as yet no evidence that the crosslinks that have been described to date provide interfibrillar connections, and the only mechanism proposed for such connections between intersecting fibers is unlikely on stereochemical grounds. We propose that both type IX collagen and an intermediary molecule are necessary for network stabilization and that proteoglycans are likely candidates for the role of intermediary.

Animals↗
PubMed1997

Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels.

This review summarizes the data on 278 different mutations found to date in the genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. A majority (217 mutations; 78% of the total) of the mutations are single-base and either change the codon of a critical amino acid (63%), or lead to abnormal RNA splicing (13%). Most of the amino acid substitutions are those of a bulkier amino acid for the obligatory glycine of the repeating-Gly-X-Y-sequence of the collagen triple helix (155; 56%). Altogether, 26 different mutations (9.4% of the mutations) occur in more than one unrelated individual. The 65 patients in whom the 26 mutations were characterized constitute almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in types I, II, III, IX, X, and XI collagens cause a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV and VII of the Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familial aneurysms.

Animals↗
PubMed1986

Use of monoclonal antibodies to locate the chondroitin sulfate chain(s) in type IX collagen.

Recent results show that type IX collagen isolated from chicken cartilage is associated with one or perhaps two chondroitin sulfate chains. To locate the chondroitin sulfate chain(s) along the type IX collagen molecule, rotary shadowing was performed in the presence of monoclonal antibodies which recognize stubs of chondroitin sulfate generated after chondroitinase ABC digestion. Monoclonal antibodies 9-A-2 and 2-B-6 which recognize stubs of chondroitin 4-sulfate were found to bind specifically to the NC3 domain of type IX collagen, and this binding was dependent on prior digestion of the preparation with chondroitinase ABC. Monoclonal antibody 1-B-5, which recognizes unsulfated stubs of chondroitin sulfate, did not show any specific binding to type IX collagen either with or without chondroitinase ABC digestion. As a control, monoclonal antibody 2C2 was used, which in previous work was shown to bind specifically to an epitope located close to or at the NC2 domain. Binding of this antibody to NC2 was unaffected by chondroitinase ABC digestion, and no specific binding of the antibody to the NC3 domain was detected either before or after chondroitinase ABC digestion.

Animals↗
PubMed1988

Type IX collagen: a possible function in articular cartilage.

The effect of type IX on in vitro fibrillogenesis of type II collagen indicated that, while not preventing fibrillogenesis, the presence of type IX collagen reduced the size of the type II fibre aggregates. This observation is consistent with the in vivo localisation studies of type IX collagen. Using the immunogold labelling technique, type IX collagen was shown to be located evenly on small fibrils which occur at higher concentration closer to the cell. Therefore type IX collagen may function as a regulator of fibre diameter in articular cartilage.

Animals↗
PubMed2005

Type IX collagen is crucial for normal hearing.

cDNA microarray analysis indicated that COL9A1 and COL9A3 are highly expressed in the human inner ear, suggesting that type IX collagen has a crucial functional role in the inner ear. This study further confirmed, by means of real-time PCR, the presence of collagen type IX genes in the mouse inner ear. Immunocytochemical analysis also revealed that type IX collagen is distributed in the tectorial membrane, where it co-localizes with type II collagen, indicating that type IX collagen may contribute to the three-dimensional integrated structure of type II collagen molecules. Mice with targeted disruption of the col9a1 gene were shown through assessment by auditory brain stem response to have hearing loss, suggesting an important role of type IX collagen in maintaining normal hearing. At the light microscopic level, the tectorial membrane of knock-out mice was found to be abnormal in shape, and electron microscopy confirmed disturbance of organization of the collagen fibrils. An antibody against type II collagen failed to detect type II collagen in the tectorial membrane of type IX collagen knock-out mice, suggesting that a lack of type IX collagen may affect the three-dimensional structure of type II collagen molecules. These findings indicate that genes encoding each chain of type IX collagen may fulfill an important function associated with the tectorial membrane in the auditory system.

Animals↗
PubMed1989

Molecular cloning of rat and human type IX collagen cDNA and localization of the alpha 1(IX) gene on the human chromosome 6.

Type IX collagen is found in hyaline cartilage, where it is associated with type II collagen in quarter-staggered collagen fibrils. Chicken type IX collagen has been extensively characterized and shown to contain molecules with three triple-helical domains, interspersed with non-triple-helical sequences. The molecule contains three, genetically distinct, subunits and one of these subunits carries a covalently bound glycosaminoglycan side chain. In the present report, we describe for the first time the primary structure of mammalian type IX collagen chains, based on cloning and sequencing of cDNA from rat and human cDNA libraries. The results suggest that mammalian alpha 1(IX) chains have the same multi-domain structure as the avian protein. We also demonstrate, by in situ hybridization of chromosome spreads, that the human alpha 1(IX) collagen gene is located on the long arm of chromosome 6. The cloning of human type IX collagen cDNA provides a probe for molecular studies of human chondrodysplasias that may involve abnormalities in this extracellular collagen-proteoglycan.

Amino Acid Sequence↗
PubMed1999

Different therapeutic and bystander effects by intranasal administration of homologous type II and type IX collagens on the collagen-induced arthritis and pristane-induced arthritis in rats.

To assess the efficiency of nasally administered cartilage-specific collagens as vaccination against development of arthritis and to ameliorate already established chronic arthritis, experimental models which develop chronic arthritis, pristane-induced arthritis (PIA), and homologous collagen-induced arthritis (CIA) in the rat were selected. Cartilage-specific collagens type IX (CIX) and type II (CII) were used for vaccination intranasally. A single dose of 250 microg CII instilled intranasally in rats with established PIA ameliorated the disease. For the prevention of disease, the same dose given before immunization was found to be most effective. Most importantly, the disease was more severe if this dose was given three times. For treatment of PIA, CIX was found to be more effective than CII, whereas for treatment of CIA only CII was effective. The amelioration of CIA was associated with a marked suppression of delayed type hypersensitivity and the flare reaction to CII and lower levels of IgG2b anti-CII antibodies in serum, i.e., with suppression of the TH1 rather than the TH2 response to CII. These findings, that cartilage proteins, if given intranasally, can both prevent and ameliorate established chronic arthritis in rats, are of significant importance for possible use in rheumatoid arthritis. The identification of two different cartilage-specific proteins (CII and CIX) effective against a disease induced with a well-defined nonimmunogenic adjuvant such as pristane will be of value for enhancing the effectiveness of the treatment.

Administration, Intranasal↗
PubMed1994

Cellular invasion and collagen type IX in the primary corneal stroma in vitro.

During different stages in the development of the avian cornea, various collagen types have been shown to participate in matrix formation and have been implicated in morphogenesis. One of these is the fibril-associated collagen type IX. This molecule is present when the primary corneal stroma is in a compact state, but rapidly disappears just prior to stromal swelling and its invasion by mesenchymal cells. The temporospatial pattern of the disappearance of type IX collagen in the developing cornea suggests that this molecule may be involved in stabilizing the primary corneal stromal matrix by interacting either with other type IX collagen molecules or with other matrix components. To explore further whether the removal of type IX collagen is involved in stromal swelling, we have employed an in vitro culture system in which swelling of the primary stroma and mesenchymal cell invasion can be experimentally manipulated by culturing chick corneal explants on a Nuclepore filter support in the presence or absence of an associated lens. We have also examined the effect of exogenously added human recombinant tissue inhibitor of metalloproteinases (TIMP-1) on the presence of type IX collagen and cellular invasion. When stage 25-26+ corneal explants were cultured with an associated lens, the primary stroma did not swell; immunohistochemically detectable type IX collagen was still present, and mesenchymal cell invasion failed to occur. Conversely, when the same stages of corneal explants were cultured without an associated lens, the primary stroma swelled; type IX collagen disappeared, and mesenchymal cell migration occurred. Under both conditions, however, the type II collagen of the stroma, which is known to be a component of the striated fibrils, remained clearly detectable and with time even seemed to increase in amount. This result is consistent with the proposition that type IX collagen is one factor involved in maintaining the primary stroma as a compact matrix, possibly by functioning as a bridging/stabilizing factor. When TIMP was added to cultures of corneal explants, type IX collagen remained detectable in focal regions, suggesting that one or more metalloproteinases are involved in the removal of the type IX collagen. In addition, some of these type IX-containing regions contained mesenchymal cells, suggesting that in addition to type IX collagen other factors are likely to be involved in regulating mesenchymal cell migration.

Animals↗
PubMed1987

Synthesis of type IX collagen: effect of beta-xylosides.

Type IX collagen contains a chondroitin sulfate side chain and therefore may be considered as a proteoglycan. We investigated the effect of beta-xylosides on type IX collagen synthesis. Treatment of chondrocytes with beta-xylosides results in the loss of synthesis of large and small molecular weight proteoglycans, but the synthesis of type IX collagen was unaffected. It is likely that the mechanism of addition of sugar residues to type IX collagen is distinct from that of other cartilage proteoglycans.

Animals↗
PubMed1990

Arthritogenicity of minor cartilage collagens (types IX and XI) in mice.

Native type II collagen, the major cartilage collagen, is immunogenic and arthritogenic in rodents. To investigate whether minor cartilage collagens are arthritogenic, we immunized DBA/1 mice with the pepsin-soluble fractions of type IX or type XI collagen emulsified in Freund's complete adjuvant. Both collagens were arthritogenic in DBA/1 mice after only 1 injection. However, the incidence of the polyarthritis was lower and the severity was lesser than with that induced by bovine type II collagen, even when a booster injection was administered. All mice developed a humoral response to the immunizing antigen, without any relationship to the arthritic status. Interestingly, competition experiments showed that antibodies raised against type XI collagen also bound with high avidity to type II collagen. In contrast, sera from type IX collagen-immunized mice did not react with either type II or type XI collagen. We conclude that types IX and XI minor cartilage collagens are both arthritogenic and immunogenic in DBA/1 mice. Whether the recognition of epitopes common to different collagens is relevant to the articular pathology remains to be elucidated.

Animals↗
PubMed1992

Notochord of chick embryos secretes short-form type IX collagen prior to the onset of vertebral chondrogenesis.

The notochord of embryonic chicks produces type IX collagen, as well as type II collagen, prior to the onset of vertebral chondrogenesis. To address the question of whether the notochord secretes the "long-form" type IX collagen found in cartilage or the "short-form" type IX found in the cornea and vitreous humor, we examined immunoreactivity of the notochordal type IX collagen using two different monoclonal antibodies. The antibody 2C2 recognizes an epitope close to the carboxyl-terminus of the HMW fragment, which is present in both the long- and short-form type IX collagens, whereas another antibody 4D6 recognizes an epitope in the NC4 domain of the long-form type IX collagen, which is absent in the short-form type IX collagen. Therefore, the long-form is recognized by its reaction with both 2C2 and 4D6, while the short-form by its reaction with only 2C2 and no reaction with 4D6. Immunostaining of vertebral sections with 2C2 shows an identical distribution of staining with that for type II collagen, although the staining with 2C2 is less intense. The 2C2-reactive type IX collagen is found within the notochord at stage 14 and in the notochordal sheath at stage 20. Deposition of this collagen in the perinotochordal matrix increases with time and reaches a level comparable with that for type II at stage 31. In contrast, the 4D6-reactive type IX collagen is not found within the notochord nor in the notochordal sheath.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Covalent interactions of type IX collagen in cartilage.

The cross-linking of type IX collagen in fetal bovine cartilage was investigated. The main cross-link was dihydroxy-lysinonorleucine (borohydride-reduced) with a lesser amount of the mature cross-link, pyridinoline. Dihydroxylysinonorleucine was present in all three chains of the COL2 domain of the type IX molecule, but only two of them contained pyridinoline even in mature cartilage. Amino acid sequence analysis of individual tryptic peptides that contained 3H-labeled cross-links showed that they had derived from sites of covalent interaction between type IX collagen and the telopeptide sequences of type II collagen. One two-chained peptide was a helical sequence of alpha 2 (IX) COL2 linked to an alpha 1 (II) N-telopeptide. A second peptide was a different helical sequence from another type IX chain linked to an alpha 1(II) c-telopeptide. This latter helical sequence was also the principal site of pyridinoline cross-linking in type IX collagen.

Animals↗
PubMed2005

Type IX collagen knock-out mouse shows progressive hearing loss.

Type IX collagen is one of the important components, together with type II, V, and XI collagens, in the tectorial membrane of the organ of Corti. To confirm the significance of type IX collagen for normal hearing, we assessed the detailed morphological and electrophysiological features of type IX collagen knock-out mice, which have recently been reported as a deafness model. Through assessment by auditory brainstem response (ABR), knock-out mice were shown to have progressive hearing loss. At the light microscopic level, the tectorial membrane of knock-out mice was found to be abnormal in shape. These morphological changes started in the basal turn and were progressive toward the apical turn. Electron microscopy confirmed disturbance of organization of the collagen fibrils. These results suggest that mutations in type IX collagen genes may lead to abnormal integrity of collagen fibers in the tectorial membrane.

Acoustic Stimulation↗
PubMed1989

Type XII collagen. A large multidomain molecule with partial homology to type IX collagen.

Three overlapping cDNAs encoding alpha 1 (XII) collagen have been isolated and sequenced. The DNAs define five sequence domains within the chain. Three domains are nontriple-helical; two are relatively short triple-helical regions. The amino acid sequences of tryptic peptides derived from 16- and 10-kDa pepsin-resistant fragments isolated from tendon extracts are in full agreement with the deduced sequences of the triple-helical regions. Two of the five sequence domains in alpha 1 (XII), one triple-helical and one nontriple-helical, show a high degree of similarity to regions in type IX collagen chains. In addition, examination of seven exons in the alpha 1 (XII) gene shows that the gene is, in part, similar to the structure of type IX collagen genes. Therefore, collagen types IX and XII are partially homologous. The alpha 1 (XII) sequence data predict an asymmetric structure for type XII collagen molecules, fully consistent with the rotary shadowing images. These images show a triple-helical 75-nm tail attached through a central globule to three finger-like structures, each 60 nm long (Dublet, B., Oh, S., Sugrue, S. P., Gordon, M. K., Gerecke, D. R., Olsen, B. R., and van der Rest, M. (1989) J. Biol. Chem. 264, 13150-13156).

Amino Acid Sequence↗
PubMed1988

Embryonic chicken cornea and cartilage synthesize type IX collagen molecules with different amino-terminal domains.

We have analyzed embryonic chicken cornea for the presence of type IX collagen mRNA and protein. Using RNA transfer blot analysis, we demonstrate that alpha 1(IX) and alpha 2(IX) mRNAs are expressed by corneal epithelial cells at the time that the primary stromal components are synthesized. The levels of the mRNAs decrease with increasing developmental age and are barely detectable at day 11 of development. In contrast, type IX collagen protein is detectable by immunofluorescence at days 5 and 6 and undetectable by day 8. Using probes specific for alpha 1(IX) and alpha 2(IX) mRNAs, we demonstrate that the size of alpha 2(IX) mRNA is the same in cornea as in chondrocytes, the major source of type IX collagen. However, the alpha 1(IX) mRNA is about 700 nucleotides shorter in the cornea than in cartilage because the corneal form of the mRNA does not contain the 5' region that encodes the non-triple-helical amino-terminal globular domain of cartilage type IX collagen. Therefore, corneal type IX collagen must lack this domain. This structural modulation of an extracellular matrix protein is likely to contribute to the functional differences between cartilage matrix and the early corneal stroma, both of which are rich in type II collagen.

Amino Acid Sequence↗