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PubMed1991

Rotary shadowing of elastic system microfibrils in the ocular zonule, vitreous, and ligamentum nuchae.

Rotary shadowing of zonular fibrils in human and bovine eyes revealed a "string of beads" configuration with multiple interconnecting filaments, identical to that recently reported in fibrils of unknown type within the vitreous. These 29 nm beaded fibrils were the only macrostructures present in zonular samples, showing ultrastructural features correlating with both the macro and microperiodicity of zonular fibrils in tissues. Interbead periodicity varied from 30-57 nm and interbead filaments appeared capable of stretching even further, possibly explaining the inherent elasticity of zonular fibrils. The junctions between outer filaments and beads were fibrillin-positive. Similar beaded fibrils were found in the human and bovine anterior vitreous along with type II and IX collagen fibrils, proteoglycan filaments and other unidentified fibrils. After collagenase and elastase digestion, bovine ligamentum nuchae showed type VI collagen fibrils and clumps of beaded fibrils like those in zonule and vitreous. This distribution indicates that the beaded fibril is the microfibril which constitutes the basic unit of the elastic system.

Animals↗
PubMed1995

Modulated expression of type X collagen in Meckel's cartilage with different developmental fates.

Mammalian Meckel's cartilage undergoes regionally diverse histodifferentiation: the caudal end of Meckel's cartilage extends to the developing ear and gives rise to malleus and incus through endochondral ossification while its major distal region differentiates into sphenomandibular ligament and the anterior ligament of the malleus tympanic plate through fibrous transformation. Since the entire Meckel's cartilage develops up to chondrocyte hypertrophy, the regional extracellular matrix components in the hypertrophic Meckel's cartilage may differ in association with the diverse developmental fates. In this project, the expressions of cartilage collagens were investigated in developing rat Meckel's cartilage and particular interest was given to type X collagen. A cDNA, HP114, encoding the NC1 domain of rat alpha 1(X) collagen was cloned, and a synthetic peptide based on the sequence deduced from HP114 was used to generate a monospecific antibody. In situ hybridization of newborn rat condylar and angular cartilages undergoing endochondral ossification showed restricted labeling with the alpha 1(X) collagen probe in the hypertrophic chondrocyte layer. In contrast, the alpha 1(X) collagen probe totally failed to label the major distal portion of Meckel's cartilage even in the hypertrophic cartilage zone. Immunohistochemistry using the anti-type X collagen monospecific antibody consistently failed to recognize the epitope in the corresponding portion of Meckel's cartilage throughout the experimental periods of gestational Day 17, newborn, and Postnatal Day 7, while the strictly localized positive staining was found in the posterior part of Meckel's cartilage which gave rise to malleus and incus. Since major cartilage collagens type II and type IX were found to be present throughout Meckel's cartilage, we postulate that the regulatory molecular mechanism of type X collagen expression may be closely associated with the developmental fates of fibrous transformation and endochondral ossification in mammalian Meckel's cartilage.

Amino Acid Sequence↗
PubMed1999

Maintenance of regional histodifferentiation patterns and a spatially restricted expression of type X collagen in rat Meckel's cartilage explants in vitro.

The major, central portion of Meckel's cartilage undergoes fibrous transformation and contributes to the sphenomandibular ligament, whereas its distal end undergoes endochondral ossification ultimately giving rise to inner-ear ossicles. This regional histodifferentiation of Meckel's cartilage is known to be associated with the spatially restricted expression of type X collagen. The objective of this study was to determine if this unique histodifferentiation is regulated by local environmental factors or by a preprogrammed genetic mechanism. Meckel's cartilage, and condylar cartilage used for comparison, were isolated from 17-day-old rat embryos and from newborn rats, respectively. The cartilage explants were maintained in vitro for 50 days with or without supplementation with 10% fetal bovine serum. When the explants were cultured under serum-free conditions, well-regulated cartilage development was observed. Expression of type X collagen, a differentiation marker for hypertrophic cartilage, was restricted to the distal end of Meckel's cartilage, whereas type II and IX collagens were found uniformly along the entire explant. Matrix calcification was examined histochemically using alizarin red S staining and found to be restricted to the distal end of Meckel's cartilage. Both Meckel's and condylar cartilage cultured with 10% fetal bovine serum developed unregulated dysmorphogenesis. These data suggest that, although Meckel's cartilage has an intrinsic potential to differentiate to its terminal stage, external regulatory factors can significantly influence its normal development at the molecular level.

Animals↗
PubMed1995

Expression of cartilage-specific molecules is retained on long-term culture of human articular chondrocytes.

Normal human adult articular chondrocytes were used to determine how the chondrocyte phenotype is modulated by culture conditions following long-term culture. We report here for the first time that human articular chondrocytes have a lifespan in the range of 34-37 population doublings. While chondrocytes cultured as monolayers displayed a fibroblastoid morphology and grew faster, those cultured as suspensions over agarose adopted a round morphology and formed clusters of cells reminiscent of chondrocyte differentiation in intact cartilage, with little or no DNA synthesis. These morphologies were independent of the age of the culture. Despite, these morphological differences, however, chondrocytes expressed markers at mRNA and protein levels characteristic of cartilage: namely, types II and IX collagens and the large aggregating proteoglycans, aggrecan, versican and link protein, but not syndecan, under both culture conditions. However, they also expressed type I collagen alpha 1(I) and alpha 2(I) chains. It has been suggested that expression of collagen alpha 1(I) by chondrocytes cultured as monolayers is a marker of the loss of the chondrocyte phenotype. However, we show here, using reverse transcriptase/polymerase chain reaction, that normal fresh intact human articular cartilage expresses collagen alpha 1(I). The data show that following long-term culture human articular chondrocytes retain their differentiated characteristics and that cell shape does not correlate with the expression of the chondrocyte phenotype. It is proposed that loss of the chondrocyte phenotype is marked by the loss of one or more cartilage-specific molecules rather than by the appearance of non-cartilage-specific molecules.

Adult↗
PubMed1995

Immunohistochemical and biochemical analyses of 20,000-25,000-year-old fossil cartilage.

A cracked, irregular pellicle adhering to fossilized bone excavated from the Enlène cave (Ariège) and estimated to date from 20,000-25,000 years BP was examined to verify its cartilaginous nature, suggested previously on the basis of optical and electron microscopic investigations. Immunolabeling of the organic component revealed the presence of type II and IX collagens, associated with residual glycosaminoglycans, in the external zone of the pellicle. The cartilaginous nature of the pellicle was also demonstrated by biochemical identification of type II collagen as the major protein in the demineralized sample: the amino acid compositions of insoluble and soluble fractions were similar to that of pure type II collagen; cyanogen-bromide-generated peptides, prepared after reduction of the sample, had an electrophoretic pattern similar to that of cyanogen bromide peptides derived from type II collagen. The amino acid sequences of four tryptic peptides were identical to the corresponding human type II sequences. It was impossible to isolate intact alpha chains. All of the solubilized fractions were composed of a wide range of low-molecular-mass peptides demonstrating significant degradation of the collagen molecules that was not reflected in the well-preserved fibrillar structure observed at the ultrastructural level. The mineral fraction, characterized by X-ray diffraction, consisted of apatite (as in sub-chondral bone) associated with contaminating poorly crystallized components originating from the cave sediment. Energy dispersive spectrometry showed that the cartilaginous zone contained three times less phosphorus and calcium than the underlying bone. These results confirm the cartilaginous nature of the sample and the preservation of tissue-specific components, and suggest that the process of fossilization is closely related to a mechanism of phosphatization.

Amino Acid Sequence↗
PubMed1988

Monoclonal antibodies to type X collagen. Biosynthetic studies using an antibody to the amino-terminal domain.

Monoclonal antibodies to chick type X collagen have been used to study the structure, biosynthesis, and location of type X in cartilage. The antibodies were produced by injecting purified type X collagen into female SJL/J mice and then fusing their spleen cells with Sp2/0 myeloma cells. Hybridoma culture supernatants were screened for antibodies to type X collagen by enzyme-linked immunosorbent assay and Western blots. Positive supernatants did not cross-react with other collagen types (I, II, IX, XI) or with fibronectin. Three monoclonal antibodies were chosen for further characterization. Two of them (1A6 and 6F6) recognize a pepsin-sensitive domain of type X collagen. Rotary shadowing showed that 1A6 and 6F6 both recognize the same end of type X, probably the aminoterminal non-triple helical domain. Amino acid sequencing of the intact protein and of the epitope-containing peptide confirmed that the antibody recognition sites for 1A6 and 6F6 are within the amino-terminal domain. Monoclonal antibody 2B3 reacts with the pepsinized (45 kDa) and weakly with the nonpepsinized (59 kDa) forms of type X collagen. The monoclonal antibodies were used for immunolocalization of type X in hypertrophic chondrocytes and reacted only with tissue samples from areas undergoing endochondral ossification, e.g. growth plate and fracture callus. Antibody 6F6, when coupled to Sepharose, selectively binds to type X collagen from cell and organ cultures. In a pulse-chase experiment, no processing of the 59-kDa form of type X could be detected. Two components with molecular masses of approximately 70 and 85 kDa, arising from a disulfide-bonded aggregate, were synthesized by both the permanent and calcifying cartilage organ cultures but did not react with the antibody, suggesting that these proteins are not related to type X. In summary, the pulse-chase results and the immune precipitation with monoclonal antibody 6F6 did not detect biosynthetic precursors larger than 59 kDa or proteolytically processed forms of type X.

Amino Acid Sequence↗
PubMed1998

Expression of cartilage extracellular matrix and potential regulatory genes in a new human chondrosarcoma cell line.

A human chondrosarcoma cell line has been established from an aggressive chondrosarcoma. The cells grow in a monolayer culture (doubling time: 2 days) and form aggregates. The aggregates consist of a rim of cells surrounding a hollow core. The cell line exhibits a unique pattern of mRNA expression with several molecules characteristic of the chondrocyte phenotype. Consistent with the chondrocyte phenotype, mRNAs encoding types IX and XI collagens were present along with an abundant expression of mRNAs encoding the core protein of the cartilage proteoglycans biglycan and aggrecan. No expression of mRNAs encoding types I or II fibrillar collagens or the proteoglycan decorin was observed. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of [35S]sulfate-radiolabeled material confirmed the translation of proteoglycans containing glycosaminoglycan chains. The expression of molecules that contribute to cartilage development and tumorigenesis was examined. The cell line produces abundant mRNA that encodes transforming growth factor-beta1, a member of a family of cartilage and bone inductive proteins. The expression of mRNA encoding two proteins associated specifically with chondrogenesis was detected: Cart-1, a homeobox protein involved in cartilage differentiation, and CD-RAP, a secreted molecule restricted under normal conditions to differentiating chondrocytes and cartilage. Overexpression of p53, a tumor-suppressor gene, was detected. DNA analysis revealed a loss of heterozygosity at the chromosomal locus encoding p53, with the deletion of one p53 allele and the mutation of the remaining allele in both the parent tumor and the cell line. The malignant chondrosarcoma phenotype may be related to the unique gene expression pattern that is characteristic in many ways of differentiating chondroblasts, as well as to the inactivation of the p53 function that could contribute to the proliferative capacity of the cell line. This cell line may serve as a biological model for further investigation of the etiology of human chondrosarcomas and for the synthesis and regulation of cartilage-specific genes.

Adult↗
PubMed1992

Extracellular matrix in the rat spiral limbus.

The matrix of the spiral limbus is obviously a special form of the intercellular substance. In the present study, the rat's spiral limbus was investigated by electron microscopy after fixation with ruthenium red and tannic acid and immunofluorescence to demonstrate matrix components. Collagen types I, II, V, VI, VII, IX and XI and fibronectin were not observed. Collagen type II and cartilage-specific proteoglycans, however, occurred in large quantities. The basal lamina of interdental cells and inner sulcus cells did not contain any collagen type IV, while the basal lamina of the capillaries had only minor amounts. Laminin and nidogen appeared in large amounts in the basal lamina. After fixation with tannic acid, the matrix between the interdental cells and the capillaries contained 20- to 22-nm-thick single and irregularly running fibrils as well as plaques of a fine granular material. After fixation with ruthenium red, 30- to 60-nm-thick, electron-dense granules occurred and most probably consisted of proteoglycans. These findings indicate that the composition of the matrix of the spiral limbus is similar to that of cartilage but not identical.

Animals↗
PubMed2000

Immunolocalization of collagen types II and III in single fibrils of human articular cartilage.

Type II and III fibrillar collagens were localized by immunogold electron microscopy in resin sections of human femoral articular cartilage taken from the upper radial zone in specimens from patients with osteoarthritis. Tissue samples stabilized by high-pressure cryofixation were processed by freeze-substitution, either in acetone containing osmium or in methanol without chemical fixatives, before embedding in epoxy or Lowicryl resin, respectively. Ultrastructural preservation was superior with osmium-acetone, although it was not possible to localize collagens by this method. In contrast, in tissue prepared by low-temperature methods without chemical fixation, collagens were successfully localized with mono- or polyclonal antibodies to the helical (Types II and III) and amino-propeptide (Type III procollagen) domains of the molecule. Dual localization using secondary antibodies labeled with 5- or 10-nm gold particles demonstrated the presence of Types II and III collagen associated within single periodic banded fibrils. Collagen fibrils in articular cartilage are understood to be heteropolymers mainly of Types II, IX, and XI collagen. Our observations provide further evidence for the complexity of these assemblies, with the potential for interactions between at least 11 distinct collagen types as well as several noncollagenous components of the extracellular matrix.

Cartilage, Articular↗
PubMed1989

Separation of collagens by capillary zone electrophoresis.

Collagen (types I, II, V, IX and XI) constituting polypeptide chains and their polymers and cyanogen bromide-cleaved peptides of collagen type I and type III were investigated by means of capillary zone electrophoresis. Separations were effected in 2.5 mM sodium tetraborate buffer in less than 15 min. A 50 cm x 0.1 mm I.D. fused-silica capillary was used. The separations were run at 18 kV per capillary. The results of the separation were monitored at 220 nm with an on-tube detection system. Using the Offord equation, relative retention times of cyanogen bromide cleavage fragments were plotted against M(2-3)/Z, where M is the molecular mass of a polypeptide and Z its valency. A linear relationship was observed. Collagen alpha-chains and their polymers were also satisfactorily resolved.

Collagen↗
PubMed1989

A longitudinal study of anticollagen antibodies in patients with rheumatoid arthritis.

Antibodies to native and denatured collagens (types I, II, IX, and XI) were measured in sequential serum samples collected over 1.5-8.7 years (median 4.3) from 15 patients with rheumatoid arthritis. Eleven patients were seropositive and 4 were seronegative. Disease duration ranged from 3 years to 25 years before the first sample was tested. The patients showed a selective and varying response to collagens, even after disease had been present for a long time. Changes in the levels of antibody to one collagen type were not necessarily linked to changes in the levels of antibody to other collagens. Only some patients showed a strong correlation between C-reactive protein levels (a measure of disease activity) and antibodies to individual collagens. These findings suggest that rheumatoid arthritis patients produce antibodies to a wide variety of epitopes on these collagen molecules, as a result of different antigenic epitopes being exposed by cartilage degradation at different times throughout the disease.

Adult↗
PubMed2001

Structure, chromosomal location, and tissue-specific expression of the mouse opticin gene.

PURPOSE: To determine the structure, location, and tissue-specific expression of the mouse opticin gene (Optc) and to compare expression in the eye with that of Prelp, collagen II, and collagen IX. METHODS: Expressed sequence tags (ESTs) to mouse opticin were identified and the full-length sequence obtained after PCR reactions using a 15-day-postconception (dpc) whole-mouse embryo cDNA library. The mouse chromosomal localization of Optc was determined by radiation hybrid mapping and its genomic structure determined using an Optc-containing BAC clone. Tissue-specific expression of opticin, PRELP, collagen II, and collagen IX mRNAs was investigated by in situ hybridization and by dot blot hybridization for opticin. RESULTS: The Optc gene was localized to mouse chromosome 1 at 74.3 cM and consisted of seven exons spanning 10 kb. The Optc gene was less than 4 kb from the Prelp gene. In situ hybridization localized opticin mRNA exclusively to the presumptive ciliary body during development and to the nonpigmented ciliary epithelium of the adult mouse eye. Expression of Prelp was also detected in the nonpigmented ciliary epithelium of the adult eye. However, expression of collagen types II and IX was detected largely in the developing mouse eye, with type IX expression confined primarily to the presumptive ciliary body. CONCLUSIONS: The Optc, Prelp, and fibromodulin (Fmod) genes form a cluster on mouse chromosome 1. Opticin may represent a marker for ciliary body differentiation. Continued expression of opticin in the adult mouse eye suggests functions other than that of putative regulator of vitreous collagen fibrillogenesis.

Amino Acid Sequence↗
PubMed2004

Biology of fibrocartilage cells.

Fibrocartilage is an avascular tissue that is best documented in menisci, intervertebral discs, tendons, ligaments, and the temporomandibular joint. Several of these sites are of particular interest to those in the emerging field of tissue engineering. Fibrocartilage cells frequently resemble chondrocytes in having prominent rough endoplasmic reticulum, many glycogen granules, and lipid droplets, and intermediate filaments together with and actin stress fibers that help to determine cell organization in the intervertebral disc. Fibrocartilage cells can synthesize a variety of matrix molecules including collagens, proteoglycans, and noncollagenous proteins. All the fibrillar collagens (types I, II, III, V, and XI) have been reported, together with FACIT (types IX and XII) and network-forming collagens (types VI and X). The proteoglycans include large, aggregating types (aggrecan and versican) and small, leucine-rich types (decorin, biglycan, lumican, and fibromodulin). Less attention has been paid to noncollagenous proteins, although tenascin-C expression may be modulated by mechanical strain. As in hyaline cartilage, matrix metalloproteinases are important in matrix turnover and fibrocartilage cells are capable of apoptosis.

Animals↗
PubMed1990

Visualization of sulfur-containing components associated with proliferating chondrocytes from rat epiphyseal growth plate cartilage: possible proteoglycan and collagen co-migration.

Electron microscopy of epiphyseal growth plate cartilage from normal 4-5-week-old rats has revealed extensive fibrillar aggregates and globules in the pericellular spaces of proliferating chondrocytes. These cells contained small globules and diffusely coiled, fine filaments located within large, membrane-invested vacuoles. All such structures were observed after a variety of different tissue fixation regimes, including glutaraldehyde, osmium tetroxide, and potassium pyroantimonate. The fibrillar aggregates and globules were often overlapping and intermeshed and extended to 0.5 micron in length from their point of origin at cell membranes. Vacuoles were usually found at the periphery of cells, and some, by membrane fusion with the cell envelope, appeared contiguous with extracellular spaces wherein their contents could be discharged. Fine filaments and globules were occasionally observed in the Golgi complex and cisternae of endoplasmic reticulum of the chondrocytes. Further characterization of the cellular and pericellular components by electron microscopic radioautography, electron probe microanalysis, and electron spectroscopic imaging indicated the presence of sulfur, a result suggesting these aggregates, filaments, and globules in part represent proteoglycans in various stages of synthesis, secretion, and assembly. Additional radioautography utilizing 3H-proline implied that filament bundles are also composed of collagen, a result posing the possibility that this protein and the putative proteoglycans may co-migrate both intracellularly and within pericellular matrices. In extracellular matrices adjacent to cell lacunae, the fibrillar aggregates appeared in close association with typical collagen type II fibrils, an observation providing evidence for proteoglycan-collagen network formation in this region of the rat epiphysis. These microscopic and analytical data in situ would support certain studies in vitro of proteoglycan-collagen type II and IX association and are important in describing the interaction of such cartilage components ultimately involved in matrix formation.

Animals↗
PubMed2001

Age-dependent changes in the expression of matrix components in the mouse eye.

Although the presence of 'cartilage-specific' collagens in the eye has been documented earlier, very little is known about their synthesis rates during ocular development, growth and aging. The purpose of the present study was to follow changes in the mRNA levels and distribution of key components of the extracellular matrix in the eyes of normal and transgenic Del1 mice, harboring a short deletion mutation in the type II collagen gene, during ocular growth and aging. Total RNAs extracted from mouse eyes were studied by Northern analysis for mRNA levels of type I, II, III, VI, IX and XI collagens, biglycan, fibromodulin and decorin. A predominant finding of the present study was the marked reduction in the mRNA levels of type I and II collagens in the eye upon aging. The changes in the mRNA levels of type III and VI collagen and proteoglycans were smaller. Localization of type II and IX collagen in the eye was performed by immunohistochemistry. Despite the reduction in the type II collagen mRNA levels, immunohistochemistry confirmed widespread distribution of the protein also in aging mouse eyes, suggesting its slow turnover. Although the Del1 mutation caused gradual degenerative lesions in the eyes, the distribution of the protein remained essentially unchanged. The widespread distribution and marked downregulation of type II collagen production in the mouse eye upon aging probably explain the gradual development of degenerative lesions, particularly in the eyes of transgenic Del1 mice, where production of mutant type II collagen chains also contributes to the process.

Aging↗
PubMed1991

Mechanisms of disruption of the articular cartilage surface in inflammation. Neutrophil elastase increases availability of collagen type II epitopes for binding with antibody on the surface of articular cartilage.

We recently observed that specific antibodies to type II collagen do not bind in appreciable amounts to the intact surface of articular cartilage, whereas antibodies to the minor collagen types V, VI, and IX do. These results suggest that the outermost cartilage surface layer prevented interaction of the antibodies with the major collagen type in articular cartilage. The present studies were designed to investigate the pathogenic mechanisms involved in the disruption of the cartilage surface layer in inflammatory arthritis. Articular cartilage obtained from rabbits undergoing acute antigen-induced arthritis of 72 h duration showed a significant increase in binding of anti-type II antibody to cartilage surfaces compared with normal control cartilage (P less than 0.01). Augmentation of anti-type II binding was also observed upon in vitro incubation of bovine articular slices or intact rabbit patellar cartilage for 1 h with human polymorphonuclear neutrophils (PMN), PMN lysates, or purified human PMN elastase. This increase was not inhibited by sodium azide, nor was it enhanced by incubation of cartilage with the strong oxidant hypochlorous acid. Chondrocyte-mediated matrix proteoglycan degradation in cartilage explants cultured in the presence of cytokines failed to increase antibody binding appreciably. The augmentation in antibody binding seen with PMN lysates was inhibited by the nonspecific serine-esterase inhibitor PMSF, but not by the divalent metal chelator EDTA. The elastase-specific inhibitor AAPVCMK also inhibited most of the PMN-induced increase in antibody binding, whereas the cathepsin G-specific inhibitor GLPCMK was much less effective. Incubation of intact cartilage with purified human PMN elastase indicated that this serine esterase could account for the increase in anti-type II collagen antibody binding to intact cartilage surfaces. These studies suggest that in an inflammatory response, PMN-derived elastase degrades the outer layer of articular cartilage, exposing epitopes on type II collagen. They also help clarify the pathogenic mechanisms involved in early articular cartilage damage in inflammatory joint diseases.

Animals↗
PubMed1994

Analysis of aggrecan and tenascin gene expression in mouse skeletal tissues by northern and in situ hybridization using species specific cDNA probes.

Cartilage matrix is an interacting multicomponent system of collagen fibrils, fibril-associated small proteoglycans, and large proteoglycans and glycoproteins entrapped within the fibrillar network. In order to better understand the relationships between these different components we have constructed short cDNA clones for detection of mRNAs for two major noncollagenous macromolecules of cartilage matrix, aggrecan and tenascin. We subsequently determined their corresponding mRNA levels by Northern analysis in a panel of total RNAs isolated from several newborn mouse tissues. The expression of aggrecan was strictly restricted to cartilages while tenascin mRNA was present at variable levels in most of the tissues studied. The cDNA clones were also used to identify the cells responsible for aggrecan and tenascin production in newborn mouse tissues by in situ hybridization. With this technique aggrecan mRNA was detected in chondrocytes throughout the developing skeleton in a pattern very similar but not identical to those of type II and IX collagen mRNAs. In the newborn mouse skeleton tenascin and aggrecan mRNAs were expressed essentially in a mutually exclusive manner, tenascin transcripts being present in osteoblasts, periosteal and perichondrial cells, and in cells at articular surfaces. None of these cells expressed the cartilage specific collagen or aggrecan genes. The results further suggest different patterns of gene expression in chondrocytes based on their location in the different cartilages.

Aggrecans↗
PubMed2004

Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice.

Human genetic studies indicate that mutations in type IX and XI collagens result in early-onset osteoarthritis (OA) with a wide spectrum of osteochondrodysplasia. However, a convincing causal chain of events underlying the role of these collagen mutations in the pathogenesis of OA has not been elucidated. Here we show that the expression of a cell surface collagen receptor, discoidin domain receptor 2 (DDR2), is increased in chondrocytes of the articular cartilage of knee joints in mice that develop OA as a result of a heterozygous mutation in type XI collagen. At the same time point, 6 months, we also found increased expression and activity of matrix metalloproteinase 13 (MMP-13) in the mutant mouse knee cartilage. The expression of both DDR2 and MMP-13 was increased in chondrocytes cultured on plates coated with native type II collagen but not on gelatin, and overexpression of DDR2, but not of a truncated form, was found to induce the expression of MMP-13 when chondrocytes were cultured on type II collagen but not on plastic. The DDR2-induced expression of MMP-13 appears to be specific, since we did not observe induction of MMP-1, MMP-3, MMP-8, ADAMTS-4, ADAMTS-5, and IL-1 transcripts in human chondrocytes or Mmp-3, Mmp-8, Adamts-4, Adamts-5, and Il-1 in mouse chondrocytes. Our data suggest that the defect in the cartilage matrix of mice that are heterozygous for a type XI collagen mutation (cho/+) permits activation and up-regulation of DDR2 in chondrocytes. This could be due to increased exposure of chondrocytes to type II collagen as a result of the decreased amount of type XI collagen in the mutant cartilage. The specific induction of MMP-13 by DDR2 in response to its cartilage-specific ligand, type II collagen, may contribute to cartilage damage in hereditary OA.

Animals↗