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PubMed1988

Interactions between the immune system and connective tissue in arthritis. Possible significance of an affinity between IgG and native type II collagen.

The synovial inflammation in rheumatoid arthritis (RA) resembles inflammatory reactions in other tissues concerning features such as increased expression of MHC class II antigens and infiltration of large amounts of activated T lymphocytes. The present communication is concerned with how to explain features such as local production of rheumatoid factors that distinguish the synovial inflammation in seropositive RA from other chronic inflammatory reactions; We show here that monomeric IgG and, to an even higher extent, aggregated IgG show a high binding capacity for native collagen type II. This finding is discussed in the light of previous findings that native collagen II structures are readily exposed to the environment in the cartilage of inflamed joints, and the evidence that T-cell reactivity to cartilage-derived molecules among them collagen II appears to be a common feature in seropositive RA. We suggest that an enhanced formation of IgG-collagen II complexes in RA joints, together with activation of T-cells to collagen II or collagen II-associated structures may constitute the basis for local rheumatoid factor production and to disease perpetuation in seropositive RA.

Animals↗

PubMed1994

Antibodies to the collagen-like region of C1q and type II collagen are independent non-cross-reactive populations in systemic lupus erythematosus and rheumatoid arthritis.

The collagen-like region (CLR) of the first component of complement, C1q, and type II collagen are structurally similar, raising the possibility of epitopes in common, and of the existence of autoantibodies that are cross-reactive. Accordingly, antibodies to the CLR of C1q and to type II collagen were measured in patients' sera with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) by an ELISA. IgG antibodies to the CLR of C1q were present in 17% of patients with SLE but none with RA, and IgA antibodies were present in 10% and 8% of patients with SLE and RA, respectively. IgG antibodies to type II collagen were present in 15% and 25% of patients with SLE and RA, respectively, and IgA antibodies in 15% and 28% of patients with SLE and RA, respectively. There was no correlation in either disease between the serum levels of antibodies to the CLR of C1q and antibodies to type II collagen. For sera with antibodies to both antigens, neither competitive inhibition by ELISA nor preabsorption with the alternative antigen affected the level of reactivity to the other antigen. Thus antibodies to the CLR of C1q and antibodies to type II collagen are independent and non-cross-reactive populations, and presumably occur by different types of immunogenic stimulation.

Antibody Specificity↗

PubMed1999

Amelioration of type II collagen induced arthritis in rats by treatment with sodium diethyldithiocarbamate.

OBJECTIVE: Sodium diethyldithiocarbamate (Ditiocarb, DDTC), which is used in the treatment of heavy metal poisoning, effectively inhibits NF-kappaB activation and cytokine secretion in vitro. To investigate the antiinflammatory and immunosuppressive potency of DDTC, we examined its influence on the course of collagen induced arthritis in rats. METHODS: Arthritis was induced in female DA rats by injection of rat collagen type II emulsified in incomplete Freund's adjuvant into the tail base. After onset of arthritis, the animals received DDTC or vehicle by intraperitoneal injections or subcutaneous infusion using osmotic pumps. Disulfiram, which is cleaved into DDTC within the gastrointestinal tract, was administered orally via gastric gavage. The course of arthritis was followed by clinical scoring and measurement of joint swelling. RESULTS: Collagen induced arthritis was significantly ameliorated by intraperitoneal injection (2 x 300 mg/kg/day) and subcutaneous infusion (120 mg/kg/day) of DDTC and by enteral administration of disulfiram (200 and 300 mg/kg/day). CONCLUSION: Dithiocarbamates may provide an effective new approach for the treatment of arthritis and other inflammatory diseases.

Animals↗

PubMed1998

Treatment with an anti-IL-4 monoclonal antibody blocks suppression of collagen-induced arthritis in mice by oral administration of type II collagen.

Oral administration of type II collagen (CII) has been shown to suppress collagen-induced arthritis (CIA) in experimental animals. However, the exact mechanism by which CIA is suppressed following administration of CII remains to be investigated, although it was demonstrated that active suppression by regulatory T cells might be involved in the suppression. Therefore, we have examined whether the inhibitory cytokine IL-4 plays a role in the suppression of CIA, by using an anti-IL-4 mAb (11B11 mAb). Mice were fed daily with CII over a period of 10 days before immunization with CII. 11B11 mAb was i.p. injected 30 min before each oral administration of CII. The results showed that treatment with 11B11 mAb markedly blocked suppression of CIA by the oral Ag. The blockade of suppression of CIA by the anti-IL-4 mAb was associated with the blockade of augmentation of IL-4 secretion in CII-fed mice. The treatment with 11B11 mAb also resulted in the prevention of decreases in anti-CII IgG2a Ab production, DTH responses to CII, proliferation of lymphoid cells to CII, and IFN-gamma secretion in mice given CII orally. Thus, the neutralization of IL-4 by an anti-IL-4 Ab appears to be effective in blocking suppression of CIA by oral administration of CII, suggesting that IL-4 may be critically involved in its suppression.

Administration, Oral↗

PubMed2005

Analysis for the major contributor of collagenase to the primary cleavage of type II collagens in cartilage degradation.

Degradation of type II collagen is a central process in cartilage destruction seen in osteoarthritis and rheumatoid arthritis. Primary cleavage of type II collagen at the collagenase site is rate-limiting and is, therefore, a critical step for its degradation. The major contributor to this cleavage was identified in three isozymes of collagenase in human cartilage. Primary cultured human chondrocytes were used for the study. The production of collagenase-1 was major in total production for three isozymes of collagenase after stimulations with any concentration of tumor necrosis factor-alpha and/or interleukin-1 at 48 and 72 h, comprising 98% or greater of the total collagenase. When the production of collagenase-1 was specifically suppressed by the transfection with duplexes of 21-nucleotide small interfering ribonucleic acid into the cells, the activity of type II collagen cleavage was linearly decreased at neutral pH after activation. The relative contribution of collagenase-1 to the primary cleavage of type II collagen was determined to be 85%-93%. These findings suggest that collagenase-1 is a major contributor to the primary cleavage of type II collagens in human cartilage and is a potential therapeutic target for osteoarthritis and rheumatoid arthritis.

Journal Article↗

PubMed1980

Collagen type II differs from type I in native molecular packing.

Native molecular packing of types I and II collagens were compared by low-angle X-ray diffraction. Fibers from human intervertebral disc that contained different proportions of types I and II collagens were studied by X-ray diffraction, and were then analyzed biochemically to measure the constituent collagen species. Other cartilages, containing exclusively type I or type II collagen, were also examined. The equatorial diffraction established that in wet, native type II collagen, the molecules are spaced farther apart laterally than in type I collagen under the same conditions. For the disc the average lateral spacing ranged from about 14 A for a fiber from the outer annulus fibrosus containing mostly type I collagen, to 16-17 A for nucleus pulposus that contained all type II collagen. No differences were evident among dried specimens. We have also found that the meridional diffraction pattern from dry fibers of type II collagen differed from that of type I collagen. The findings indicate that under physiological conditions type II collagen fibrils contain more water than type I fibrils. Calculations suggest 50-100% more water. We propose that this difference is an inherent property of type II collagen and that it may be significant for the function of type II collagen in tissues that dissipate compressive forces. The content of glycosylated hydroxylysine residues is the chemical variable likely to be modulating fibrillar hydration.

Adolescent↗

PubMed1983

Construction and characterization of type II collagen complementary deoxyribonucleic acid clones.

The mRNA for type II collagen was purified from embryonic chick sternum or from purified sternal chondrocytes with guanidine thiocyanate as the extractant. Double-stranded cDNAs to procollagen mRNAs from sternum were synthesized and dC-tailed. After annealing with PstI-cleaved, dG-tailed pBR322, this DNA was used to transform Escherichia coli X1776. Transformed colonies were screened by colony hybridization to type I and II collagen cDNAs. Clones that preferentially hybridized to type II cDNA were characterized further. Four such cDNA clones, pCgII-2, 3, 10 and 12, with inserts of 400, 320, 260 and 750 bp, have been identified as type II collagen cDNA clones by several criteria, including their preference for hybridizing with type II rather than type I collagen mRNAs in hybrid-selected translation experiments.

Animals↗

PubMed2001

Regulation of type-II collagen gene expression during human chondrocyte de-differentiation and recovery of chondrocyte-specific phenotype in culture involves Sry-type high-mobility-group box (SOX) transcription factors.

During ex vivo growth as monolayer cultures, chondrocytes proliferate and undergo a process of de-differentiation. This process involves a change in morphology and a change from expression of chondrocyte-specific genes to that of genes that are normally expressed in fibroblasts. Transfer of the monolayer chondrocyte culture to three-dimensional culture systems induces the cells to re-acquire a chondrocyte-specific phenotype and produce a cartilaginous-like tissue in vitro. We investigated mechanisms involved in the control of the de-differentiation and re-differentiation process in vitro. De-differentiated chondrocytes re-acquired their chondrocyte-specific phenotype when cultured on poly-(2-hydroxyethyl methacrylate) (polyHEMA) as assayed by morphology, reverse transcriptase PCR of chondrocyte-specific mRNA, Western-blot analysis and chondrocyte-specific promoter activity. Essentially, full recovery of the chondrocyte-specific phenotype was observed when cells that had been cultured for 4 weeks on plastic were transferred to culture on polyHEMA. However, after subsequent passages on plastic, the phenotype recovery was incomplete or did not occur. The activity of a gene reporter construct containing the promoter and enhancer from the human type-II collagen gene (COL2A1) was modulated by the culture conditions, so that its transcriptional activity was repressed in monolayer cultures and rescued to some extent when the cells were switched to polyHEMA cultures. The binding of Sry-type high-mobility-group box (SOX) transcription factors to the enhancer region was modulated by the culture conditions, as were the mRNA levels for SOX9. A transfected human type-II collagen reporter construct was activated in de-differentiated cells by ectopic expression of SOX transcription factors. These results underscore the overt change in phenotype that occurs when chondrocytes are cultured as monolayers on tissue-culture plastic substrata.

Animals↗

PubMed1988

Susceptibility of cartilage collagens type II, IX, X, and XI to human synovial collagenase and neutrophil elastase.

The action of purified rheumatoid synovial collagenase and human neutrophil elastase on the cartilage collagen types II, IX, X and XI was examined. At 25 degrees C, collagenase attacked type II and type X (45-kDa pepsin-solubilized) collagens to produce specific products reflecting one and at least two cleavages respectively. At 35 degrees C, collagenase completely degraded the type II collagen molecule to small peptides whereas a large fragment of the type X molecule was resistant to further degradation. In contrast, collagen type IX (native, intact and pepsin-solubilized type M) and collagen type XI were resistant to collagenase attack at both 25 degrees C and 35 degrees C even in the presence of excess enzyme. Mixtures of type II collagen with equimolar amounts of either type IX or XI did not affect the rate at which the former was degraded by collagenase at 25 degrees C. Purified neutrophil elastase, shown to be functionally active against soluble type III collagen, had no effect on collagen type II at 25 degrees C or 35 degrees C. At 25 degrees C collagen types IX (pepsin-solubilized type M) and XI were also resistant to elastase, but at 35 degrees C both were susceptible to degradation with type IX being reduced to very small peptides. Collagen type X (45-kDa pepsin-solubilized) was susceptible to elastase attack at 25 degrees C and 35 degrees C as judged by the production of specific products that corresponded closely with those produced by collagenase. Although synovial collagenase failed to degrade collagen types IX and XI, all the cartilage collagen species examined were degraded at 35 degrees C by conditioned culture medium from IL1-activated human articular chondrocytes. Thus chondrocytes have the potential to catabolise each cartilage collagen species, but the specificity and number of the chondrocyte-derived collagenase(s) has yet to be resolved.

Arthritis, Rheumatoid↗

PubMed1992

VNTR polymorphism of the collagen type II, alpha 1 (COL2A1) gene detected by PCR.

The 3' side of the human type II collagen alpha 1 (COL2A1) gene contains a region consisting of a variable number of tandemly repeated short A + T-rich DNA sequences (VNTR). We amplified this region accurately by the polymerase chain reaction (PCR). Genomic DNA was purified from isolated buffy-coat cells, and thermostable Taq polymerase was used to amplify the target region. The amplification products were directly visualized after polyacrylamide gel electrophoresis. In this way, five alleles were distinguished in chromosomes from 33 unrelated Japanese, and named A, B, C, D, and E in decreasing order of length. The relative frequencies of the COL2A1 3' VNTR alleles A through E were 0.045, 0.075, 0.469, 0.015, and 0.393, respectively. Co-dominant segregation was observed in two informative families. The COLA2A1 3' VNTR locus was estimated to have a heterozygosity index of 62% and a polymorphic information content of 0.55.

Alleles↗

PubMed1994

Production of type II collagen specific monoclonal antibodies.

Immunoassays are used for the specific measurement of type II collagen, a major cartilage protein, which is lost in osteoarthritic joints. Poor immunogenicity and species dependent immune response to type II collagen make it difficult to obtain specific antibodies required for immunoassay development. In addition, type II collagen antibodies exhibit reactivity to structurally dissimilar antigens such as actin, myoglobin, thyroglobulin and ssDNA, complicating the isolation of specific antibodies. It is therefore necessary to characterize the antibody reactivity against both noncollagenous antigens and different collagen types. In this study, immune response to type II collagen was improved by conjugation to carrier proteins, KLH and BSA. Hybridomas were generated by fusions of lymphocytes derived from lymph nodes or spleens with X63-653-Ag8 myeloma cells. Compared to spleens, the utilization of lymph nodes as a source of lymphocytes resulted in a 23% higher number of hybridomas secreting type II collagen antibodies. Hybridomas secreting polyreactive antibodies were identified based on their reactivity to thyroglobulin and eliminated. Extensive testing of the remaining monoclonal antibodies with other structurally dissimilar antigens and various types of collagen for reactivity, allowed us to isolate specific monoclonal antibodies to type II collagen. We emphasize the importance of characterization of the reactivity of type II collagen monoclonal antibodies before employing them for immunoassays.

Adjuvants, Immunologic↗

PubMed2000

[Immunohistochemical study of type I and type II collagen in the remodelling of the supraosseous tissue of mandibular condyle].

OBJECTIVE: Previous studies focused on the pathological changes of the supraosseous tissue of mandibular condyle (STMC), but little is known about extracellular matrix during the remodelling activity of temporomandibular joint (TMJ). This study will examine the characteristics of type I and type II collagen during this process. METHODS: The animal model was established by extracting the left lower molars of adult rabbits. Temporomandibular joints of two sides were taken after 2 weeks, 1 month and 3 months respectively, and embedded in paraffin. Then 5 microns-thick sections were cut and processed for immunohistochemistry and haematoxylin-eosin staining. An immunohistochemical ABC method was used to determine the local changes of type I and type II collagen. The positive cells were counted in order to analyze quantitative changes. RESULTS: After loss of teeth from 2 weeks to 3 months, the number and arrangement of chondrocytes changed. Some chondrocyte clusters were also observed in the non-extraction side of TMJ. Most STMC cells stained positively with anti-type I collagen, but weakly in chondrocytes and hypertrophic chondrocytes. On the other hand, type II collagen only existed in chondrocytes and some hypertrophic chondrocytes. The expression of type I collagen decreased after 2 weeks and became stronger after 1 and 3 months, furthermore distributed unevenly in STMC. Some hypertrophic chondrocytes in the non-extraction side showed strong positive staining with anti-type I collagen. Type II collagen in two sides decreased after 2 weeks, then became stronger after 1 and 3 month, but the whole level was less than that of the control group. Expressions of two kinds of collagen were compared between two sides. Type I collagen in the non-extraction side was stronger than that in the extraction side, while type II collagen had an opposite result. CONCLUSION: Adult rabbits have a limited remodelling ability, and the synthesis and secretion of type I and type II collagen will change when the remodelling is beyond a proper extent, which will lead to impaired resistance and elasticity of fibrocartilage.

Animals↗

PubMed1994

Monoclonal antibody to the aminotelopeptide of type II collagen: loss of the epitope after stromelysin digestion.

A monoclonal antibody was prepared to the aminotelopeptide of type II collagen after immunization of DBA/1 mice with lathyritic type II collagen and subsequent screening for antibodies that recognize lathyritic but not pepsin-digested type II collagen. One antibody (called 5B2) was identified that recognized a short peptide sequence in the aminotelopeptide of chicken type II collagen but did not recognize other collagen types. Further characterization of the epitope was achieved using a Multipin system and the epitope was localized to a short linear sequence of six amino acids. The antibody recognized type II collagen from a variety of species including man and mouse. The epitope for 5B2 was found to be susceptible to cleavage with recombinant stromelysin without cleavage of the major collagen triple helix. Comparison was made between MAb 5B2 and two other antibodies (called MAb 2B1 and MAb 6B3) that recognize separate epitopes located along the triple helix of the type II collagen molecule.

Amino Acid Sequence↗

PubMed1990

Extracellular matrix production by embryonic epithelium cultured on type IV collagen. Deposition of a primary corneal stroma-like structure containing large irregular type I fibrils without type II collagen.

The corneal stroma of the chick embryo is deposited in two steps. The primary stroma is laid down by the corneal epithelium and it contains type I, type II and type IX collagens. Its formation is subsequent to the presumptive epithelial cells' migration onto the lens capsule (which is rich in type IV collagen). The secondary, ultimate stroma is synthesized by fibroblasts which, on day 5 of development, invade the swollen primary stroma. It is composed of a matrix of thin (25 nm), regular fibrils containing type I and type V collagens. We found that a chick corneal epithelium isolated from either a 6-day or a 14-day embryo was able to produce, in vitro, stroma-containing type I collagen fibrils. However, the amount of collagen deposited and its organization were highly dependent on the substratum used. Plastic or purified bovine type I collagen substrata led to the release of very few fibrils. Purified human type IV collagen induced the production of an abundant matrix made of large irregular collagen fibrils. When compared to native corneal stroma, there were two aspects in which this matrix differed: (1) it contained only type I collagen, as shown by indirect immunofluorescence, and (2) there were numerous large, irregular fibrils of about 100 to 130 nm in diameter. In conclusion, it is suggested that purified type IV collagen substitutes, in part, for the basement membrane and allows the production of a corneal stroma-like matrix by an embryonic corneal epithelium in culture. This production is possible even with a 14-day epithelium which, in vivo, is no more involved in the synthesis of the stroma collagens. Moreover, the regulatory effect of type II collagen, previously suggested by in vivo observations, may be confirmed in this in vitro system by the appearance of large fibrils in the newly deposited stroma that are made only by type I collagen.

Animals↗

PubMed1986

Coordinate regulation of type IX and type II collagen synthesis during growth of chick chondrocytes in retinoic acid or 5-bromo-2'-deoxyuridine.

Chondrocytes isolated from 15-day-old embryonic chick sterna were cultured as monolayers for 7 days in control medium or in medium supplemented with retinoic acid or 5-bromo-2'-deoxyuridine. Control cells exhibited characteristic polygonal morphology and maintained the synthesis of cartilage-specific collagens, i.e. type II, type IX, 1 alpha, 2 alpha, and 3 alpha chains, and 45 K (presumptive type X). Type IX was the second most prevalent collagen and represented 12-15% of the phenotype. When exposed to retinoic acid, chrondrocytes displayed a fibroblast-like morphology and decreased collagen synthesis by day 2. The synthesis of collagen types II and IX declined in parallel along with that of the other cartilage collagens and ceased by day 7. During the same period, the synthesis of collagen types I, III, and V and two unidentified collagen chains was initiated and stimulated. Similar changes in collagen expression were caused by 5-bromo-2'-deoxyuridine but were delayed, beginning after day 4. Type III collagen, however, was never detected in 5-bromo-2'-deoxyuridine or control cultures. Because two different agents and two rates of modulation produced parallel changes in the synthesis of collagen types II and IX, these collagens appear to be coordinately regulated.

Animals↗

PubMed1991

An immunofluorescence test to determine the occurrence of type II collagen in muscle biopsies from cattle with rectovaginal constriction.

Type II collagen occurs in the muscles of rectovaginal constriction (RVC) affected and carrier cattle but not in normal cattle. Muscle biopsies from known RVC affected and carrier cattle and normal cattle were examined for the presence of Type II collagen using affinity purified goat anti-collagen II serum in a fluorescent antibody test. Type II collagen was consistently found in RVC affected animals (22 of 23 samples score positive). Rectovaginal constriction carrier animals had variable staining for the Type II collagen (25 of 47 samples scored positive). Some positive staining was also observed in the control animals (8 of 34 samples scored positive). Because of the variable occurrence of Type II collagen, the value of fluorescent antibody staining to identify RVC carrier animals is uncertain.

Animals↗

PubMed1984

Specificity of anti-type II collagen antibody response in rats.

Specificity of the rat antibody against type II collagen was investigated using rat, bovine and human type II collagen preparations. PVG/c rats showed the highest antibody level in assays with autologous rat type II collagen than with heterologous (bovine or human) type II collagen even when immunized with heterologous one. On the other hand, the rat exhibited significantly low antibody response when they were immunized with autologous type II collagen. The results indicate that rats develop strong antibody response against self type II collagen when immunized with heterologous collagen and this unique specificity of anti-type II collagen antibody response suggests that autoimmunity is involved in the pathogenesis of collagen-induced arthritis in rats.

Animals↗

PubMed1987

Collagen type IX: evidence for covalent linkages to type II collagen in cartilage.

A major site of pyridinoline cross-linking in bovine type IX collagen was traced to a tryptic peptide derived from one of the molecule's HMW chains. This peptide gave two amino acid sequences (in 2/1 ratio) consistent with it being a three-chained structure. The major sequence matched exactly that of the C-telopeptide of type II collagen from the same tissue. A second HMW chain that contained pyridinoline cross-links also gave two amino-terminal sequences, one from its own amino terminus, the other matching exactly the N-telopeptide cross-linking sequence of type II collagen. We conclude that type IX collagen molecules are covalently cross-linked in cartilage to molecules of type II collagen, probably at fibril surfaces.

Animals↗