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PubMed1987

Experimental arthropathy induced in rhesus monkeys (Macaca mulatta) by intradermal immunization with native bovine type II collagen.

Over a 6-month time course, polyarticular arthritis was induced in 7 male rhesus monkeys by 3 intradermal injections of bovine type II collagen emulsified in complete Freund's adjuvant, followed later by 2 intradermal injections of type II collagen in incomplete Freund's adjuvant. All animals exhibited delayed-type hypersensitivity to type II collagen by skin test and had serum anti-type II collagen titers of greater than 10,000 (at 1 month) and 20,000 to 160,000 (at 6 months) by enzyme-linked immunosorbent assay. Gross joint changes were observed in 6 of 7 monkeys, especially in the knee and elbow; synovial cell hyperplasia, increased vascularization and a focal mononuclear cell infiltrate were the most frequent findings. Chronic arthritis with destructive cartilage lesions was most prominent in the phalangeal joints of the hands (7 of 7 animals). Microscopically, these changes consisted of fibrosis of the synovium with increased vascularization, villous synovial membrane hyperplasia and focal mononuclear cell infiltration, as well as fibrous metaplasia of the articular cartilage adjacent to pannus formations. Also evident was a loss of safranin O staining intensity in the cartilage and loss of continuity of the articular surface. The 7 control monkeys (received Freund's adjuvant without collagen) were delayed-type hypersensitivity-negative, had no serum anti-type II collagen antibodies, and had grossly and microscopically normal joints. This primate model resembles collagen-induced arthritis seen in rodents and, to some degree, human rheumatoid arthritis.

Animals↗
PubMed2003

Essential role of Fc gamma receptors in anti-type II collagen antibody-induced arthritis.

Anti-type II collagen (anti-CII) Ab is a well-known autoantibody observed in patients with rheumatoid arthritis. Injection of anti-CII Ab and LPS induces arthritis in mice in which anti-CII Ab as well as inflammatory cytokines, IL-1beta and TNF-alpha, play critical roles. We investigated the involvement of IgG FcRs (FcgammaRs) in this arthritis model. BALB/c mice injected with the F(ab')(2) of anti-CII Ab showed no signs of arthritis. Arthritis development was not observed in FcRgamma(-/-) mice and was partially suppressed in FcgammaRIII(-/-) mice despite the binding of anti-CII Ab and C3 to cartilage surface. Surprisingly, BALB/c mice lacking FcgammaRIIB, which is known as an inhibitory FcgammaR, developed arthritis with no exacerbation in arthritis score compared with wild-type (WT) mice, and only slight exacerbation was observed in the histopathological analysis. In contrast, aged FcgammaRIIB(-/-) BALB/c mice developed arthritis without LPS injection, suggesting an augmented susceptibility to arthritis in aged FcgammaRIIB(-/-) mice. No significant difference was observed among BALB/c-WT, -FcRgamma(-/-), and -FcgammaRIIB(-/-) mice on cytokine production induced by anti-CII Ab and LPS injection. Severe arthritis developed in BALB/c-WT and -FcgammaRIIB(-/-) mice, but not in BALB/c-FcRgamma(-/-) mice, after the injection of anti-CII Ab and inflammatory cytokines. These results suggest that the reason behind the nondevelopment of arthritis in FcRgamma(-/-) BALB/c mice is not due to a disorder in transient cytokine production, but to an irregularity downstream of cytokine production.

Aging↗
PubMed2005

Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis.

Collagen type II (CII) is a relevant joint-specific autoantigen in the pathogenesis of rheumatoid arthritis (RA). Whereas the reasons for the breakage of self tolerance to this major cartilage component are still enigmatic, T cell responses to glycosylated CII determinants in RA patients indicate that post-translational modifications play a role. Since the conversion of arginine into citrulline by peptidylarginine deiminases (PAD) in some non-joint-specific antigens such as filaggrin or fibrin has been shown to give rise to RA-specific humoral immune responses, we investigated whether PAD modification of cartilage-specific CII might affect its recognition by circulating autoantibodies in early RA. In vitro treatment with purified PAD led to arginine deimination of native CII or of synthetic CII peptides as evidenced by amino acid analysis. The citrullination resulted in modified recognition of the immunodominant CII epitope C1(III) (amino acid residues 359-369) by murine and human antibodies. In a cohort of early RA patients (n=286), IgG antibodies directed toward a synthetic citrullinated C1(III) peptide (citC1(III)-P) were detectable with a prevalence of 40.4%. The partial autoantibody cross-reactivity between citC1(III)-P and citrullinated peptides mimicking epitopes of the cytoskeletal autoantigen filaggrin suggests that autoimmunity to cartilage-specific modified self might be a critical intermediate bridging recognition of PAD-modified extra-articular autoantigens with the disruption of tolerance to native cartilage constituents.

Amino Acid Sequence↗
PubMed1993

Antibodies to type II collagen in early rheumatoid arthritis.

Antibodies to native and denatured type II collagen were investigated in a group of 79 patients with rheumatoid arthritis (RA) of disease duration less than 12 months (median 8 months; range 3-12 months). Using a solid-phase ELISA to measure these antibodies, the incidence of patients with levels above the upper limit of normal (mean of normal plus 3 SD) was low as compared to previous findings in patients with established disease. The majority of positive sera contained small amounts of IgM antibodies to denatured type II collagen whilst a few had IgG antibodies to native and denatured type II collagen. These findings suggest that the production of high levels of serum anti-type II collagen antibodies in patients with RA is a secondary phenomenon, which may exacerbate the disease rather than be a primary cause of disease.

Adult↗
PubMed1989

Limited proliferative response to type II collagen in rheumatoid arthritis.

In order to define the potential importance of type II collagen in the activation of rheumatoid arthritis (RA) synovial fluid (SF) lymphocytes, we examined the proliferative response of matched peripheral blood and SF lymphocytes to type II collagen. The mean proliferative response to the collagen was somewhat greater (p less than 0.05) with SF, compared to peripheral blood lymphocytes. However, the magnitude of this response was relatively weak as determined by stimulation indices, and it did not approach that observed with peripheral blood lymphocytes in response to tetanus toxoid. Sixty-seven percent of peripheral bloods and 50% of SF demonstrated positive responses to the control antigen, tetanus toxoid. In contrast, only 6 and 28%, respectively, were positive in response to type II collagen. The addition of exogenous interleukin 2 augmented responses to the tetanus toxoid, however, no such enhancement with type II collagen was noted in our patients. Our collagen was arthritogenic in experimental animals. These observations do not support the existence of T cell specificity toward type II collagen as a common mechanism for the expansion of synovial lymphocytes in RA.

Adult↗
PubMed2003

Mouse Snail family transcription repressors regulate chondrocyte, extracellular matrix, type II collagen, and aggrecan.

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snail-related transcription repressors during chondrocyte differentiation.

Aggrecans↗
PubMed1993

T cell epitopes of type II collagen that regulate murine collagen-induced arthritis.

Chick type II collagen (CII), a protein commonly found in joint cartilage, induces an autoimmune arthritis when administered to susceptible strains of mice. A cyanogen bromide fragment of CII, CB11, contains the requisite epitopes critical for inducing collagen-induced arthritis. If administered as a tolerogen, however, before immunization, CB11 prevents the onset of disease. Therefore, delineation of structural elements of CB11 that can regulate autoreactive T cells became the goal of this study. To delineate the structural elements of CB11 antigenic to T cells, 14 peptides containing overlapping sequences of CB11 were generated. Mononuclear cells from CII-immunized DBA/1 mice were cultured with these peptides and the resulting supernatants examined for the production of IFN-gamma. Two peptides, CII 181-209 and CII 245-270, generated the greatest responses. The ability of these two peptides to regulate arthritis was tested by administering them to neonatal DBA/1 mice as tolerogens before immunization with CII. Both peptides suppressed the incidence of arthritis whereas no other peptide used as a tolerogen significantly altered the course of the disease. T cells from four arthritis-resistant murine strains did not recognize either peptide when immunized with CII, whereas cells from the disease-susceptible B10.Q mice responded well to both. Thus, the coincidence of T cell responses to CII 181-209 and CII 245-270 in CIA-susceptible mice and the lack of response in disease-resistant strains or CII-tolerized mice identify these two peptides as containing important T cell epitopes that regulate CIA.

Amino Acid Sequence↗
PubMed1998

Characterization of helical cleavages in type II collagen generated by matrixins.

Several vertebrate collagenases have been reported to cleave type II collagen, leading to irreversible tissue destruction in osteoarthritis. We have investigated the action of MMP-1 and MMP-13 on type II collagen by use of neoepitope antibodies and N-terminal sequencing. Previous studies have suggested that the initial cleavage of type II collagen by MMP-13 is followed by a second cleavage, three amino acids carboxy-terminal to the primary cleavage site. We show here that this cleavage is also produced by APMA-activated MMP-1 in combination with MMP-3 (i.e. fully activated MMP-1). The use of a selective inhibitor of MMP-3 has shown that it is this enzyme, rather than interstitial collagenase which had been exposed to MMP-3, which makes the second cleavage. In addition we have identified, through N-terminal sequencing, a third cleavage site, three residues carboxy-terminal to the secondary site. Since MMP-2 is thought to be responsible for gelatinolytic action on type II collagen we have investigated the effect of MMP-2 after the initial helical cleavage made by either MMP-1 or MMP-13. A combination of MMPs-1, -2 and -3 results in both the second and third cleavage sites; adding MMP-2 to MMP-13 did not alter the cleavage pattern produced by MMP-13 on its own. We conclude that none of the three cleavage sites will provide information about the specific identity of the collagenolytic enzymes involved in collagen cleavage in situ. Staining of cartilage sections of osteoarthritis patients with the neoepitope antibodies revealed type II collagen degradation starting at or near the articular surface and extending into the mid and deep zones with increasing degeneration of the cartilage.

Animals↗
PubMed1986

Homologous type II collagen induces chronic and progressive arthritis in mice.

Native mouse type II collagen was used for immunization of DBA/1 mice. Arthritis developed exclusively in male animals and was characterized by a variable and delayed onset, a slow and progressive development, and frequent exacerbations of disease in several joints including those that were previously affected. Titers of anti-type II collagen autoantibodies were found not to correlate well with arthritis development. It appears that experimental arthritis induced with homologous type II collagen resembles rheumatoid arthritis in humans, both in certain clinical features and in the lack of correspondence between anti-type II collagen autoantibody titers and disease symptoms.

Animals↗
PubMed1994

Type II collagen is transiently expressed during avian cardiac valve morphogenesis.

We present new evidence of the temporal and spatial expression of type II collagen in the embryonic chick heart during the very early stages of its development. In particular, we emphasize the distribution of its mRNA and protein during valve formation. Type II collagen as well as several other fibrillar collagens (types I, III, and V) are present in stage 18 endocardial cushion mesenchymal cells. At stage 23, alpha 1 (II) collagen transcripts and the cognate polypeptide colocalize in the atrioventricular valves. As development proceeds, the relative abundance of alpha 1 (II) collagen transcripts decreases during the stages studied (stages 22 to 45; day 3.5 to day 19) as assayed by RNA blotting of extracts of whole hearts. Type II collagen protein was immunologically undetectable in stage 38 (day 12) hearts, although collagens I, III, and V persisted and localize in the valve regions, in the endothelial lining of the heart, and in the epicardium. In keeping with other observations of type II collagen expression in non-chondrogenic regions of a variety of vertebrate embryos, the avian heart also exhibits transient type II collagen expression.

Animals↗
PubMed2002

An improved method to prepare hyaluronic acid and type II collagen composite matrices.

An improved method to prepare hyaluronic acid (HyA) and type II collagen composite matrices was developed. HyA and type II collagen formed polyion complex (PIC) in aqueous solution due to their opposite electrostatic charges. Therefore, optimal conditions at which PIC was not formed between HyA and type II collagen were determined in order to directly crosslink using a water-soluble carbodiimide [WSC; 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride]. HyA-collagen composite matrices were successfully obtained using WSC in the presence of 0.4M NaCl, which was found the optimal concentration to suppress PIC formation. Fourier transformed infrared spectra of the obtained matrices showed ester bond formation, indicating that the crosslinking reaction between HyA molecules, HyA and collagen molecules, and collagen molecules proceeded. The swelling ratio of a HyA-collagen composite matrix depended on the WSC concentration and HyA content. From scanning electron microscopy observations, the lyophilized matrices possess multi pore structures. The HyA-collagen composite matrices using this improved method will be useful in the preparation of cartilage regenerative scaffolds, and this methodology may be applied to other polyanion-polycation combinations as well.

Biocompatible Materials↗
PubMed2005

Sensitive immunoassays for the autoantibodies reacting against citrullinated carboxy-terminal telopeptides of type I and type II collagens in patients with rheumatoid arthritis.

We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic peptides derived from type I and type II collagens in patients with rheumatoid arthritis (RA). These peptides were tested with the chemiluminescence method (Nichols Advantage System). In 44 RA patients out of 120, the sera showed increased binding of citrullinated synthetic C-telopeptide derived from the alpha1 chain of type I collagen (p=0.003 compared to controls). For a corresponding C-telopeptide pair from the alpha1 chain of type II collagen, 35 patient sera bound the citrullinated peptide more strongly than the arginine peptide, but the difference compared to the controls was not significant (p=0.074). Correlation between the two carboxy-telopeptides was r=0.473 (p<0.001). The anti-CCP assay (antibodies against citrullinated filaggrin sequence-derived peptides) was positive in 59% of our RA patients. There was no relationship between the anti-CCP results and the antibodies against collagen C-telopeptides, but both are increased in RA patients. We demonstrated autoantibodies in RA patients that bound citrullinated C-telopeptides derived from type I and type II collagen antigens. The peptide sequences detected (-YYXA and -YMXA) were different from that based on the cyclic filaggrin antigen (-STXG-, where X represents citrulline).

Adult↗
PubMed1993

Resistance to collagen-induced arthritis in rats and rhesus monkeys after immunization with attenuated type II collagen.

Immunization of susceptible rodent or primate species with type II collagen (b-CII) from bovine origin induces type II collagen-induced arthritis (CIA). The disease is characterized as a systemic polyarthritis associated with humoral and cellular autoimmunity to CII and shares similarity with human arthritic diseases. The objective of this study was to develop a procedure for induction of resistance to CIA in animals, which possess a certain major histocompatibility complex phenotype that makes them prone to develop CIA (susceptible). It is shown that by immunization with an attenuated form of CII, in which arthritogenic epitopes have been destroyed by heat denaturation, disease resistance is induced in a susceptible inbred rat strain (RT-1u) and in an outbred population of susceptible rhesus monkeys (lacking the Mamu-A26 allele). In both species the disease resistance is connected with modulation of anti-CII autoantibodies of the IgM isotype. This protocol may provide a basis for effective and safe methods to induce protection to autoimmune arthritis in those subjects that are genetically prone to develop such a disease.

Animals↗
PubMed2002

HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen.

Rheumatoid arthritis is an autoimmune disease in which susceptibility is strongly associated with the expression of specific HLA-DR haplotypes, including DR1 (DRB1*0101) and DR4 (DRB1*0401). As transgenes, both of these class II molecules mediate susceptibility to an autoimmune arthritis induced by immunization with human type II collagen (hCII). The dominant T cell response of both the DR1 and DR4 transgenic mice to hCII is focused on the same determinant core, CII(263-270). Peptide binding studies revealed that the affinity of DR1 and DR4 for CII(263-270) was at least 10 times less than that of the model Ag HA(307-319), and that the affinity of DR4 for the CII peptide is 3-fold less than that of DR1. As predicted based on the crystal structures, the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe(263); however, unexpectedly the adjacent Lys(264) also contributed significantly to the binding affinity of the peptide. Only these two CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. Affinity-enhancing substitutions frequently involved replacement of a negative charge, or Gly or Pro, hallmark amino acids of CII structure. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides that bind to these alleles.

Amino Acid Sequence↗
PubMed2003

Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects.

Spondyloepiphyseal dysplasia (SED) Maroteaux type is an autosomal dominant skeletal dysplasia, characterized by spondylar dysplasia, mild epiphyseal dysplasia of the large joints, and type E-like brachydactyly. These manifestations overlap with those of spondyloperipheral dysplasia (SPD), in which a sporadic case with a mutation of COL2A1 has been reported. We report on three patients (an affected woman and her son and a sporadic case of an affected man) with SED Maroteaux type. The affected adults were severely short along with stubby hands and feet, and one developed myelopathy as a result of thoracolumbar gibbus. The affected child was mildly short at birth, and developed brachydactyly in early childhood. The radiological hallmarks of these patients included severe platyspondyly with square-shaped vertebral bodies, iliac hypoplasia, epiphyseal hypoplasia of the large joints, and strikingly short metacarpals and phalanges. These radiological findings appeared already apparent in early childhood. SED Maroteaux type was radiologically discriminative from SPD. Brachydactyly was much severe in the former than in the latter, and spondylar dysplasia manifestation was different between both disorders. Mutation screen by polymerase chain reaction-direct sequencing for all exons and their flanking regions of COL2A1 did not reveal any mutations in the three patients.

Adult↗
PubMed1994

Roles of the nucleational core complex and collagens (types II and X) in calcification of growth plate cartilage matrix vesicles.

Matrix vesicles (MV) were shown to initiate mineralization in cartilage and other vertebrate tissues. However, the factors that drive this process remain to be fully elucidated. Recent studies have shown that a preformed nucleational core consisting mainly of a Ca(2+)-phosphatidylserine-Pi complex, is necessary for the accumulation of Ca2+ by MV. In addition, the collagens attached to the MV surface were shown to play an important role in stimulating Ca2+ uptake. In this study, we extend this knowledge by showing that both, the nucleational core and the collagens (types II and X), are co-requirements for rapid influx of Ca2+ into intact MV. MV to which collagen fragments were attached were released from hypertrophic chicken cartilage by trypsin and collagenase digestion (trypsin/collagenase-released MV (TCRMV), while "collagen-free" MV were released by hyaluronidase and collagenase digestion (hyaluronidase/collagenase-released MV (HCRMV). In contrast to TCRMV which showed active uptake of Ca2+, HCRMV showed only little uptake. However, binding of native type II collagen to HCRMV stimulated uptake of Ca2+. Sucrose gradients separated TCRMV and HCRMV into three different density fractions: a low density top fraction (SI), an intermediate density middle fraction (SII), and a high density pellet fraction (SIII). The SIII fractions of TCRMV and HCRMV contained significantly higher levels of mineral ions than did the SI and SII fractions. Only the SIII fraction of TCRMV which contained a stable nucleational core and surface-attached collagens, showed active Ca2+ uptake; all other sucrose fractions of TCRMV and HCRMV showed little or no uptake. Detergent treatment to purposely rupture the membrane greatly enhanced Ca2+ uptake by the SIII fraction of HCRMV, presumably by exposing the internal nucleational core. Addition of either native type II or type X collagen to the intact SIII fraction of HCRMV stimulated Ca2+ uptake to a level similar to that of the SIII fraction of TCRMV; however, incubation of the SI and SII fractions of either TCRMV or HCRMV with type II or X collagen did not activate Ca2+ uptake. These findings indicate that both a functional nucleational core and surface-attached collagens need to be present to support active mineralization of MV.

Animals↗
PubMed1992

Type II collagen defect in two sibs with the Goldblatt syndrome, a chondrodysplasia with dentinogenesis imperfecta, and joint laxity.

We report on a syndrome of spondylo-epimetaphyseal dysplasia, dentinogenesis imperfecta, and ligamentous hyperextensibility in two sibs born to nonconsanguineous parents. This chondrodysplasia was characterized by severe shortness of stature and an osteoporosis without fractures. Electron microscopic examination of the cartilage documented large vacuoles of dilated rough endoplasmic reticulum within the cytoplasm of chondrocytes. Gel electrophoresis of pepsin-soluble collagen extracted from cartilage demonstrated the presence of type II collagen chains with an abnormal mobility. Prolyl and lysyl hydroxylations were slightly increased. The abnormal molecules melted at a higher temperature than the normal ones. CNBr peptide mapping of type II collagen showed an altered electrophoretic migration of peptides CB 11, CB 8, and CB 10,5 whereas CB 9,7 looked normal. In addition, two small non-collagenous proteins isolated from cartilage were not found in an age-matched control individual but were detected in a normal newborn infant. The quantitation of proline-labelled collagen synthesized by dermal fibroblasts demonstrated a 50% reduction of total collagen. This decrease essentially affected the amount of extracellular type I collagen, which was secreted less efficiently than in control cells. Nevertheless, type I collagen chains behaved normally on 5% polyacrylamide gels. The reduced mRNA levels of alpha 1I and alpha 2I chains might reflect either a transcriptional defect or a decreased stability of mRNA transcripts. We suggest that the association of both pathological chondrocytes producing altered collagen type II and decreased synthesis of type I could be responsible for this peculiar phenotype. The overmodification of alpha 1II CNBr peptides is consistent with the presence of a single-base substitution in the COL2A1 gene. Whether there is a direct causal relationship between the type II collagen defect and the underexpression of type I collagen will require clarification.

Abnormalities, Multiple↗