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PubMed2000

Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1).

OBJECTIVE: To examine whether type II collagen cleavage by collagenase and loss of proteoglycan are excessive in human osteoarthritic (OA) articular cartilage compared with nonarthritic articular cartilage, and whether this can be inhibited by a selective synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1 [MMP-1]). METHODS: Articular cartilage samples were obtained during surgery from 11 patients with OA and at autopsy from 5 adults without arthritis. The articular cartilage samples were cultured in serum-free medium. A collagenase-generated neoepitope, which reflects cleavage of type II collagen, and proteoglycan glycosaminoglycan (GAG), which predominantly reflects aggrecan release, were assayed in culture media. In addition, cultures were performed using either of 2 synthetic MMP inhibitors, both of which inhibited collagenase 2 (MMP-8) and collagenase 3 (MMP-13), but one of which spared collagenase 1. Cultures were also biolabeled with 3H-proline in the presence and absence of these inhibitors to measure collagen synthesis (as tritiated hydroxyproline) and incorporation in articular cartilage. RESULTS: As a group, cleavage of type II collagen by collagenase was significantly increased in OA cartilage samples. In contrast, proteoglycan (GAG) release was not increased. This release of a collagenase-generated epitope was inhibited by both MMP inhibitors in 2 of 5 nonarthritic samples and in 9 of 11 OA cartilage samples. The inhibitor that spared collagenase 1 was generally more effective and inhibited release from 4 of 5 nonarthritic cartilage samples and the same OA cartilage samples. Group analyses revealed that the inhibition of collagenase neoepitope release by both inhibitors was significant in the OA patient cartilage, but not in the nonarthritic cartilage. Proteoglycan loss was unaffected by either inhibitor. Newly synthesized collagen (predominantly, type II) exhibited increased incorporation in OA cartilage, but only in the presence of the inhibitor that arrested collagenase 1 activity. CONCLUSION: These results further indicate that the digestion of type II collagen by collagenase is selectively increased in OA cartilage, and that this can be inhibited in the majority of cases by a synthetic inhibitor that can inhibit collagenases 2 and 3, but not collagenase 1. The results also suggest that in OA, newly synthesized collagen is digested, but in a different manner than that of resident molecules. Proteoglycan release was not increased in OA cartilage and was unaffected by these inhibitors. Inhibitors of this kind may be of value in preventing damage to type II collagen in human arthritic articular cartilage.

Adult↗

PubMed1984

Role of anchorin CII, a 31,000-mol-wt membrane protein, in the interaction of chondrocytes with type II collagen.

We have previously reported the isolation of a hydrophobic, type-II collagen-binding glycoprotein of molecular weight 31,000 (31,000-mol-wt protein) from chick chondrocyte membranes (Mollenhauer, J., and K. von der Mark, EMBO Eur. Mol. Biol. Organ. J., 2:45-50). The function of this protein in anchoring pericellular type II collagen to the chondrocyte surface was inferred from its ability to bind native type-II collagen either when detergent solubilized or when inserted into liposomes. In the present study we have used specific antibodies to localize this protein, which we now call anchorin CII, to the surface of chondrocytes in both cartilage sections, and in cell culture. In immunofluorescence studies of isolated chondrocytes we observed a dense, punctate distribution of anchorin CII on the cell surface when chondrocytes were enclosed by a pericellular type II collagen matrix. Removal of the pericellular matrix with trypsin also removed anchorin CII. The membrane protein character of anchorin CII was indicated by the demonstration of antibody-induced patching and capping on the chondrocyte surface at 22 degrees C and 37 degrees C, respectively. In monolayer culture, the amount of anchorin CII appeared reduced on flattened chondrocytes lacking a pericellular type II collagen matrix but was prominent upon intercellular cell processes. Fab' fragments prepared from either anchorin CII antiserum or an antiserum directed against the entire chondrocyte membrane inhibited the attachment of chondrocytes to a type II collagen substrate. In each case, the inhibition of attachment was neutralized by preincubation of Fab' fragments with purified anchorin CII.

Animals↗

PubMed1999

Small deletions in the type II collagen triple helix produce kniest dysplasia.

Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.

Base Sequence↗

PubMed1994

High levels of anti-type II collagen IgG in west African patients with rheumatoid arthritis.

OBJECTIVE: To compare levels of antitype II collagen IgG in West African and British patients with rheumatoid arthritis (RA). METHODS: IgG levels to native and denatured type II collagen were measured by ELISA: RESULTS: Serum levels of antinative type II collagen IgG were raised in 17 of 58 (29%) West African patients with RA. In contrast, 14 of 89 (16%) British RA patients had raised levels of antinative type II collagen IgG. Levels of antinative type II collagen IgG were also higher in West African patients with RA than in the British patients. CONCLUSION: Our results suggest that type II collagen autoimmunity plays a more prominent role in RA in West Africa than in Britain.

Africa, Western↗

PubMed2000

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder.

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.

Achondroplasia↗

PubMed2000

Chlorination of pyridinium compounds. Possible role of hypochlorite, N-chloramines, and chlorine in the oxidation of pyridinoline cross-links of articular cartilage collagen type II during acute inflammation.

Reactive oxygen species produced by activated neutrophils and monocytes are thought to be involved in mediating the loss of collagen and other matrix proteins at sites of inflammation. To evaluate their potential to oxidize the pyridinoline (Pyd) cross-links found in collagen types I and II, we reacted hydrogen peroxide (H(2)O(2)), hypochlorous acid/hypochlorite (HOCl/OCl(-)), and singlet oxygen (O(2)((1)delta g)) with the Pyd substitutes, pyridoxamine dihydrochloride and vitamin B(6), which share the same chemical structure and spectral properties of Pyd cross-links. Neither H(2)O(2) (125-500 microm) nor O(2)((1)delta g) (10-25 microm) significantly changed the spectral properties of pyridoxamine or vitamin B(6). Reaction of HOCl/OCl(-) (12.5-50 microm) with pyridoxamine at pH 7.2 resulted in a concentration-dependent appearance of two new absorbance peaks and a decrease in fluorescence at 400 nm (excitation 325 nm). The new absorbance peaks correlated with the formation of an N-chloramine and the product of its subsequent reaction with pyridoxamine. In contrast, the extent to which HOCl reacted with vitamin B(6), which lacks a primary amine group, was variable at this pH. At lysosomal pH 5.5, Cl(2)/HOCl/OCl(-) reacted with both pyridoxamine and vitamin B(6). Four of the chlorinated products of this reaction were identified by gas chromatography-mass spectrometry and included 3-chloropyridinium, an aldehyde, and several chlorinated products with disrupted rings. To evaluate the effects of Cl(2)/HOCl/OCl(-) on Pyd cross-links in collagen, we exposed bone collagen type I and articular cartilage type II to HOCl. Treatment of either collagen type with HOCl at pH 5. 0 or 7.2 resulted in the oxidation of amine groups and, for collagen type II, the specific decrease in Pyd cross-link fluorescence, suggesting that during inflammation both oxidations may be used by neutrophils and monocytes to promote the loss of matrix integrity.

Cartilage, Articular↗

PubMed1989

Type II collagen screening in the human chondrodysplasias.

Abnormalities of type II collagen have been considered strong candidates for causing human condrodysplasias. We have employed peptide mapping to screen for several types of type II colagen abnormalities in cartilage samples from 66 patients with 20 separate disorders. Except for achondrogenesis type II (Langer-Saldino) and spondyloepiphyseal dysplasia (SED) congenita in which abnormalities have been described and diastrophic dysplasia in which the changes were probably secondary, no abnormalities were detected. Within the limitations of the screening technique, the results combined with other data from the literature suggest that abnormalities of this molecule are not common causes of chondrodysplasias outside of the achondrogenesis type II-SED congenita family of disorders.

Adolescent↗

PubMed1997

Type-II collagen gene expression is transiently upregulated in experimentally induced degeneration of rabbit intervertebral disc.

To clarify phenotypic alterations of intervertebral disc cells during the repair process, we cloned partial type-II collagen cDNA from rabbits and analyzed the level of expression of type-II collagen mRNA in disc degeneration. An animal model was created by surgical denucleation of rabbit intervertebral discs through an extraperitoneal approach. Eight animals each from an experimental and a control group were killed at 2, 4, 8, or 16 weeks postoperatively, and the disc samples were used for this study. Round chondrocyte-like cells that filled the herniated space showed intense signal of type-II collagen mRNA and significant pericellular immunostaining of type-II collagen but no clear staining of type-I collagen. Northern blot analysis revealed that the expression of type-II collagen mRNA of the repair disc cells was transiently increased at 4 weeks postoperatively. The cells were able to change their morphology in response to mechanical stimulation by surgical denucleation and to induce a significant increase in the gene expression of type-II collagen at an early phase of disc degeneration. The present results indicate the transient enhancement of repair activity in the degenerative process of injured fibrocartilage.

Animals↗

PubMed2006

Regulation of type II collagen synthesis during osteoarthritis by prolyl-4-hydroxylases: possible influence of low oxygen levels.

Osteoarthritic (OA) chondrocytes are metabolically active, displaying increased synthesis of type II collagen. Here, we show by immunohistochemistry and polymerase chain reaction that in comparison with healthy cartilage, OA articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. Exposure of primary human articular chondrocytes to 1% oxygen enhanced accumulation of native type II collagen and stabilized hypoxia-inducible factor-1alpha (HIF-1alpha). This effect was abolished by addition of the HIF-1 inhibitor 2-methoxyestradiol. Real-time polymerase chain reaction analyses of mRNAs from these cultures revealed increased transcript levels of both alpha-subunits of prolyl-4-hydroxylase (P4HA1, approximately 2-fold; P4HA2, approximately 2.3-fold) and of classical HIF-1 target genes (glucosetransporter-1, approximately 2.1-fold; phosphoglyceratekinase-1, approximately 2.2-fold). Treatment of hypoxic chondrocytes with 2-methoxyestradiol reduced transcriptional activity of HIF-1 and synthesis of alpha(II), and to a lesser extent alpha(I), subunits of collagen prolyl-4-hydroxylases. mRNA levels of type II collagen (Col2A1) and the beta-subunit (P4HB) of prolyl-4-hydroxylase, however, displayed only modest changes at 1% oxygen. From these results and our in vivo data, we inferred that besides increased Col2A1 mRNA expression by OA chondrocytes, accelerated posttranslational modification processes might contribute to the increased synthesis and accumulation of type II collagen during OA and experimental hypoxia.

Cartilage, Articular↗

PubMed2003

Urinary collagen type II C-telopeptide fragments are sensitive markers of matrix metalloproteinase-dependent cartilage degradation in rat adjuvant-induced arthritis.

OBJECTIVE: To assess the relevance of collagen type II C-telopeptide fragments (CTX-II) as markers of cartilage degradation during adjuvant-induced arthritis in rats. METHODS: Rats were injected with Freund's adjuvant on day 0 and treated orally for 21 days twice a day with vehicle or 10 or 20 mg/kg of a newly designed matrix metalloproteinase inhibitor (MMP-Inh). Urine samples were collected for 24 h between days 19 and 20 and the concentration of the cartilage-derived CTX-II was measured with a 2-site, sandwich-type ELISA. To assess arthritis, inflammatory scores were determined, and changes in paw volumes were measured by plethysmography. RESULTS: On day 21, the inflammation was generalized in rats injected with Freund's adjuvant. The urinary concentration of CTX-II was significantly higher in arthritic rats than in control non-injected rats. Oral treatment of arthritic rats with MMP-Inh dramatically decreased the concentration of CTX-II in urine, with values returning to those of controls. Treatment simultaneously reduced the clinical variables of the disease. CONCLUSION: These results demonstrate that fragments of type II collagen in urine can be used as a measure of cartilage degradation in arthritic rats as well as potent non-invasive markers of the efficacy of chondroprotective treatments.

Animals↗

PubMed1985

Type II collagen induced autoimmune salpingitis in the rat.

Previous studies showed type II collagen induced autoimmune salpingitis in Wistar rats. In this study we increased the number of animals and investigated whether or not type II collagen induced salpingitis is transferable by immune sera. Histopathological observations of salpingitis in the serum transferred rats were similar to those observed in the immunized rats but the degree of otopathological changes was less than that of immunized rats. Electronmicroscopic findings indicate an increased permeability in the capillaries and intercellular space and cellular infiltration in the submucosa of the immunized rats.

Animals↗

PubMed1986

Type II collagen of lamprey.

The major collagen in lamprey notochord is type II, as determined by its amino acid composition and solubility properties. This collagen has a distribution of charged residues indistinguishable from higher vertebrate Type II collagens as judged by its SLS banding pattern. Lamprey type II collagen has a higher thermal stability than lamprey skin collagen, in contrast to the identical melting temperatures for these types in mammals. A minor collagen in lamprey notochord has solubility properties, amino acid composition, and electrophoretic mobility similar to that of 1 alpha, 2 alpha, 3 alpha collagen in human cartilage.

Amino Acids↗

PubMed1990

Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen.

Adjuvant arthritis is induced by intradermal injection of Mycobacterium tuberculosis (MT) in oil. The role of immunity to type II collagen (CII) in adjuvant arthritis (AA) has not been well defined. We found that oral administration of chicken CII given 3 micrograms per feeding on days -7, -5, and -2 before disease induction consistently suppressed the development of AA. A decrease in delayed-type hypersensitivity responses to CII was also observed that correlated with suppression of AA. AA was optimally suppressed by 3 and 30 micrograms of collagen type II variably by 300 micrograms, and not by 0.3 microgram or 1 mg. Oral administration of collagen type I also suppressed AA; only minimal effects were seen with collagen type III. Suppression was Ag specific: feeding CII did not suppress experimental autoimmune encephalomyelitis; feeding myelin basic protein suppressed experimental autoimmune encephalomyelitis, but not AA. Suppression of AA could not be consistently obtained by feeding MT. Suppression of AA could be adoptively transferred by T cells from CII fed animals and could be obtained when CII was fed after disease onset. Our results suggest that autoimmunity to CII has a pathogenic role in AA and raise the possibility that cross-reactive epitopes exist between CII and MT. Alternatively, the pathogenesis of AA may be dependent on developing immunity to CII. These results further demonstrate the effectiveness of oral tolerance as a means to suppress experimental autoimmune diseases.

Administration, Oral↗

PubMed1993

Prevention of experimental autoimmune arthritis with a peptide fragment of type II collagen.

Collagen arthritis is induced in inbred rats with the injection of native type II collagen. The pathogenesis of this experimental autoimmune disease is T cell dependent. This study demonstrates that collagen-specific T cells, derived from pathogenic and nonpathogenic rat T cell lines, both recognize the same peptide epitope. The epitope, consisting of amino acids 58-73 of cyanogen bromide fragment 11 of type II collagen, was as effective as whole collagen in stimulating a panel of collagen-specific rat/mouse T cell hybridomas. This peptide may, therefore, constitute a dominant epitope for CD4+ rat T cells in their response to type II collagen. Administration of the peptide to either neonatal or adult rats prevented the subsequent induction of experimental arthritis with whole collagen, demonstrating that the in vivo response to this dominant epitope is, therefore, relevant in the pathogenesis of arthritis. Despite its ability to prevent collagen-induced arthritis, administration of this peptide in incomplete Freund's adjuvant intradermally did not induce disease.

Amino Acid Sequence↗

PubMed1985

Type II collagen mediated autoimmune middle ear disease: eustachian tube disease, otitis media with effusion and tympanosclerosis.

Intact Eustachian tube and tympanic cavity functions are essential for normal middle ear physiology. Type II collagen is an essential component of ear tissue. Autoimmune response to this type II collagen produces sensorineural hearing loss, vestibular dysfunction, endolymphatic hydrops, otospongiosis-like lesions, Eustachian tube inflammation and Eustachian tube chondritis. In addition, these autoimmune responses occasionally produce otitis media with effusion (not infectious). Tympanosclerosis, which is a frequent sequelae of otitis media with effusions, was also induced by type II collagen immunization together with surgical incision of the tympanic membrane. The exact mechanisms of this type II collagen autoimmune mediated middle ear disease are not clear. However, the animals thus induced have higher antibody titers and cell mediated immune responses to type II collagen. The tympanic membrane showing tympanosclerosis also had C3 and Ig deposits. All the animals with otitis media with effusion induced by type II collagen immunization also had Eustachian tube disease. This could be due to a malfunction of the Eustachian tube. Thus, this model might provide a rational approach for the study of otitis media with effusion associated with vasculitis. Further studies are needed to elucidate the immunologic mechanism involved in the pathogenesis of otitis media with effusion.

Animals↗

PubMed1995

Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice.

The induction of arthritis in DBA/1 mice usually requires immunization with the antigen type II collagen emulsified with Mycobacterium tuberculosis in oil. Here we describe that interleukin 12 (IL-12) can replace mycobacteria and cause severe arthritis of DBA/1 mice when administered in combination with type II collagen. Immunization of DBA/1 mice with type II collagen emulsified in oil alone resulted in a weak immune response, and only a few animals (10-30%) developed arthritis. Administration of IL-12 for 5 days simultaneously with each immunization strongly enhanced the anti-type II collagen immune response. Collagen-specific interferon gamma (IFN-gamma) synthesis by ex vivo activated spleen cells was enhanced 3- to 10-fold. IFN-gamma was almost completely produced by CD4+ T cells. Furthermore, the production of collagen-specific IgG2a and IgG2b antibodies was upregulated 10- to 100-fold. As a consequence, the incidence of arthritis in the group of mice immunized with collagen plus IL-12 was very high (80-100%). The developing arthritis was severe, involving approximately 50% of all limbs with strongly increased footpad thickness in most cases. Furthermore, histological examination revealed massive, mainly polymorphonuclear cell infiltration, synovial hyperplasia, cartilage and bone destruction, as well as new bone formation. In many cases, this resulted in the complete loss of joint structure. Neutralization of IFN-gamma in vivo prevented the development of arthritis in collagen-immunized and IL-12-treated mice. In conclusion, our data show that in vivo administered IL-12 can profoundly upregulate a T helper I-type autoimmune response, resulting in severe joint disease in DBA/1 mice.

Animals↗

PubMed2000

[Regulating effects of transforming growth factor-beta (TGF-beta) on gene expression of collagen type II in human intervertebral discs].

OBJECTIVE: To assess the regulating effects of TGF-beta on gene expression of collagen type II in the human intervertebral discs. METHODS: In situ hybridization was used to investigate the effect of TGF-beta1 on collagen mRNA in confluent primary and passaged monolayer cell cultures of annulus fibrosus (AF) as well as nucleus pulposus (NP). The mean photodensitometry of cell smears as semi-quantitative analysis was evaluated by VIDAS software. RESULTS: In primary cultures, 1 ng/ml and 10 ng/ml TGF-beta1 inhibited the collagen type II mRNA levels by 74.6% and 60.2% respectively in AF; they also inhibited the mRNA levels by 69.6% and 55.5% respectively in NP. In passaged cultures in which the notochordal cells and chondrocytes were in dedifferentiation status, 1 ng/ml and 10 ng/ml TGF-beta1 increased the collagen type II mRNA levels by 151% and 166% respectively in AF and also increased the mRNA levels by 145% and 198% respectively in NP. CONCLUSIONS: The regulation effect of TGF-beta on collagen type II gene expression is dependent on whether the cells are fully differentiated or undergoing phenotype loss, and TGF-beta may play an important role in the repair process during early disc degeneration, especially in nucleus pulposus.

Cells, Cultured↗

PubMed1990

[Histopathological study of arthritic lesions induced by immunization with type II collagen in DBA/1J mouse].

Eight male DBA/1J mice immunized twice by intradermal injection of type II collagen were autopsied 12 weeks after the first immunization and analyzed for anti-type II collagen antibody level, and the limb joints were examined radiologically and histopathologically. Clinical onset of swelling and erythema in the limb joints occurred about 5 weeks after the first immunization and deformity of the limbs was observed in a few animals about 5 weeks later. Although there were marked individual differences, serum anti-type II collagen antibody levels were elevated in all animals. Histopathologically, the changes were similar to those seen in human rheumatoid arthritis and were characterized by proliferation of synovial lining cells, formation of granulation tissue with destruction of cartilage and subchondral bone, and ankylosis. Systematic examination of various joints of the fore- and hind-limbs revealed definitely that the sequence of arthritic lesions was not uniform. The knee joint was involved most frequently, but smaller joints such as the phalangeal joints were involved less frequently but exhibited severe changes. The significance of histopathological examinations in the evaluation of effects of anti-rheumatic drugs was discussed with reference to this model.

Animals↗