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PubMed1986

[Induction of arthritis in mice by injection of homologous type II collagen].

Immunization with heterologous type II collagen (CII) induces arthritis in DBA/1 mice, a strain genetically susceptible to this disease. In order to develop an experimental model of autoimmunity more adequate for the study of human Rheumatoid Arthritis, DBA/1 mice were injected with homologous native CII. About 6 weeks later, the animals developed a chronic progressive polyarthritis assessed by clinical observations and histologic examination. The incidence of arthritis as well as the severity of the disease are clearly higher in males. Conversely, the secretion of autoantibodies raised against mouse CII is correlated neither with sex nor with activity score of the arthritis.

Acute Disease↗
PubMed1988

Early appearance of activated CD4+ T lymphocytes and class II antigen-expressing cells in joints of DBA/1 mice immunized with type II collagen.

Arthritis induced with type II collagen in DBA/1 mice, was analyzed by immunohistochemical techniques. In the earliest detectable pathologic changes, before any macroscopic signs, an accumulation of Mac1+, macrophage-like cells, and an increased expression of major histocompatibility class II antigens were observed focally in the synovial lining layer. In these foci, CD4+ and interleukin 2 receptor expressing T lymphocytes were regularly detected, but not usually other sets of lymphocytes such as B lymphocytes and CD8+ lymphocytes. In clinically detectable arthritis, there was a prominent infiltration of Mac1+ cells, both polymorphonuclear-like and macrophage-like cells. T cells were relatively few, suggesting that they do not play a primary effector role, but rather that they may regulate or permit the self-perpetuative inflammation.

Animals↗
PubMed1996

Suppression of adjuvant arthritis in rats by oral administration of type II collagen in combination with type I interferon.

The oral administration of 3 micrograms but not 300 micrograms of type II collagen (CII) significantly suppressed adjuvant arthritis in rats that was induced by immunization with Mycobacterium tuberculosis. Feeding 5000 units of type I interferon was also effective in downregulating the disease. More suppression of adjuvant arthritis was observed when both CII and interferon were orally given. Delayed-type hypersensitivity responses to M. tuberculosis were inhibited in interferon- but not in CII-fed animals. There were no delayed responses to CII in M. tuberculosis-immunized rats fed either CII or interferon. However, the delayed response to M. tuberculosis plus CII was significantly reduced by CII as well as interferon given orally. Feeding both CII and interferon was more effective in suppressing the delayed responses to M. tuberculosis plus CII. A similar suppression was observed in proliferative responses of lymph-node cells to M. tuberculosis, CII, or M. tuberculosis plus CII in-vitro. These results suggest that the suppression of adjuvant arthritis by oral administration of CII is due to tolerance to CII in which a bystander suppression mechanism appears to be involved. Orally administered interferon seems to suppress nonspecifically cellular immune responses. The oral administration of CII in combination with interferon may be a novel way to treat T cell-mediated diseases.

Administration, Oral↗
PubMed1985

Characterization of monoclonal antibody specific for human type II collagen: possible implication in collagen-induced arthritis.

We obtained monoclonal antibodies specific for human type II collagen and characterized them using human collagen type I, II, III and V and tropocollagen A (3/4) (TCA) and tropocollagen B (1/4) (TCB) fragments of type II collagen which were obtained by digestion with tadpole collagenase. These antibodies were of the IgG2a class and specific for the conformational determinant of TCA fragment of type II collagen. When injected intravenously into DBA/1J mice, one of the monoclonal antibodies induced arthritis, which was characterized by early onset, mildness in severity and preferential localization mainly in the peripheral joints of the lower extremities. These results suggest that, at least, one of the arthritogenic determinants of type II collagen for collagen-induced arthritis of mice exists in the three quarter region from the N-terminus of type II collagen.

Animals↗
PubMed1992

[Human type II collagen induced autoimmune inner ear lesions in guinea pigs].

Guinea pigs were immunized with human type I, type II or type III collagen. Inner ear lesions were induced in some guinea pigs by immunizing them with human type II collagen. Histopathologic changes included endolymphatic hydrops, organ of Corti lesions and endolymphatic duct contained a large number of inflammatory cells. These histologic changes resembled those observed in patient with Meniere's disease. We didn't discover any inner ear lesions in guinea pigs by immunizing them with human type I and type III collagen, although their serum antibody titers were high and antibody presented in perilymph. Immunohistochemical study showed the presence of type II collagen in the cochlea tissues--spiral ligament, basilar membrane, tectorial membrane, spiral limb and Rosenthal's canal. We didn't discover type I and type III collagen in these area.

Animals↗
PubMed1989

Expression of type II and type XI collagens in canine mammary mixed tumors and demonstration of collagen production by tumor cells in collagen gel culture.

The development of cartilaginous collagen types, II and XI, in canine mammary mixed tumors was studied biochemically and immunohistochemically. In mixed tumor, an alcian blue-positive myxomatous region appeared in the stroma, where round-shaped proliferating myoepithelial cells were scattered. Type II collagen was distributed in metaplastic cartilage matrix, while type XI was located only in the pericellular region, where proliferating cells were positively stained with anti-actin and anti-keratin antibodies. The accumulation of collagen types II and XI in the tumor mass was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by immunoblotting of the extract of the lesion using type-specific antibodies to collagen types II and XI. Tumor cells isolated from metaplastic tumor mass expressed both collagen types II and XI and myoepithelial types of cytoskeleton in gel culture, in which an alcian blue-positive substance became detectable in the pericellular region on day 3 and type II and type XI collagens on day 5. This may be a useful model for studying chondrocyte-type gene expression during tumorigenesis.

Animals↗
PubMed2003

Covalent cross-linking of the NC1 domain of collagen type IX to collagen type II in cartilage.

From a study to understand the mechanism of covalent interaction between collagen types II and IX, we present experimental evidence for a previously unrecognized molecular site of cross-linking. The location relative to previously defined cross-linking sites predicts a specific manner of interaction and folding of collagen IX on the surface of nascent collagen II fibrils. The initial evidence came from Western blot analysis of type IX collagen extracted by pepsin from fetal human cartilage, which showed a molecular species that had properties indicating an adduct between the alpha1(II) chain and the C-terminal domain (COL1) of type IX collagen. A similar component was isolated from bovine cartilage in sufficient quantity to confirm this identity by N-terminal sequence analysis. Using an antibody that recognized the putative cross-linking sequence at the C terminus of the alpha1(IX) chain, cross-linked peptides were isolated by immunoaffinity chromatography from proteolytic digests of human cartilage collagen. They were characterized by immunochemistry, N-terminal sequence analysis, and mass spectrometry. The results establish a link between a lysine near the C terminus (in the NC1 domain) of alpha1(IX) and the known cross-linking lysine at residue 930 of the alpha1(II) triple helix. This cross-link is speculated to form early in the process of interaction between collagen IX molecules and collagen II polymers. A model of molecular folding and further cross-linking is predicted that can spatially accommodate the formation of all six known cross-linking interactions to the collagen IX molecule on a fibril surface. Of particular biological significance, this model can accommodate potential interfibrillar as well as intrafibrillar links between the collagen IX molecules themselves, so providing a mechanism whereby collagen IX could stabilize a collagen fibril network.

Adult↗
PubMed1999

Autoimmune deafness is not related to hyperreactivity to type II collagen.

The pathogenic role of anti-type II collagen was analysed in a variety of hearing losses, in age-matched controls and in different autoimmune diseases. The immune reactivity of peripheral blood lymphocytes to type II collagen was studied by the degree of proliferation measured as the incorporation of bromodeoxyuridine in cultured lymphocytes. The anti-type II collagen antibodies showed a very low incidence in the hearing loss group. Lymphocytes of otosclerosis, Meniere's disease and other sensorineural deafness patients proliferated in response to concanavalin A and to type II collagen to a lower extent than peripheral blood lymphocytes from healthy controls. Nonetheless, these differences were not statistically significant. The immune hyperreactivity to type II collagen cannot explain the autoimmune mechanism of hearing losses. Humoral and cellular hyperreactivities to inner ear proteins different from type II collagen, could explain the autoimmune mechanism of deafness.

Adolescent↗
PubMed2005

Increase in degraded collagen type II in synovial fluid early in the rabbit meniscectomy model of osteoarthritis.

OBJECTIVE: The objective of this study was to determine whether collagen type II breakdown products in synovial fluid (SF), detected by an enzyme-linked immunoassay, represent a useful marker for early events in osteoarthritis (OA) in the rabbit medial meniscectomy model. DESIGN: Complete medial meniscectomy was performed on the right knee joints of 32 rabbits. Balanced groups of rabbits were then sacrificed at 2, 4, 8, and 12 weeks post-surgery. An additional 8 unoperated and 11 sham-operated animals served as controls. SF lavages were performed on right and left knee joints of the same animals at sacrifice. The proteolytic epitope of type II collagen was monitored using an enzyme-linked immunoassay. RESULTS: Macroscopically visible surface fibrillation and focal erosions appeared as early as 2 weeks after meniscectomy in the femorotibial joint (P<0.01). OA developed gradually during the later observation period, and then predominantly on the medial tibial plateau and medial femur. Significant histological alterations in cartilage, including a loss of proteoglycans, surface irregularities, and clefts, were detected at 2 weeks after meniscectomy (P<0.01). Collagen type II epitope levels in SF lavage samples were elevated peaking at 2 weeks after meniscectomy (P<0.02). Levels decreased at later time points, but they were still raised at 12 weeks (P< or =0.05). Highly significant correlations were found between the SF collagen type II epitope levels and the macroscopic and microscopic scoring results (Spearman rho correlation coefficient, macroscopy-collagen type II epitope r=0.222, P=0.025; microscopy-collagen type II epitope r=0.436, P< or =0.01). CONCLUSION: In this rabbit model of medial meniscectomy, levels of type II collagen fragments in SF appear to provide a useful marker of the early degenerative changes.

Animals↗
PubMed1994

Transcriptional suppression by interleukin-1 and interferon-gamma of type II collagen gene expression in human chondrocytes.

Type II collagen is one of the predominant extracellular matrix macromolecules in cartilage responsible for maintenance of integrity of this specialized tissue. We showed previously that interleukin-1 (IL-1) and interferon-gamma (IFN-gamma) are capable of decreasing the levels of alpha 1(II) procollagen mRNA and suppressing the synthesis of type II collagen in cultured human chondrocytes. Data reported here show that these effects of IL-1 and IFN-gamma on the expression of the human type II collagen gene (COL2A1) are mediated primarily at the transcriptional level. This conclusion is based on three types of experimental evidence: (1) in nuclear run-off assays, preincubation of chondrocytes with either IL-1 or IFN-gamma decreased COL2A1 transcription; (2) experiments with the protein synthesis inhibitor cycloheximide and the transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) indicated that the suppression of alpha 1(II) procollagen mRNA by IL-1 could not be ascribed to decreased mRNA stability; and (3) a plasmid (pCAT-B/4.0) containing 4.0 kb of 5'-flanking sequences of COL2A1 (-577/+3428), encompassing the promoter, exon 1 and the putative enhancer sequence in the first intron, linked to the chloramphenicol acetyltransferase (CAT) reporter gene, was transfected in human chondrocytes. A high level of expression of pCAT-B/4.0 was observed in human chondrocytes incubated with an insulin-containing serum substitute that is permissive for expression of the COL2A1 gene. Expression of pCAT-B/4.0 in these cells was inhibited by either IL-1 or IFN-gamma. Furthermore, expression of pCAT-B/4.0 was not detected in human dermal fibroblasts. When the putative enhancer fragment in the first intron was removed, the expression in chondrocytes was greatly reduced. These studies demonstrate that expression of COL2A1 is tissue specific and that suppression by either IL-1 or IFN-gamma is mediated primarily at the transcriptional level.

Animals↗
PubMed2002

Effect of different solvents and crosslinkers on cytocompatibility of Type II collagen scaffolds for chondrocyte seeding.

Type II collagen extracted from porcine costal cartilage was evaluated as scaffolds for cartilage tissue engineering. Chemical crosslinkers were employed to improve the mechanical properties and the resistance toward degradation. Films and porous scaffolds were prepared from collagen solutions dissolved in 3% acetic acid (designated A) or in deionized water (designated W) and crosslinked by an epoxy (designated E) or by a carbodiimide (designated C). Immortalized rat chondrocytes and rabbit chondrocytes were used to assess cytocompatibility of crosslinked collagen matrices. Cell adhesion rate onto the films made by different preparations ranked in the order of WE > or = WC > AC > or = AE. Cell proliferation ranked in the order of AC > WC > AE > or = WE. Cells maintained round morphology only on AC and WC films. In 3-D seeding, AC scaffolds also were found to be the most cytocompatible. WC scaffolds, however, had better dimensional stability. It was concluded that Type II collagen scaffolds, when prepared by using deionized water as the solvent and carbodiimide as the crosslinker, could promote chondrocyte growth and matrix production.

Animals↗
PubMed2004

Single molecule mechanical properties of type II collagen and hyaluronan measured by optical tweezers.

Type II collagen and hyaluronan are the two major components of extracellular molecules in cartilage and play an important role in mechanical functions of extracellular matrix. Currently, their mechanical properties have been investigated only at the gross-level. In this study, the mechanical properties of single type II collagen and hyaluronan molecules were directly measured using optical tweezers technique. The persistence length was found to be 11.2+/-8.4 nm in type II collagen and 4.5+/-1.2 nm in hyaluronan. This result suggested that type II collagen is stiffer than hyaluronan at the individual molecule level, which supports the general concept that collagen is responsible for resisting tensile force. The experimental system developed here also provides a powerful tool for quantifying mechanical properties of extracellular matrix at the single molecule level.

Animals↗
PubMed1996

Effect of reduced articular function on deposition of type I and type II collagens in the mandibular condylar cartilage of the rat.

A group of rats was fed a soft diet after weaning and the incisors shortened regularly to keep them out of occlusion. The controls were fed a hard diet. Immunohistochemical techniques and image analysis were employed to investigate deposition of pro-type I collagen and type II collagen, and the thickness of articular cartilage layers in the mandibular condyle. The immunostaining against pro-type I collagen was most intense intracellularly in the fibrous and upper chondroblast layers in 30- and 50-day-old rats fed a hard diet. In the rats fed a soft diet, marked intra- and extracellular staining against pro-type I collagen was visible in the upper chondroblast and upper hypertrophic layers but also in the lower hypertrophic layer. The intensity of staining against type II collagen was weak in animals on a soft diet, while in the animals fed a hard diet the staining was intense in the superior layers of mature chondroblasts. The total number of chondroblasts recorded was reduced by 35 percent at the age of 50 days in the soft-diet compared to the hard-diet animals. The results show that the deposition of type I and II collagens, the thickness of the cartilage cell layers and the number of chondrocytes are sensitive to alterations in loading.

Animals↗
PubMed1983

Collagen-induced arthritis in rats: antigen-specific suppression of arthritis and immunity by intravenously injected native type II collagen.

Collagen-induced arthritis (CIA) developed in 70 to 90% of rats immunized with heterologous type II collagen. CIA was reduced to 0 to 18% when rats were injected i.v., i.e., pretreated, with 1 mg of soluble native type II collagen before immunization. Concomitant with the suppression of CIA were significant suppression of IgM, IgG, and delayed-type hypersensitivity (DTH) responses to type II collagen. Suppression of CIA and immunity to collagen was antigen-specific, related to dose and route of administration, and occurred only when 1 mg of collagen was injected i.v. either 32, 7, or 4 days before, or 7 days after immunization. Once CIA was established, however, neither arthritis nor immunity could be suppressed. To determine if adjuvant-induced arthritis (AIA), like CIA, could be suppressed by i.v. pretreatment with type II collagen, rats were given 1 mg of type II collagen or PBS i.v. before injection with mycobacteria and oil. AIA was not suppressed, and arthritis appeared in both groups at a similar incidence and severity. Sera from 26 rats with severe AIA that was collected between days 14 and 35 after injection were assayed for IgG to homologous rat type II collagen and were found to be negative. These findings further support the hypothesis that CIA in rats is mediated by immunity to type II collagen and also suggest that CIA and AIA have different primary pathogenic mechanisms.

Animals↗
PubMed1989

Experimental arthropathy induced in rhesus monkeys and DBA/1 mice by a novel method: intraperitoneal implantation of type II collagen adsorbed onto nitrocellulose filters.

A novel method which avoids the use of complete Freund's adjuvant (which can be arthritogenic) has been used to induce collagen II arthritis in both primates and mice. A solution of bovine type II collagen was dried onto nitrocellulose filters and implanted in the peritoneal cavity of experimental animals. Primate and mouse joints were scored by clinical as well as gross and microscopic parameters. The polyarthritis that developed in both rhesus monkeys (Macaca mulatta) and DBA/1 LAC J mice was characterized by synovial cell proliferation and endothelial cell hyperplasia, and by a perivascular mononuclear cell infiltrate of the synovium. Primates were analyzed further for anti-type II collagen antibody titers and delayed type hypersensitivity to type II collagen. Anti-type II collagen serum titers appeared to be unrelated to the disease pathology; the primates did not display delayed-type hypersensitivity to type II collagen. Control monkeys and mice implanted with collagen-free nitrocellulose filters were normal upon clinical and histopathological analysis. This protocol offers the advantage of the induction of arthritis due solely to immunization with antigen.

Animals↗
PubMed1994

Synthesis of a phenotypically abnormal type XI: type II collagen ratio by chondrocytes from canine osteoarthritic cartilage.

Collagen synthesis by osteoarthritic cartilage from dogs that had undergone anterior cruciate ligament transection was measured in short-term organ cultures and chondrocyte suspension cultures. Slices of osteoarthritic cartilage from unstable knees 2, 6 or 12 weeks after anterior cruciate ligament transection converted approximately 10% of the total incorporated 14C-proline to 14C-hydroxyproline, while the value for cartilage from the contralateral knee or from knees of normal control dogs was generally less than 1%. The increase in collagen synthesis in the osteoarthritic cartilage was not related to the duration of knee instability, but was greater in grossly fibrillated cartilage than in the total pooled cartilage from the osteoarthritic joint. The collagen that was synthesized was predominantly type II, although some type XI and/or type V collagen was also synthesized. Chondrocytes isolated from osteoarthritic knee cartilage of dogs 12 weeks after anterior cruciate ligament transection showed changes in collagen synthesis similar to those seen in the cartilage organ cultures. As in the organ culture studies, type II collagen was the predominant species synthesized. When cell-associated collagen was considered, type II collagen accounted for 87+/-7% of the total collagen synthesized and retained by the osteoarthritic chondrocytes. The corresponding value for cells from the contralateral knee was 63+/-10%. Since the collagen fiber in articular cartilage is a heteropolymer of type II, type XI and type IX collagen, it is likely that the newly synthesized collagens in this model of osteoarthritis form fibers that are phenotypically different from those in normal articular cartilage.

Animals↗
PubMed2005

Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs.

DeParle L. A., Gupta R. C., Canerdy T. D., Goad J. T., D'Altilio M., Bagchi M., Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J. vet. Pharmacol. Therap.28, 385-390. In large breed dogs, arthritis is very common because of obesity, injury, aging, immune disorder, or genetic predispositions. This study was therefore undertaken to evaluate clinical efficacy and safety of undenatured type-II collagen (UC-II) in obese-arthritic dogs. Fifteen dogs in three groups received either no UC-II (Group I) or UC-II with 1 mg/day (Group II) or 10 mg/day (Group III) for 90 days. Lameness and pain were measured on a weekly basis for 120 days (90 days treatment plus 30 days post-treatment). Blood samples were assayed for creatinine and blood urea nitrogen (markers of renal injury); and alanine aminotransferase and aspartate aminotransferase (evidence of hepatic injury). Dogs receiving 1 mg or 10 mg UC-II/day for 90 days showed significant declines in overall pain and pain during limb manipulation and lameness after physical exertion, with 10 mg showed greater improvement. At either dose of UC-II, no adverse effects were noted and no significant changes were noted in serum chemistry, suggesting that UC-II was well tolerated. In addition, dogs receiving UC-II for 90 days showed increased physical activity level. Following UC-II withdrawal for a period of 30 days, all dogs experienced a relapse of overall pain, exercise-associated lameness, and pain upon limb manipulation. These results suggest that daily treatment of arthritic dogs with UC-II ameliorates signs and symptoms of arthritis, and UC-II is well tolerated as no adverse effects were noted.

Administration, Oral↗
PubMed1999

Type II collagen degradation in spontaneous osteoarthritis in C57Bl/6 and BALB/c mice.

OBJECTIVE: Degradation of type II collagen during osteoarthritis (OA) is thought to be the key process leading to cartilage destruction. In this study, we investigated whether OA is characterized by either a generalized breakdown of the collagenous network or a localized process. Furthermore, we determined if collagen degradation was linked to cell death. METHODS: Two mouse strains that develop spontaneous OA, C57Bl/6 and BALB/c mice, were examined. Type II collagen degradation in type II collagen-induced arthritis was also examined for comparison. Immunolocalization with the COL2-3/4m and COL2-3/4C antibodies was used to demonstrate denatured type II collagen and the collagenase cleavage site in type II collagen, respectively. RESULTS: Both the C57Bl/6 and the BALB/c mice developed OA changes, although clear compartmental differences existed between the two strains. In both strains, type II collagen degradation was clearly present at sites of degeneration, but was absent from intact articular cartilage. Collagen degradation was absent from areas with cell death. CONCLUSION: These results indicate that type II collagen degradation in spontaneous murine OA is associated with degeneration and is a localized, instead of a generalized, process.

Animals↗