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July 2012

The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease.

This contribution reviews the structure and organization of collagen molecules found in cartilage and the roles that they may play in rheumatic diseases. Cartilage is unique in its physical properties and molecular composition, and contains sufficient amounts of types II, IX, X, and XI collagen to deem these molecules as “cartilage-specific.” The vitreous body of the eye, a “cartilage-like” tissue is also rich in the same collagens but is type X deficient. Types VI and XII collagen are present in cartilage as well as noncartilaginous tissues. Types II, IX, and XI collagen are organized into matrix fibrils, where type II constitutes the bulk of the fibril, type XI regulates fibril size, and type IX facilitates fibril interaction with proteoglycan macromolecules. Genetic defects in these collagens can produce mild to severe developmental abnormalities, including spondyloepiphyseal dysplasia often accompanied by an accelerated form of osteoarthritis. Sensitization with collagen can produce experimental rheumatic diseases. Type II collagen induces an erosive polyarthritis in certain strains of rats, mice, and higher primates which can resemble rheumatoid arthritis and relapsing polychondritis. Type XI collagen is arthritogenic in rats but not mice; type IX induces autoimmunity in both species but not arthritis. Arthritis is initiated by complement fixing antibodies that bind to type II collagen in autologous cartilage, and the production of these antibodies is MHC restricted and T cell dependent. It is unclear whether T cells alone can induce arthritis, although they probably help sustain it. Mapping and characterizing the of T cell epitopes on type II collagen has resulted in the synthesis of small homolog and substituted peptides of type II collagen which suppress arthritis in an antigen-specific manner by a variety of routes, including mucosal. Moreover, collagen-induced arthritis has proven a valuable model to study the contribution of cytokines and other biological agents in the pathogenesis of joint injury and how they might be used to develop new therapies. Collagen autoimmunity has been implicated in the pathogenesis rheumatoid arthritis and polychondritis. Circulating antibodies to type II collagen are found in both diseases. Antibodies to types IX and XI collagen are also present in rheumatoid sera but are less prevalent. Rheumatoid cartilage and synovium contain antibodies to type II collagen at a prevalence far greater than serum, suggesting an intra-articular antigen-driven immune process. Although effective in animal models, attempts to treat rheumatoid arthritis with orally administered type II collagen have proven elusive. Different approaches using newer formulations and selected or modified oligopeptides remain to be tested and could prove effective in the treatment of the human rheumatic diseases.

J Agric Food Chem. 2011 Nov 23;59(22):12254-63

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.

J Vet Pharmacol Ther. 2005 Aug;28(4):385-90

Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs.

This investigation was undertaken to evaluate the therapeutic efficacy and safety of glycosylated undenatured type II collagen (UC-II) alone or in combination with glucosamine HCl and chondroitin sulfate in arthritic dogs. Twenty dogs divided into four groups (n = 5) were daily treated orally for 120 days: group I, placebo; group II, 10 mg UC-II; group III, 2,000 mg glucosamine + 1,600 mg chondroitin; group IV, UC-II (10 mg) + glucosamine (2,000 mg) + chondroitin (1,600 mg), followed by a 30-day withdrawal period. On a monthly basis, dogs were examined for overall pain, pain upon limb manipulation, and exercise-associated lameness. Serum samples were analyzed for markers of liver function (ALT and bilirubin) and renal function (BUN and creatinine). Body weight was also measured at a monthly interval. Dogs in group I exhibited no change in arthritic conditions. Dogs receiving UC-II alone showed significant reductions in overall pain within 30 days (33%) and pain upon limb manipulation and exercise-associated lameness after 60 days (66% and 44%, respectively) of treatment. Maximum reductions in pain were noted after 120 days of treatment (overall pain reduction, 62%; pain reduction upon limb manipulation, 91%; and reduction in exercise-associated lameness, 78%). The overall activity of the dogs in the UC-II supplemented with glucosamine and chondroitin group (group IV) was significantly better than the glucosamine + chondroitin-supplemented group (group III). Glucosamine and chondroitin alleviated some pain, but in combination with UC-II (group IV) provided significant reductions in overall pain (57%), pain upon limb manipulation (53%), and exercise-associated lameness (53%). Following withdrawal of supplements, all dogs (groups II to IV) experienced a relapse of pain. None of the dogs in any groups showed any adverse effects or change in liver or kidney function markers or body weight. Data of this placebo-controlled study demonstrate that daily treatment of arthritic dogs with UC-II alone or in combination with glucosamine and chondroitin markedly alleviates arthritic-associated pain, and these supplements are well tolerated as no side effects were noted.

Toxicol Mech Methods. 2007;17(4):189-96

Effects of oral administration of type II collagen on rheumatoid arthritis.

Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

Science. 1993 Sep 24;261(5129):1727-30

Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. METHODS: Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 microg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for > or = 30% reduction in both swollen and tender joint counts. RESULTS: Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 microg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 microg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. CONCLUSION: Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Arthritis Rheum. 1998 Feb;41(2):290-7

A pilot trial of oral type II collagen in the treatment of juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy of oral chicken type II collagen (CCII) in the treatment of juvenile rheumatoid arthritis (JRA). METHODS: Ten patients with active JRA were treated with CCII for 12 weeks. Efficacy parameters, which included swollen and tender joint count and score, grip strength, 50-foot walking time, duration of morning stiffness, and patient and physician global scores of disease severity, were assessed monthly. RESULTS: All patients completed the full course of therapy. Eight patients had reductions in both swollen and tender joint counts after 3 months of CCII. The mean changes from baseline in swollen and tender joint counts for the 8 responders at the end of the study were -61% and -54%, respectively. Mean values for other efficacy parameters also showed improvement from baseline. There were no adverse events that were considered to be treatment related. CONCLUSION: Oral CCII may be a safe and effective therapy for JRA, and its use in this disease warrants further investigation.

Arthritis Rheum. 1996 Apr;39(4):623-8

Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration.

Arthritis afflicts approximately 43 million Americans or approximately 16.6% of the US population. The two most common and best known types of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA). A significant amount of scientific research has been done in attempts to explain what initiates forms of arthritis, how it is promoted and perpetuated and how to effectively intervene in the disease process and promote cartilage remodeling. Current pharmacological strategies mainly address immune suppression and antiinflammatory mechanisms and have had limited success. Recent research provides evidence that alterations in the three-dimensional configuration of glycoproteins are responsible for the recognition/response signaling that catalyzes T-cell attack. Oral administration of autoantigens has been shown to suppress a variety of experimentally induced autoimmune pathologies, including antigen-induced RA. The interaction between gut-associated lymphoid tissue in the duodenum and epitopes of orally administered undenatured type II collagen facilitates oral tolerance to the antigen and stems systemic T-cell attack on joint cartilage. Previous studies have shown that small doses of orally administered undenatured type II chicken collagen effectively deactivate killer T-cell attack. A novel glycosylated undenatured type II collagen material (UC-II) was developed to preserve biological activity. The presence of active epitopes in the UC-II collagen is confirmed by an enzyme-linked immunosorbent assay test and distinguishes this form from hydrolyzed or denatured collagen. Oral intake of small amounts of glycosylated UC-II presents active epitopes, with the correct three-dimensional structures, to Peyer’s patches, which influences the signaling required for the development of immune tolerance. UC-II has demonstrated the ability to induce tolerance, effectively reducing joint pain and swelling in RA subjects. A pilot study was conducted for 42 days to evaluate the efficacy of UC-II (10 mg/day) in five female subjects (58-78 years) suffering from significant joint pain. Significant pain reduction including morning stiffness, stiffness following periods of rest, pain that worsens with use of the affected joint and loss of joint range of motion and function was observed. Thus, UC-II may serve as a novel therapeutic tool in joint inflammatory conditions and symptoms of OA and RA.

Int J Clin Pharmacol Res. 2002;22(3-4):101-10

The role of the cartilage matrix in osteoarthritis.

Osteoarthritis (OA) involves all the structures of the joint. How the disease is initiated and what factors trigger the disease process remain unclear, although the mechanical environment seems to have a role. Our understanding of the biology of the disease has been hampered by the lack of access to tissue samples from patients with early stage disease, because clinically recognizable symptoms appear late in the osteoarthritic process. However, new data about the early processes in articular cartilage and new tools to identify the early stages of OA are providing fresh insights into the pathological sequence of events. The progressive destruction of cartilage involves degradation of matrix constituents, and rather active, yet inefficient, repair attempts. The release of fragmented molecules provides opportunities to monitor the disease process in patients, and to investigate whether these fragments are involved in propagating OA, for example, by inducing inflammation. The role of bone has not been fully elucidated, but changes in bone seem to be secondary to alterations in articular cartilage, which change the mechanical environment of the bone cells and induce them, in turn, to modulate tissue structure.

Nat Rev Rheumatol. 2011 Jan;7(1):50-6

A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis.

INTRODUCTION: Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. A 24-week, double-blind, double-dummy, randomized, methotrexate (MTX)-controlled study was conducted to evaluate the efficacy and safety of CCII in the treatment of rheumatoid arthritis (RA). METHODS: Five hundred three RA patients were included in the study. Patients received either 0.1 mg daily of CCII (n = 326) or 10 mg once a week of MTX (n = 177) for 24 weeks. Each patient was evaluated for pain, morning stiffness, tender joint count, swollen joint count, health assessment questionnaire (HAQ), assessments by investigator and patient, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) by using the standard tools at baseline (week 0) and at weeks 12 and 24. Additionally, rheumatoid factor (RF) was evaluated at weeks 0 and 24. Measurement of a battery of biochemical parameters in serum, hematological parameters, and urine analysis was performed to evaluate the safety of CCII. RESULTS: Four hundred fifty-four patients (94.43%) completed the 24-week follow-up. In both groups, there were decreases in pain, morning stiffness, tender joint count, swollen joint count, HAQ, and assessments by investigator and patient, and all differences were statistically significant. In the MTX group, ESR and CRP decreased. RF did not change in either group. At 24 weeks, 41.55% of patients in the CCII group and 57.86% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR-20) and 16.89% and 30.82%, respectively, met the ACR 50% improvement criteria (ACR-50). Both response rates for ACR-20 and ACR-50 in the CCII group were lower than those of the MTX group, and this difference was statistically significant (P < 0.05). The DAS28 (disease activity score using 28 joint counts) values of the two treatment groups were calculated, and there was a statistically significant difference between the two treatment groups (P < 0.05). Gastrointestinal complaints were common in both groups, but there were fewer and milder side effects in the CCII group than in the MTX group. The incidence of adverse events between the two groups was statistically significant (P < 0.05). CONCLUSIONS: CCII is effective in the treatment of RA and is safe for human consumption. CCII exerts its beneficial effects by controlling inflammatory responses through inducing oral tolerance in RA patients.

Arthritis Res Ther. 2009;11(6):R180. Epub 2009 Dec 1

Oral administration of type-II collagen peptide 250-270 suppresses specific cellular and humoral immune response in collagen-induced arthritis.

Oral antigen is an attractive approach for the treatment of autoimmune and inflammatory diseases. Establishment of immune markers and methods in evaluating the effects of antigen-specific cellular and humoral immune responses will help the application of oral tolerance in the treatment of human diseases. The present article observed the effects of chicken collagen II (CII), the recombinant polymerized human collagen II 250-270 (rhCII 250-270) peptide and synthesized human CII 250-270 (syCII 250-270) peptide on the induction of antigen-specific autoimmune response in rheumatoid arthritis (RA) peripheral blood mononuclear cells (PBMC) and on the specific cellular and humoral immune response in collagen-induced arthritis (CIA) and mice fed with CII (250-270) prior to immunization with CII. In the study, proliferation, activation and intracellular cytokine production of antigen-specific T lymphocytes were simultaneously analyzed by bromodeoxyuridine (BrdU) incorporation and flow cytometry at the single-cell level. The antigen-specific antibody and antibody-forming cells were detected by ELISA and ELISPOT, respectively. CII (250-270) was found to have stimulated the response of specific lymphocytes in PBMC from RA patients, including the increase expression of surface activation antigen marker CD69 and CD25, and DNA synthesis. Mice, fed with CII (250-270) before CII immunization, had significantly lower arthritic scores than the mice immunized with CII alone, and the body weight of the former increased during the study period. Furthermore, the specific T cell activity, proliferation and secretion of interferon (IFN)-gamma in spleen cells were actively suppressed in CII (250-270)-fed mice, and the serum anti-CII, anti-CII (250-270) antibody activities and the frequency of specific antibody-forming spleen cells were significantly lower in CII (250-270)-fed mice than in mice immunized with CII alone. These observations suggest that oral administration of CII (250-270) can suppress the cellular and humoral immune response in collagen-induced arthritis, and the simultaneous analysis of antigen-specific cellular and humoral immune responses at single-cell level will help the understanding of the oral tolerance mechanisms in CIA and the development of innovative therapeutic intervention for RA.

Clin Immunol. 2007 Jan;122(1):75-84. Epub 2006 Oct 11