Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral arthritis is produced in BALB/c mice after hyperimmunization with the cartilage proteoglycan aggrecan (PG). Adoptive transfer studies have suggested the roles of T cells including CD8+ T cells in the disease process. To evaluate the roles of CD4+ and CD8+ T cell subsets in vivo in the induction of this disease by immunization, PG-immunized mice were treated with isotype-controlled rat IgG2b monoclonal anti-CD4 or anti-CD8 antibodies, or were left untreated. CD4+ T cell depletion resulted in total inhibition of the disease with markedly decreased anti-PG antibody responses. CD8+ T cell depletion, however, significantly enhanced the severity of the disease without affecting peak anti-PG antibodies, as compared to the control mice. These results demonstrate a crucial role for CD4+ T cells in the pathogenesis of this disease. However, CD8+ T cells do not seem to be required for the induction of arthritis by immunization but instead may play an immunoregulatory role.
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PMID:The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells. 135 36

Cartilage contains a number of matrix macromolecules not present in other connective tissues. In tissue processes in disease and in normal turnover of the matrix these molecules are fragmented and released into surrounding fluids, in the case of joints into the synovial fluid. Immunoassay techniques have been developed to quantify these fragments. It appears that increased levels in synovial fluid (SF) correlate to a process in the joint cartilage. With successful therapy the level returns to normal. Interestingly, in early rheumatoid arthritis, i.e., with no discernible cartilage damage by radiography, a high SF level of one major cartilage component (proteoglycan aggrecan/fragments) is prognostic for future extensive cartilage destruction. There are major differences in the levels of proteoglycan fragments between different disease groups. Thus, patients with acute reactive arthritis have high SF levels, while patients with late rheumatoid arthritis with extensive cartilage destruction not surprisingly have subnormal values. Patients with osteoarthritis, even those with fairly extensive cartilage destruction, have elevated levels of proteoglycans/fragments in their SF, perhaps indicative of a more pronounced reparative phase.
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PMID:Macromolecular markers in joint disease. 202 21

The destruction of articular cartilage in immune inflammatory arthritic disease involves the proteolytic degradation of its extracellular matrix. The role of activated matrix metalloproteinases (MMPs) in the chondrodestructive process was studied by identifying a selective cleavage product of aggrecan in murine arthritis models initiated by immunization with either type II collagen or proteoglycan. We conducted semiquantitative immunocytochemical studies of VDIPEN341 using a monospecific polyclonal antibody requiring the free COOH group of the COOH-terminal Asn for epitope detection. This antibody recognizes the aggrecan G1 domain fragment generated by MMP [i.e., stromelysin (SLN) or gelatinase A] cleavage of aggrecan between Asn341-Phe342 but does not recognize intact aggrecan. VDIPEN was undetectable in normal mouse cartilage but was observed in the articular cartilage (AC) of mice with collagen-induced arthritis 10 d after immunization, without histological damage and clinical symptoms. This aggrecan neoepitope was colocalized with high levels of glycosaminoglycans (GAGs) in pericellular matrices of AC chondrocytes but was not seen at the articular surface at this early time. Digestion of normal (VDIPEN negative) mouse paw cryosections with SLN also produced heavy pericellular VDIPEN labeling. Computer-based image analysis showed that the amount of VDIPEN expression increased dramatically by 20 d (70% of the SLN maximum) and was correlated with GAG depletion. Both infiltration of inflammatory cells into the synovial cavity and early AC erosion were also very prominent at this time. Analysis of adjacent sections showed that both induction of VDIPEN and GAG depletion were strikingly codistributed within sites of articular cartilage damage. Similar results occurred in proteoglycan-induced arthritis, a more progressive and chronic model of inflammatory arthritis. These studies demonstrate for the first time the MMP-dependent catabolism of aggrecan at sites of chondrodestruction during inflammatory arthritis.
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PMID:VDIPEN, a metalloproteinase-generated neoepitope, is induced and immunolocalized in articular cartilage during inflammatory arthritis. 753 57

Immunization of BALB/c mice with chondroitin sulfate-depleted proteoglycan (aggrecan) of fetal human cartilage produces progressive polyarthritis and ankylosing spondylitis. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immune responses against the host mouse cartilage proteoglycan (PG). Although cartilage PGs from various species have many biochemical and immunological similarities, only a select group of PGs from fetal and newborn human, fetal pig and canine articular cartilages, human osteophytes and human chondrosarcomas are able to induce arthritis in BALB/c mice. Arthritis develops only in mice that also develop autoantibodies to self-cartilage PGs, although autoantibodies occasionally are present in non-arthritic animals as well. The protease-sensitive auto/arthritogenic epitope(s) is located in, or close to, the chondroitin sulfate (CS) attachment region of the PG molecule. The primary structure of the core protein is responsible for the autoimmune/arthritogenic effect of this select group of PGs, whereas the core protein epitopes are masked by glycosaminoglycan (GAG)-side chains. The CS side chains seem to inhibit antigen recognition in all aggrecans with arthritogenic potential, whereas a similar effect with keratan sulfate (KS) appears only in PGs of aging cartilages.
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PMID:Mapping of arthritogenic/autoimmune epitopes of cartilage aggrecans in proteoglycan-induced arthritis. 753 28

Cartilage proteoglycan (aggrecan)-induced polyarthritis in BALB/c mice is characterized by chronic inflammation and destruction of joint tissues similar to that observed in human rheumatoid arthritis. The immunization of mice with fetal human proteoglycan (PG) elicits specific antibodies to the immunizing antigen of which a population cross-reacts with native mouse PG. This (auto)antibody production is immediately followed by an explosive proliferation of autoreactive T cells, suggesting that PG-specific B cells may participate in antigen presentation of PG to autoreactive T cells. We therefore isolated B cells from the spleens and lymph nodes of PG-immunized mice and examined their ability to present PG to a PG-specific T cell hybridoma. The antigen-specific T cell responses elicited by B cells from PG-immunized mice (both arthritic and clinically asymptomatic) were markedly higher than those of non-immune mice and keyhole limpet haemocyanin (KLH)-immunized mice, and these B cells could present low PG concentrations. Levels of B cell presentation corresponded with the serum levels of PG-specific antibodies, implying that these B cells were presenting the PG specifically via their surface immunoglobulin. This B cell-T cell interaction was strongly dependent on MHC class II/T cell receptor (TCR), LFA-1/intercellular adhesion molecule-1 (ICAM-1) and CD28/B7 interactions, as antibodies to Ia, ICAM-1 and B7-2 (but not to B7-1) markedly reduced presentation. These data indicate that PG-specific B cells may play an essential role in governing the development of PG-induced arthritis.
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PMID:Antigen-specific B cells present cartilage proteoglycan (aggrecan) to an autoreactive T cell hybridoma derived from a mouse with proteoglycan-induced arthritis. 766 87

The joint fluid levels of several molecules that reflect the anabolism and catabolism of cartilage matrix and its inflammation were quantitated in patients with primary osteoarthritis (OA) and traumatic arthritis. The carboxy terminal type II procollagen increased in primary OA and traumatic arthritis joint fluid and was thought to be a good marker of the repair response of chondrocytes. We found that the increase of this molecule in the joint correlated well with body mass index in primary OA and the degree of cartilage erosion caused by joint instability in traumatic arthritis. Chondroitin 6-sulfate, an integral part of human aggrecan, was also high in OA and traumatic arthritis joint fluids, and showed a similar distribution with keratan sulfate in each disease group. Stromelysin-1 and tissue inhibitor of metalloproteinases-1 levels in joint fluid were very high in RA, but levels in patients with OA were low. Carboxy terminal type II procollagen appeared most sensitive in the evaluation of risk factors of OA such as obesity and joint instability, compared to other markers tested.
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PMID:Significance of the levels of carboxy terminal type II procollagen peptide, chondroitin sulfate isomers, tissue inhibitor of metalloproteinases, and metalloproteinases in osteoarthritis joint fluid. 775 46

Articular cartilage has important load bearing properties. These depend on the integrity of its matrix which is formed by a dense network of collagen fibres (mainly type II) and a high concentration of proteglycan (mainly aggrecan). The matrix is maintained by the chondrocytes, which control the production and turnover of matrix components and are greatly affected by cytokines (such as IL-1 alpha,beta and TNF alpha) and growth factors (such as IGF-1 alpha, beta TGF beta). They have strongly antagonistic effects. IL-1 alpha, beta and TNF alpha inhibit proteoglycan synthesis and at slightly higher concentration they enhance the rates of matrix degradation. In contrast the growth factor IGF-1 stimulates proteoglycan biosynthesis and reduces matrix proteinase action. TGB beta has less direct anabolic effect on matrix biosynthesis in normal cartilage, but does not induce an anabolic response in isolated chondrocytes or in explants following IL-1 treatment. We have also investigated the action of IL-1 in inflammatory arthritis in vivo by treatment with IL-1 receptor antagonist, the natural IL-1 inhibitor. In antigen-induced arthritis the effects of the injection of rh IL-1 ra was measured over 3 days. There was little effect on the induction of joint swelling, cellular infiltration into synovium or cartilage proteoglycan depletion, but when given over a similar time in more chronic arthritis, 14 days after induction it had a major effect on suppressing synovial fibrosis although it still did not affect parameters of joint inflammation. The results suggested that IL-1 was not the major factor inducing inflammation in the joint, but was responsible for the excessive collagen deposition in the synovium in this experimental model of arthritis.
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PMID:[Regulation of cartilage matrix synthesis by chondrocytes]. 785 13

Proteoglycan (aggrecan)-induced arthritis is an autoimmune inflammatory animal model produced in genetically susceptible BALB/c mice. This animal model shows many similarities to human rheumatoid arthritis as indicated by clinical assessments, histopathological studies, and immunological parameters. The systemic immunization of mice with a select group of cartilage proteoglycans provokes immune responses to the immunizing antigen and then the production of cross-reactive antibodies to self proteoglycans. This is followed by an explosive proliferation of autoreactive T cells, especially in joint draining lymph nodes, accompanied by local (joint) inflammatory events. In the current experiments we found that lymphocytes from arthritic, or potentially arthritic but yet clinically asymptomatic animals, produced more IL-2 than those T cells obtained from animals immunized with nonarthritogenic PGs. In addition, synoviocytes isolated from prearthritic or arthritic animals produced several-fold more interleukin-1 beta (IL-1 beta) than cells from normal animals. Flow cytometric analysis indicated an autoantigen (mouse PG)-specific selective proliferation of surface Ig+/CD45R+ cells in prearthritic stages followed by the proliferation of predominantly T helper (CD4+) cells during and after the development of arthritis.
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PMID:Mediators and autopathogenic effector cells in proteoglycan-induced arthritic and clinically asymptomatic BALB/c mice. 792 85

The main "shock absorbing" molecule in cartilage is the proteoglycan, aggrecan, which is trapped within a meshwork of collagen fibrils. Articular cartilage damage in osteoarthritis is associated with damage to the aggrecan protein moiety. This results in abnormal loss of aggrecan which in turn increases the propensity of the joint surface to be damaged. Presently, the treatment for arthritis, pain-relieving drugs, affects the symptoms. End-stage osteoarthritis requires joint replacement surgery. To a certain extent, both the degradation and the repair of cartilage can be understood at the level of the biochemistry of cartilage matrix and the biology of the chondrocyte.
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PMID:Cartilage aggrecan. Biosynthesis, degradation and osteoarthritis. 819 77

The effect of expression of c-fos gene on proteoglycan synthesis, one of the important markers of cartilage metabolism, was examined by introducing the c-fos DNA into HCS 2/8 chondrocytes. The [35S]sulfate incorporation into proteoglycan was decreased in the c-fos transfectants expressing exogenous c-fos mRNA, when compared to a control transfectant. A significant increase in transcription of MMP-3 with the suppressed transcription of aggrecan and TIMP-1 were also observed in the c-fos transfectants. Moreover, analysis of the effect of AP-1 proteins on the collagenase and TIMP-1 promoters in gastric carcinoma KKLS cells revealed that c-Fos combined with any of the Jun-related proteins failed to stimulate the TIMP-1 promoter, though collagenase promoter was effectively activated by any Fos/Jun-related protein heterocomplex. These findings indicate that the c-fos expression may govern the cartilage metabolism and hence may play an important role in the pathogenesis of joint destruction in arthritis.
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PMID:Expression of c-fos gene inhibits proteoglycan synthesis in transfected chondrocyte. 860 60


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