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)

Cyclosporin A is an established immunomodulatory agent with an increasing number of clinical applications. Although its precise mechanisms of action remain elusive, one of the most important known properties of CyA is its ability to inhibit the production of cytokines involved in the regulation of T-cell activation. In particular, CyA inhibits de novo synthesis of interleukin 2(IL-2), the major cytokine involved in T-cell proliferation, as well as other cytokines, probably at the level of gene transcription, as shown by the suppression of mRNA levels in activated T-cells. Although the major actions of CyA are on T-cells, there is some evidence for possible direct effects on other cell types e.g. B-cells, macrophages and, from our own work, on bone and cartilage cells. Cyclosporin A is thought to enter cells and to bind to cyclophilins, which are members of a family of high-affinity cyclosporin A-binding proteins, now known as immunophilins. The binding of cyclosporins to such proteins appears to be closely linked to the immunosuppressive action of cyclosporins. The immunophilins possess enzyme activity, ie. peptidyl-prolyl cis-trans isomerase, also known as rotamase, which can regulate protein folding, and may therefore alter the functional state of many cell proteins. Cyclosporin A blocks peptidyl-prolyl cis-trans isomerase activity but it is not clear whether this plays a part in its selective inhibition of cytokine-gene transcription. Moreover, the ubiquitous presence of cyclophilins and immunophilins raises the question of why cyclosporin A has its apparent major effects only on T-cells. Recent proposals regarding the intracellular mode of action of CyA suggest that it interacts with cyclophilin and other regulatory proteins including calmodulin and calcineurin, which is a serine/threonine phosphatase, and thereby affects the functional state of key regulators of gene transcription in its target cells. The effects of CyA on T-cells and directly or indirectly on connective tissue cells, including bone, cartilage and synovial cells, which all can produce a range of cytokines, are of interest in relation to the tissue changes that occur in inflammatory diseases, such as rheumatoid arthritis. Thus, for example, cyclosporin A inhibits in vitro the bone resorbing activity of interleukin 1, 1,25-dihydroxy-vitamin D3, parathyroid hormone and prostaglandin E2 by apparently non-T-cell effects, while in vivo protects against bone and cartilage loss in adjuvant arthritis. More needs to be known about the direct and indirect modulation of cytokine production by cyclosporin A in connective tissues, in order to understand its potential value in clinical disorders.
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PMID:Cyclosporin A. Mode of action and effects on bone and joint tissues. 147 34

Adjuvant arthritis induced by mycobacteria in rats is a widely used model of chronic arthritis. A previously described nonapeptide (Thr-Phe-Gly-Leu-Gln-Leu-Glu-Leu-Thr, amino acid sequence 180-188) from the recombinant 65 kDa heat shock protein of Mycobacterium bovis BCG, which was found to contain a T-cell epitope recognized by both arthritogenic and protective T-cell clones in vitro, has been investigated for its vaccination and therapeutic potential in adjuvant arthritis in rats. The nonapeptide was found not to be arthritogenic, although the T cells from nonapeptide immunized rats cross-react in vitro with mycobacterial antigens. Intraperitoneal administration of 0.1 mg nonapeptide in oil at day -20 or days -2, -1 and 0, resulted in a marked reduction of incidence and severity of adjuvant arthritis. The disease process and severity were also influenced by therapeutic treatment with 0.1 mg nonapeptide injected intraperitoneally at days 7 to 10. Interestingly, subplantar or intravenous application of the nonapeptide had no influence on the disease process. Deletion of the N-terminal threonine led to complete loss of in vivo activity of the nonapeptide.
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PMID:Treatment of adjuvant arthritis in rats: vaccination potential of a synthetic nonapeptide from the 65 kDa heat shock protein of mycobacteria. 169 14

Adjuvant arthritis in Lewis rats is a model of T cell-mediated autoimmune arthritis resembling human rheumatoid arthritis. A nonapeptide from the 65-kD heat-shock protein of Mycobacterium bovis BCG, amino acid sequence 180-188, has been described to carry the dominant immunogenic epitope(s) for both arthritis-protective and arthritogenic T cell clones. Here we demonstrate that immunizations with the synthetic nonapeptide completely protected rats against adjuvant arthritis induced by M. tuberculosis. Interestingly, deletion of the N-terminal threonine of the nonapeptide resulted in loss of the protective activity. Pretreatments with the nonapeptide resulted in an immune response to the nonapeptide and to M. tuberculosis. After immunizations with the synthetic nonapeptide, only low titres of nonapeptide-specific antibodies were produced, whereas a significant cellular immune response to the nonapeptide was observed. In addition, the protection was transferable to naive rats by spleen T cells. These findings document the requirement of a T cell-specific immune response to the dominant epitope of the 65-kD mycobacterial heat-shock protein for the protection against adjuvant arthritis and suggest the feasibility of immune intervention in autoimmune arthritis through the use of synthetic peptides.
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PMID:Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein. 169 60

The tuftsin retro-inverso analogue H-Thr psi[NHCO](R,S)Lys-Pro-Arg-OH was synthesized through a novel procedure for the high-yield incorporation of isolated retro-inverso bonds into peptide chains and the use of the new Meldrum's acid derivative (CH3)2C(OCO)2CH(CH2)4NHCOCF3 followed by its efficient coupling in solution to trimethylsilylated H-D-Thr(t-Bu)NH2. Closely related peptide impurities were eliminated both from the crude final peptide and the fully protected tetrapeptide amide precursor via ion-exchange and reversed-phase displacement chromatography, respectively. The tuftsin retro-inverso analogue proved to be completely resistant to enzymatic degradation in vitro, either against isolated aminopeptidases or human plasma proteolytic enzymes. When administered either orally or intravenously, it was significantly more active than normal tuftsin in increasing the number of specific antibody secreting cells in spleen of mice immunized with sheep erythrocytes. Furthermore, the analogue exerted an enhanced stimulatory effect on the cytotoxic activity of splenocytes against YAC-1 tumor cells. Finally, retro-inverso-tuftsin was about 10-fold more potent than the native peptide in reducing rat adjuvant arthritis. The resistance of the retro-inverso analogue to peptidases might explain the increased in vivo activities and allows its further immunopharmacological characterization.
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PMID:Immunostimulation by a partially modified retro-inverso-tuftsin analogue containing Thr1 psi[NHCO](R,S)Lys2 modification. 176 1

The prevalence and clinical correlations of anti-threonyl-transfer RNA synthetase (anti-PL-7), as well as the relationship of anti-PL-7 to anti-histidyl-transfer RNA synthetase (anti-Jo-1) were studied in 109 sera from patients with myositis. Inhibition of threonine aminoacylation was used to screen for anti-PL-7. Sera from 3 patients, 2 with polymyositis and 1 with polymyositis-overlap syndrome, and a fourth serum from a patient with dermatomyositis, which was previously found to contain anti-PL-7, inhibited greater than 90% of activity (3.7% of 109 sera). All 4 sera reacted strongly in an enzyme-linked immunosorbent assay with enzyme that was either affinity purified with anti-PL-7 or was biochemically purified. There was no indication of cross-reactivity by aminoacylation inhibition or, for most sera, by enzyme-linked immunosorbent assay. Anti-PL-7 is an uncommon myositis-associated antibody that is independent of anti-Jo-1, but is directed at a functionally related enzyme.
Arthritis Rheum 1988 Apr
PMID:Antibody to threonyl-transfer RNA synthetase in myositis sera. 312 89

Phospholipase A2 (PLA2) has been purified to homogeneity from synovial fluid of arthritis patients. The 3-step purification procedure included: a) dialysis against 5mM NH4-acetate, pH 5.5, in which PLA2 precipitated with euglobulins, followed by extraction with 0.4 M NaCl/0.05 M NH4-acetate, pH 5, b) chromatography on CM-cellulose, c) preparative gel electrophoresis in the presence of 0.1% Na-dodecyl sulfate and electroelution of the band containing the enzyme. Automated sequence analysis has indicated that the protein is pure, with the following NH2-terminal sequence: Asn-Leu-Val-Asn-Phe-His-Arg-Met-Ile-Lys-Leu-Thr-Thr-. A computer search revealed that all proteins with greater than 75% analogies in NH2-terminal sequences were PLA2's from various snake venoms. When PLA2 was purified from human placental membranes and analyzed, it was found to contain an identical sequence of 13 residues from the NH2-terminus. This and other characteristics suggest that the two human enzymes are closely related, if not identical.
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PMID:Phospholipase A2 from human synovial fluid: purification and structural homology to the placental enzyme. 320 59

Proteoglycan alterations were studied in articular cartilage obtained from control and antigen induced arthritis of the rabbits. Agarose/polyacrylamide-gel electrophoretic patterns of proteoglycan revealed heterogeneity in each experiment. In the cartilage of the antigen induced arthritis the following changes were demonstrated at the early stage; 1) an increase in the non-aggregated proteoglycan content, 2) a decrease in the size of the proteoglycan, 3) a decrease in the ability to interact with hyaluronic acid, 4) a constancy in the length of the glycosaminoglycan chains, 5) a decrease in hexuronate/protein, galactosamine/glucosamine and galactosamine/amino acid ratio, and 6) a decrease in serine and threonine content of the core protein. At the late stage the following changes were most pronounced; 1) a recovery in the size of the proteoglycan, 2) a marked decrease in the ability to interact with hyaluronic acid, 3) an increase in galactosamine/glucosamine and a gradual decrease in glucosamine/amino acid ratio, and 4) an increase in serine and glycine and a decrease in half cysteine and methionine content of the core protein. The results indicate that the smaller size of the proteoglycan from articular cartilage was due to degradation of the core protein at the early stage. But there seems to be some changes of proteoglycan synthesis at the late stage.
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PMID:[Studies on the biochemical alterations of cartilage proteoglycan in antigen induced arthritis of rabbit (author's transl)]. 679 34

Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein, has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.
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PMID:Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. 928 70

Members of the TGF-beta superfamily are important regulators of skeletal development. TGF-betas signal through heteromeric type I and type II receptor serine/threonine kinases. When over-expressed, a cytoplasmically truncated type II receptor can compete with the endogenous receptors for complex formation, thereby acting as a dominant-negative mutant (DNIIR). To determine the role of TGF-betas in the development and maintenance of the skeleton, we have generated transgenic mice (MT-DNIIR-4 and -27) that express the DNIIR in skeletal tissue. DNIIR mRNA expression was localized to the periosteum/perichondrium, syno-vium, and articular cartilage. Lower levels of DNIIR mRNA were detected in growth plate cartilage. Transgenic mice frequently showed bifurcation of the xiphoid process and sternum. They also developed progressive skeletal degeneration, resulting by 4 to 8 mo of age in kyphoscoliosis and stiff and torqued joints. The histology of affected joints strongly resembled human osteo-arthritis. The articular surface was replaced by bone or hypertrophic cartilage as judged by the expression of type X collagen, a marker of hypertrophic cartilage normally absent from articular cartilage. The synovium was hyperplastic, and cartilaginous metaplasia was observed in the joint space. We then tested the hypothesis that TGF-beta is required for normal differentiation of cartilage in vivo. By 4 and 8 wk of age, the level of type X collagen was increased in growth plate cartilage of transgenic mice relative to wild-type controls. Less proteoglycan staining was detected in the growth plate and articular cartilage matrix of transgenic mice. Mice that express DNIIR in skeletal tissue also demonstrated increased Indian hedgehog (IHH) expression. IHH is a secreted protein that is expressed in chondrocytes that are committed to becoming hypertrophic. It is thought to be involved in a feedback loop that signals through the periosteum/ perichondrium to inhibit cartilage differentiation. The data suggest that TGF-beta may be critical for multifaceted maintenance of synovial joints. Loss of responsiveness to TGF-beta promotes chondrocyte terminal differentiation and results in development of degenerative joint disease resembling osteoarthritis in humans.
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PMID:Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. 933 55

Sixty patients with reactive arthritis (ReA) and 40 with rheumatoid arthritis (RA), were typed for H LA-B27 and class II antigens DR and DQ, and studied for TAP2 gene polymorphism in comparison with 60 healthy controls. TAP2 polymorphisms at positions 379, 565, 665, and 687 were analyzed using amplification refractory system-based PCR and polymorphisms at positions 386 and 651 using oligonucleotide hybridization. The frequency of the TAP2A/A genotype was 30%(12/40) in RA, in contrast to 13% (8/60) in the controls. This genotype was further associated with DRB1*04 positive RA (10/24, 42%, P=0.01), as well as the TAP2A allele (31/48, 65%, P =0.012). Thr/Thr dimorphism at TAP2 position 665 (24/40, 60%, P=0.024) and Stop/Stop dimorphism at TAP2 position 687 (24/40, 60%, P=0.024) were found to be increased in RA patients as compared to controls. When TAP2I/J polymorphism was studied, TAP2J positivity was found associated with the HLA-B27DR4-DQB1*0301-haplotype in ReA patients. 9/12 of these were positive as compared to 20/60 in random controls (P=0.010). Polymorphisms of the TAP2 gene were found to be associated with subgroups of RA and ReA patients with disease associated markers (e.g. TAP2A in DRB1*04 positive RA, or TAP2J in HLA-B27-DRB1*04-DQB1*0301 positive ReA). These may thus serve as additional markers of specific haplotypes associated with susceptibility to inflammatory arthritis.
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PMID:TAP2 alleles in inflammatory arthritis. 964 19


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