Pro-inflammatory effects of the aminobisphosphonate ibandronate in vitro and in vivo.
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OBJECTIVES: To investigate the effects of the aminobisphosphonate, ibandronate, on the course of joint inflammation in rat antigen-induced arthritis (AIA) and the release of pro-inflammatory cytokines in partially purified human peripheral blood mononuclear cells (PBMC). METHODS: Rats with AIA received a single intra-articular injection of ibandronate (1 mg) 7 days post-arthritis induction and knee swelling was measured for 7 days thereafter. The effects of ibandronate (300 microg/ml) on PBMC cytokine production and activation marker expression were determined using polymerase chain reaction (PCR)/ELISA and FACS analysis, respectively. RESULTS: Joint swelling, associated with AIA, was sustained in ibandronate-treated rats compared with saline-treated control rats. Ibandronate stimulated the production of interferon gamma (IFN-gamma) in adherent PBMC, and increased the surface expression of FcgammaRI and HLA DP, DQ, DR on the adherent monocyte population. Activation by lipopolysaccharide (LPS) of PBMC previously incubated with ibandronate led to enhanced levels of tumour necrosis factor alpha (TNF-alpha) secretion, and this could be partially inhibited by neutralizing antibodies to IFN-gamma. CONCLUSIONS: The enhanced production of TNF-alpha by ibandronate-treated PBMC in vitro involves stimulation of adherent monocytes by IFN-gamma prior to LPS-induced activation. Similar cellular interactions may be involved in the pro-inflammatory effects of ibandronate in vivo. (+info)
Active matrix metalloproteinases are present in cartilage during immune complex-mediated arthritis: a pivotal role for stromelysin-1 in cartilage destruction.
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The involvement of immune complexes during experimental arthritis in induction of metalloproteinases (MMP)-induced neoepitopes in aggrecan in cartilage, as well as the role of stromelysin-1 (SLN-1) in the induction of this neoepitope, was investigated. Passive immune complex arthritis was induced, and generation of the MMP-specific cleavage product (VDIPEN) was studied by immunolocalization. The role of SLN-1 was studied with use of SLN-1-deficient (SLN-1KO) mice. VDIPEN expression was studied in vitro by exposing the cartilage to IL-1 and subsequent activation of latent MMPs. Immune complex arthritis was characterized by an acute inflammation, with influx of mainly polymorphonuclear cells into the joint cavity. Expression of VDIPEN neoepitopes was consistently found in areas extensively depleted from proteoglycans. SLN-1KO mice did not show expression of the VDIPEN neoepitope, although inflammation and proteoglycan depletion was comparable to wild-type mice. In addition, erosions of cartilage were absent in SLN-1KO mice, but were present in wild-type mice, suggesting an important role for SLN-1 in cartilage destruction. In vitro studies showed that SLN-1 is also pivotally involved in IL-1-induced MMP activity. Stimulated polymorphonuclear neutrophils were able to activate latent MMPs present in the cartilage. Neutrophil elastase was also capable of activating IL-1-induced latent MMPs, which identifies elastase as a possible activator for latent VDIPEN-inducing MMPs. This study suggests that IC are important in the activation of latent MMPs in cartilage, possibly through polymorphonuclear neutrophil activation on the cartilage edge. SLN-1 is a pivotal enzyme in overall MMP-activity in cartilage during immune complex-mediated arthritis. (+info)
Bone marrow-derived cells are responsible for the development of autoimmune arthritis in human T cell leukemia virus type I-transgenic mice and those of normal mice can suppress the disease.
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Previously, we reported that human T cell leukemia virus type I env-pX region-introduced transgenic (pX-Tg) mice developed an inflammatory polyarthropathy associated with a development of autoimmunity. To elucidate roles of autoimmunity in the development of arthritis, the immune cells were reciprocally replaced between pX-Tg mice and non-transgenic (Tg) mice. When bone marrow (BM) cells and spleen cells from pX-Tg mice were transferred into irradiated non-Tg mice, arthritis developed in these mice. In contrast, arthritis in pX-Tg mice was completely suppressed by non-Tg BM and spleen cells. Similar results were obtained with BM cells only. After the transplantation, T cells, B cells, and macrophages were replaced completely, whereas cells in the joints were replaced partially. In those mice, serum Ig and rheumatoid factor levels correlated with the disease development, and inflammatory cytokine expression was elevated in the arthritic joints. Furthermore, involvement of T cells in the joint lesion was suggested, because the incidence was greatly reduced in athymic nu/nu mice although small proportion of the mice still developed arthritis. These observations suggest that BM stem cells are abnormal, causing autoimmunity in pX-Tg mice, and this autoimmunity plays an important, but not absolute, role in the development of arthritis in this Tg mouse. (+info)
Type II collagen degradation in spontaneous osteoarthritis in C57Bl/6 and BALB/c mice.
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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. (+info)
Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin's lymphoma.
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We describe a case involving a 53-yr-old male with a marginal zone B-cell lymphoma, associated with an IgM paraprotein and a rheumatoid factor-negative inflammatory polyarthropathy, treated with monoclonal anti-CD20 antibody. During the subsequent 12 weeks, evidence of synovitis reduced to a negligible level, despite no significant change in lymphoma bulk or paraprotein level. The relationship between the lymphoma and the arthropathy, and the likely mechanism of remission of the arthropathy, are discussed in the context of the potential value of anti-CD20 therapy in rheumatoid arthritis. (+info)
Effect of diacerein on spontaneous polyarthritis in male New Zealand black/KN mice.
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OBJECTIVE: Male New Zealand black/KN (NZB/KN) mice spontaneously develop polyarthritis, characterized by destructive damages to the articular cartilage and bone. We assessed effects of diacerein in male NZB/KN mice by radiographic and histopathologic examinations. DESIGN: Diacerein, cyclosporin A or vehicle for the control were orally administered for 7 months, initiating at 8 weeks of age when the arthritis became apparent. RESULTS: At 39 weeks of age, the NZB/KN mice developed polyarthritis in the joints of the forelimbs and hind legs, radiographically characterized by joint space narrowing, deformation of the joint surfaces, and bone erosions. Histopathologic findings showed that the tarsal joints and knee sections from the NZB/KN mice exhibited overt arthritic lesion. Radiographic and histopathologic findings showed that diacerein and cyclosporin A at a dose of 30 mg/kg/day significantly reduced the progression of arthritis. CONCLUSIONS: Diacerein shows articular protecting effects against the development of spontaneous arthritis in male NZB/KN mice and diacerein might be useful in the treatment of chronic inflammatory joint diseases during clinical use. (+info)
Klinefelter's syndrome accompanied by mixed connective tissue disease and diabetes mellitus.
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We report a rare case of Klinefelter's syndrome (KS) with mixed connective tissue disease (MCTD), diabetes mellitus (DM) and several endocrine disorders. A 57-year-old man presented with polyarthritis and tapering fingers with Raynaud's phenomenon on admission. In addition to a karyotype of 47, XXY, a marked restrictive change in respiratory functional test, a myogenic pattern in electromyogram, the positive tests for anti-RNP antibody indicated that this was a case of KS complicated with MCTD. The patients also presented DM with insulin resistance, hyperprolactinemia, slight primary hypothyroidism and hypoadrenocorticism. The mechanism for these coincidences remains to be elucidated. (+info)
Human antibody responses to VlsE antigenic variation protein of Borrelia burgdorferi.
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VlsE is a 35-kDa surface-exposed lipoprotein of Borrelia burgdorferi that was shown previously to undergo antigenic variation through segmental recombination of silent vls cassettes with vlsE during experimental mouse infections. Previous data had indicated that sera from North American Lyme disease patients and experimentally infected animals contained antibodies reactive with VlsE. In this study, sera from patients with Lyme disease, syphilis, and autoimmune conditions as well as from healthy controls were examined for reactivity with VlsE by Western blotting and enzyme-linked immunosorbent assay (ELISA). Strong Western blot reactivity to a recombinant VlsE cassette region protein was obtained consistently with Lyme disease sera. Although sera from Lyme disease patients also reacted with a band corresponding to VlsE in B. burgdorferi B31-5A3, interpretation was complicated by low levels of VlsE expression in in vitro-cultured B. burgdorferi and by the presence of comigrating bands. An ELISA using recombinant VlsE was compared with an ELISA using sonically disrupted B. burgdorferi as the antigen. For a total of 93 Lyme disease patient sera examined, the VlsE ELISA yielded sensitivities of 63% for culture-confirmed erythema migrans cases and 92% for later stages, as compared to 61 and 98%, respectively, for the "whole-cell" ELISA. The specificities of the two assays with healthy blood donor sera were comparable, but the VlsE ELISA was 90% specific with sera from syphilis patients, compared to 20% specificity for the whole-cell ELISA with this group. Neither assay showed reactivity with a panel of sera from 20 non-Lyme disease arthritis patients or 20 systemic lupus erythematosus patients. Our results indicate that VlsE may be useful in the immunodiagnosis of Lyme disease and may offer greater specificity than ELISAs using whole B. burgdorferi as the antigen. (+info)