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

MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8+ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.
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PMID:Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. 1626 57

We previously have demonstrated the ability of primary murine bone marrow-derived DC (BM-DC), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) following systemic delivery. Here we demonstrate that exosomes derived from genetically modified BM-DC expressing FasL are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH). Local administration of exosomes derived from DC expressing FasL (Exo/FasL) as well as the parental DC/FasL resulted in a significant reduction in swelling in both the treated and the untreated distal paw. However, both the DC/FasL and the Exo/FasL were unable to suppress the DTH response in lpr (Fas-deficient) mice. Gene transfer of FasL to BM-DC from gld (FasL-deficient) mice resulted in restoration of the ability of DC as well as DC-derived exosomes to suppress DTH. The ability of DC-derived exosomes and DC to suppress DTH responses was antigen specific and MHC class II dependent, but class I independent. The injected exosomes were found to be internalized into CD11c(+) cells at the site of injection and in the draining popliteal lymph node. Systemic injection of exosome/FasL into mice with established CIA resulted in significant disease amelioration. These results demonstrate that both systemic and local administration of exosomes derived from FasL-expressing DC are able to suppress antigen-specific immune responses through an MHC class II-dependent pathway, resulting in effective and sustained treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. These results suggest that DC/FasL-derived exosomes could be used clinically for the treatment of inflammatory and autoimmune diseases.
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PMID:Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. 1627 99

Lyme disease represents a complex response to Borrelia burgdorferi that involves both bacterial factors as well as host responses. This results in an inflammatory reaction at several sites, including the synovial lining of joints. Synovial tissues of inflamed joints contain cells expressing high levels of Fas and Fas ligand (FasL). Although Fas stimulation is typically associated with cell death, it can also transmit stimulatory signals to certain cell types. Among these are dendritic cells and macrophages, which are abundant in inflamed synovium. To better assess the role of FasL in the pathogenesis of Lyme arthritis, we evaluated the response to B. burgdorferi infection in C3H/HeJgld mice that bear a nonfunctional mutation in FasL. Compared to wild-type C3H+/+ mice, C3Hgld mice had a similar bacterial burden and antibody response 2 weeks and 4 weeks following infection, but they manifested a significantly reduced Borrelia-specific cytokine response. In addition, C3Hgld mice developed a greatly reduced incidence and severity of arthritis. The findings document a contribution of FasL to the host inflammatory response to B. burgdorferi.
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PMID:Fas ligand deficiency impairs host inflammatory response against infection with the spirochete Borrelia burgdorferi. 1642 64

One of the hallmarks of osteoarthritic cartilage is the loss of chondrocyte cellularity due to cell death. However, considerable controversy has recently arisen surrounding the extent of apoptotic cell death involved in development of osteoarthritis (OA). To shed light on this issue, we characterized cell death in primary OA chondrocytes mediated by the CD95 (Fas) pathway. Treatment of chondrocytes with anti-CD95 not only increased the rate of cell death but also increased the production of CD95 ligand by chondrocytes. This reveals a novel autocrine regulatory loop whereby activated chondrocytes may amplify CD95 signals by inducing synthesis of CD95 ligand. Multiple morphologic detection analyses indicated that apoptosis accounted for only a portion of chondrocyte death, whereas the other chondrocytes died by necrosis. Both chondrocyte apoptosis and necrosis depended on the activity of p38 mitogen-activated protein kinase (MAPK) within chondrocytes. Treatment of chondrocytes with the p38 MAPK inhibitor SB203580 abolished anti-CD95 induced cell death by inhibiting the activities of activating transcription factor-2 and caspase-3. In addition, inhibition of p38 MAPK activity in chondrocytes stimulated chondrocyte proliferation, as indicated by 5-bromo-2-deoxyuridine (BrdU) index. Thus, p38 MAPK is a potential therapeutic target, inhibition of which may maintain the cellularity of articular chondrocytes by inhibiting cell death and its amplification signal and by increasing cell proliferation.
Arthritis Res Ther 2006
PMID:CD95-induced osteoarthritic chondrocyte apoptosis and necrosis: dependency on p38 mitogen-activated protein kinase. 1646 15

The infiltration and accumulation of T cells in the rheumatoid arthritis (RA) synovial fluid (SF) are hallmarks of disease. We aimed to assess the functional relevance of FasL and of APO2L/TRAIL in the persistence of T cells in the rheumatoid SF. We have analyzed the expression of the activation markers HLA-DR and CD69 and also of the death receptor Fas/CD95 and death ligands FasL or APO2L/TRAIL in CD3+ lymphocytes from SF of 62 RA patients, together with their sensitivity to anti-Fas mAb or to rAPO2L/TRAIL, using as controls T lymphocytes present in SF of 20 patients with traumatic arthritis. T lymphocytes infiltrated in SF of RA patients have a chronically activated phenotype, but they are resistant to Fas-induced toxicity. However, they are more susceptible to rAPO2L/TRAIL than T cells in the SF of traumatic arthritis patients. In addition, we found very low amounts of bioactive FasL and APO2L/TRAIL associated with exosomes in SF from RA patients as compared with SF from traumatic arthritis patients. The observation on the sensitivity of RA SF T cells to rAPO2L could have therapeutic implications because bioactive APO2L/TRAIL could be beneficial as a RA treatment.
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PMID:Rheumatoid synovial fluid T cells are sensitive to APO2L/TRAIL. 1698 14

In this study, we report the in vivo effects of a decoy oligonucleotide targeting the nuclear factor kappaB (NF-kappaB) on osteoclasts during forced orthodontic tooth movement in rats. Wistar rats were subjected to orthodontic forces, in the absence or presence of treatment with a decoy molecule mimicking a nonsymmetric NF-kappaB binding site (5'-CGC TGG GGA CTT TCC ACG G-3'). TUNEL staining of fragmented DNA revealed that treatment with NF-kappaB decoy but not with scramble double-stranded oligodeoxynucleotides (ODN) induced a high level of osteoclast apoptosis in vivo. Immunohystochemical analysis for death receptor Fas revealed strong positivity only in samples treated with NF-kappaB decoys, demonstrating that osteoclasts are sensitive to death induction via Fas signaling. Induction of apoptosis in osteoclasts could be a strategy for treatment of excessive osteoclast activity in pathologic conditions such as osteoporosis, peri-articular osteolysis, inflammatory arthritis, Paget's syndrome and tumour-associated osteolytic metastases.
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PMID:Local in vivo administration of a decoy oligonucleotide targeting NF-kappaB induces apoptosis of osteoclasts after application of orthodontic forces to rat teeth. 1701 9

Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75(NTR) protein. p75(NTR) has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75(NTR) and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75(NTR) relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75(NTR) protein levels, the expression of Fas, p55(TNFR), DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before R-flurbiprofen or ibuprofen treatment with a dominant negative form of p75(NTR) to antagonize p75(NTR) activity or p75(NTR) small interfering RNA to prevent p75(NTR) protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75(NTR)-dependent decreased survival of prostate cancer cells independently of COX inhibition.
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PMID:The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. 1740 33

The characteristics of rheumatoid arthritis (RA) pathology include the infiltration of inflammatory leukocytes, the proliferation of synovial cells, and the presence of extensive angiogenesis, referred to as rheumatoid pannus. Fas ligand is critical to the homeostatic regulation of the immune response, but its role in the angiogenic process of RA remains to be defined. In this study, we investigated whether soluble Fas ligand (sFasL) induces synoviocyte apoptosis and regulates angiogenesis of endothelial cells in RA. The levels of sFasL were elevated in the synovial fluids of RA patients when compared to those of osteoarthritis (OA) patients, and they correlated inversely with vascular endothelial growth factor165 (VEGF165) concentrations. sFasL, ranging from 10 to 100 ng/ml, induced the apoptosis of RA fibroblast-like synoviocytes (FLS) in vitro, and thereby decreased VEGF165 production. In addition, sFasL inhibited VEGF165-induced migration and chemotaxis of endothelial cells to basal levels in a manner independent of the Fas-mediated cell death. sFasL dose-dependently suppressed the VEGF165-stimulated increase in pAkt expression in endothelial cells, which might be associated with its anti-migratory effect on endothelial cells. Moreover, sFasL strongly inhibited neovascularization in the Matrigel plug in vivo. Our data suggest that sFasL shows anti-angiogenic activity within RA joints not only by inducing apoptosis of VEGF165-producing cells but also by blocking VEGF165-induced migration of endothelial cells, independent of Fas-mediated apoptosis.
Arthritis Res Ther 2007
PMID:Soluble Fas ligand inhibits angiogenesis in rheumatoid arthritis. 1745 70

R-125224 is a novel humanized anti-human Fas monoclonal antibody prepared from HFE7A, which is a monoclonal mouse IgG anti-Fas antibody, by grafting the mouse complementarity-determining regions to human IgG, presently being developed as a drug for treatment of rheumatoid arthritis. In the present study, we investigated the tissue distribution of radioactivity in cynomolgus monkeys with collagen-induced arthritis at the arm joint (CIA monkeys) after intravenous administration of (125)I-labeled R-125224 ((125)I-R-125224). At 168 h after administration, we observed a high radioactivity in the bone marrow, thymus, lungs, liver, adrenals, spleen, ovaries, axillary lymph node and mesenteric lymph node compared to the radioactivity in the plasma. These tissues and organs in human are reported to express Fas antigen, strongly suggesting a specific binding of (125)I-R-125224 to Fas antigen in cynomolgus monkeys. Semi-micro autoradioluminograms of arm joint showed that radioactivity is detected in pharmacological site, such as the bone marrow and articular cavity at 168 h. The kinetics in binding of R-125224 to activated monkey lymphocytes and hepatocytes was also investigated. K(d) values of activated lymphocytes and hepatocytes were 1.51+/-0.08 and 0.60+/-0.11 nM, respectively, which were similar to those values in human lymphocytes and hepatocytes, demonstrating that R-125224 cross-reacts with the monkey Fas antigen.
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PMID:Tissue distribution of humanized anti-human Fas monoclonal antibody (R-125224) based on fas antigen-antibody reaction in collagen-induced arthritis monkeys. 1747 38

Rheumatoid arthritis is an autoimmune disease characterized by hyperplasia of the synovial lining and destruction of cartilage and bone. Recent studies have suggested that a lack of apoptosis contributes to the hyperplasia of the synovial lining and to the failure in eliminating autoreactive cells. Mice lacking Fas or Bim, two pro-apoptotic proteins that mediate the extrinsic and intrinsic death cascades, respectively, develop enhanced K/BxN serum transfer-induced arthritis. Since the pro-apoptotic protein Bid functions as an intermediate between the extrinsic and intrinsic apoptotic pathways, we examined the role that it plays in inflammatory arthritis. Mice deficient in Bid (Bid-/-) show a delay in the resolution of K/BxN serum transfer-induced arthritis. Bid-/- mice display increased inflammation, bone destruction, and pannus formation compared to wild-type mice. Furthermore, Bid-/- mice have elevated levels of CXC chemokine and IL-1beta in serum, which are associated with more inflammatory cells throughout the arthritic joint. In addition, there are fewer apoptotic cells in the synovium of Bid-/- compared to Wt mice. These data suggest that extrinsic and intrinsic apoptotic pathways cooperate through Bid to limit development of inflammatory arthritis.
Arthritis Res Ther 2007
PMID:Pro-apoptotic Bid is required for the resolution of the effector phase of inflammatory arthritis. 1750 38


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