The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
R Grant - One of the best experts on this subject based on the ideXlab platform.
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Erythropoietin and interleukin-1β modulate nitrite production in a Swiss 3T3 cell model of rheumatoid synovial fibroblasts
Biochemical Society Transactions, 2002Co-Authors: S Baig, Y Patel, P Coussons, R GrantAbstract:Erythropoietin (EPO), a haemopoietic growth factor and a primary regulator of erythropoiesis, is widely used to treat anaemia in various chronic complications of rheumatoid arthritis (RA). Fibroblast-like cells, found in the Pannus Tissue of joints, are thought to contribute to the inflammatory pathology of RA. Thus for the current study we investigated the effects of recombinant human EPO (rHuEPO) on NO metabolism, using an interleukin-1beta (IL-1beta)-stimulated Swiss 3T3 fibroblast monolayer as a model for fibroblast activity in RA. The results show that, over 3 days, both alone and in combination with the pro-inflammatory cytokine IL-1beta (10 ng/ml), rHuEPO (25 micro-units/ml) induced significant production of nitrite in cell culture supernatants. This is an indicator of NO production by nitric oxide synthase (NOS), which is a well-documented mediator of metalloproteinase-mediated Tissue remodelling in RA. It therefore appears that, through modulation of NOS-dependent NO production, rHuEPO may influence remodelling of connective Tissue in RA, independently of its established erythropoietic role.
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Erythropoietin and interleukin-1beta modulate nitrite production in a Swiss 3T3 cell model of rheumatoid synovial fibroblasts.
Biochemical Society transactions, 2002Co-Authors: S Baig, Y Patel, P Coussons, R GrantAbstract:Erythropoietin (EPO), a haemopoietic growth factor and a primary regulator of erythropoiesis, is widely used to treat anaemia in various chronic complications of rheumatoid arthritis (RA). Fibroblast-like cells, found in the Pannus Tissue of joints, are thought to contribute to the inflammatory pathology of RA. Thus for the current study we investigated the effects of recombinant human EPO (rHuEPO) on NO metabolism, using an interleukin-1beta (IL-1beta)-stimulated Swiss 3T3 fibroblast monolayer as a model for fibroblast activity in RA. The results show that, over 3 days, both alone and in combination with the pro-inflammatory cytokine IL-1beta (10 ng/ml), rHuEPO (25 micro-units/ml) induced significant production of nitrite in cell culture supernatants. This is an indicator of NO production by nitric oxide synthase (NOS), which is a well-documented mediator of metalloproteinase-mediated Tissue remodelling in RA. It therefore appears that, through modulation of NOS-dependent NO production, rHuEPO may influence remodelling of connective Tissue in RA, independently of its established erythropoietic role.
Hidehiro Yamada - One of the best experts on this subject based on the ideXlab platform.
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development of an ex vivo cellular model of rheumatoid arthritis critical role of cd14 positive monocyte macrophages in the development of Pannus Tissue
Arthritis & Rheumatism, 2007Co-Authors: Toshiko Nozaki, Kyoko Takahashi, Osamu Ishii, Sachio Endo, Kyoji Hioki, Toshihito Mori, Tadahiro Kikukawa, Dimitrios T. Boumpas, Shoichi Ozaki, Hidehiro YamadaAbstract:Objective To establish an ex vivo cellular model of Pannus, the aberrant overgrowth of human synovial Tissue (ST). Methods Inflammatory cells that infiltrated Pannus Tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST-derived inflammatory cells. Single-cell suspensions of ST-derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. ST-derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop Pannus. CD14 and CD2 cells were depleted by negative selection. Results Culture of ST-derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory Tissue in vitro within 4 weeks. Ex vivo Tissue contained fibroblasts, macrophages, T cells, and tartrate-resistant acid phosphatase–positive multinucleated cells. On calcium phosphate–coated slides, ST-derived inflammatory cell cultures showed numerous resorption pits. ST-derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor α, interleukin-8, and macrophage colony-stimulating factor. More importantly, transferring ST-derived inflammatory cells into the joints of immunodeficient mice resulted in the development of Pannus Tissue and erosive joint lesions. Both in vitro development and in vivo development of Pannus Tissue by ST-derived inflammatory cells were inhibited by depleting CD14-positive, but not CD2-positive, cells from ST-derived inflammatory cells. Conclusion These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of Pannus. This may prove informative in the screening of potential antirheumatic drugs.
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Development of an ex vivo cellular model of rheumatoid arthritis: critical role of CD14-positive monocyte/macrophages in the development of Pannus Tissue.
Arthritis and rheumatism, 2007Co-Authors: Toshiko Nozaki, Kyoko Takahashi, Osamu Ishii, Sachio Endo, Kyoji Hioki, Toshihito Mori, Tadahiro Kikukawa, Dimitrios T. Boumpas, Shoichi Ozaki, Hidehiro YamadaAbstract:Objective To establish an ex vivo cellular model of Pannus, the aberrant overgrowth of human synovial Tissue (ST). Methods Inflammatory cells that infiltrated Pannus Tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST-derived inflammatory cells. Single-cell suspensions of ST-derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. ST-derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop Pannus. CD14 and CD2 cells were depleted by negative selection. Results Culture of ST-derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory Tissue in vitro within 4 weeks. Ex vivo Tissue contained fibroblasts, macrophages, T cells, and tartrate-resistant acid phosphatase–positive multinucleated cells. On calcium phosphate–coated slides, ST-derived inflammatory cell cultures showed numerous resorption pits. ST-derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor α, interleukin-8, and macrophage colony-stimulating factor. More importantly, transferring ST-derived inflammatory cells into the joints of immunodeficient mice resulted in the development of Pannus Tissue and erosive joint lesions. Both in vitro development and in vivo development of Pannus Tissue by ST-derived inflammatory cells were inhibited by depleting CD14-positive, but not CD2-positive, cells from ST-derived inflammatory cells. Conclusion These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of Pannus. This may prove informative in the screening of potential antirheumatic drugs.
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Role of PGE2 and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy.
Endocrine metabolic & immune disorders drug targets, 2006Co-Authors: Jun Akaogi, Toshiko Nozaki, Minoru Satoh, Hidehiro YamadaAbstract:Recent progress in understanding the pathogenesis of rheumatoid arthritis (RA) in parallel with elucidation of the functional role of the prostaglandin receptor subfamily has revealed an important regulatory role of PGE2, in addition to its well-known proinflammatory role in the progression of RA. Characteristic features of RA are synovial proliferation and Pannus formation, which result in the destruction of cartilage and bone. Pannus Tissue is mainly composed of macrophages and fibroblast-like synoviocytes. Both T cell-derived IL-17 and macrophage-derived TNF-alpha seem to play a central role in the progression of proinflammatory cascades in RA. PGE2 is also produced in response to proinflammatory cytokines, which in turn negatively regulates both IL-17 and TNF-alpha expression and TNF/IL-1-induced activation of fibroblast-like synoviocytes through EP2/EP4 receptors, resulting in the modulation of proinflammatory cascades. IL-17- and TNF-activated macrophages differentiate into osteoclasts in the presence of M-CSF and RANKL expressed by fibroblast-like synoviocytes. PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression. At the same time, PGE2 suppresses osteoclastogenesis by inhibiting M-CSF expression of fibroblast-like synoviocytes as well as both IL-17 and IL-17-induced TNF-alpha expression of macrophages. PGE2-EP4 also activates osteoblastogenesis through increasing cbfa1 and osterix, two essential transcription factors required for bone formation. The net effect of PGE2 may direct toward repair of eroding bone through the suppression of inflammation and enhancement of bone remodeling. Here, we discuss a diverse action of PGE2/EP receptors and their important regulatory roles in the pathogenesis of RA, which may lead to a novel therapeutic strategy.
Yrjö T. Konttinen - One of the best experts on this subject based on the ideXlab platform.
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Pannus invasion and cartilage degradation in rheumatoid arthritis: involvement of MMP-3 and interleukin-1beta.
Clinical and experimental rheumatology, 2005Co-Authors: Mari Ainola, Mikko Liljestrom, Jami Mandelin, Mika Hukkanen, Yrjö T. KonttinenAbstract:Objective Synovial inflammation in rheumatoid arthritis (RA) leads to Pannus Tissue invasion and destruction of cartilage/bone matrix by proteinases. Our intention was to analyze some of the key matrix metalloproteinases (MMPs) in Pannus Tissue overlying evolving cartilage erosions in RA. Methods Frozen Tissue samples of Pannus and synovium from advanced RA and synovium from osteoarthritic patients were used for immunohistochemical, western blotting and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of MMP-1, -3, -13 and -14. Synovial fibroblast cultures, stimulated with tumour necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), were analyzed with enzyme-linked immunosorbent assays (ELISA) and quantitative RT-PCR. Results MMP-3 was highly expressed in Pannus Tissue compared with significantly lower expression levels of MMP-1, -13 and -14. In fibroblast cultures IL-1beta was a potent stimulus for MMP-3, whereas TNF-alpha was more potent for MMP-1. Conclusion This is the first study to demonstrate quantitatively in real time that MMP-3 mRNA expression is clearly higher in advanced RA Pannus Tissue compared to parallel RA or osteoarthritic synovium. MMP-3 mRNA levels were also clearly overexpressed in RA Pannus compared to MMP-1, -13 and -14. Advanced RA has previously been found to overexpress IL-1beta. The high expression of MMP-3 in Pannus and IL-1beta, mediated stimulation of MMP-3 suggest that MMP-3 plays a significant role in the progression of erosions through the proteoglycan-rich cartilage matrix.
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Distribution of tenascin-X in different synovial samples and synovial membrane-like interface Tissue from aseptic loosening of total hip replacement.
Rheumatology international, 2000Co-Authors: V. Warris, Ismo Virtanen, Jan Lassus, Toshimichi Yoshida, Seppo Santavirta, Yrjö T. KonttinenAbstract:The distribution of tenascin-X (Tn-X) was investigated in synovial samples from rheumatoid arthritis (RA), osteoarthritis (OA) and knee injuries, and in synovial membrane-like interface Tissue (SMLIT) from aseptic loosening of total hip replacement (THR). An affinity purified rabbit antiserum against Tn-X was applied in avidin-biotin-peroxidase complex method. Double immunofluorescence labeling was used to assess the spatial relationship of Tn-X and Tn-C. All samples showed Tn-X immunoreactivity. Strong staining appeared in the lining and lining-like layers of RA and SMLIT samples, respectively. An intensive immunoreactivity was also found in Pannus Tissue in RA, and around multinucleate giant cells and polyethylene wear debris in SMLIT. Staining intensity/extent varied significantly in different samples in the following rank order: SMLIT, RA, OA, knee synovium membrane. Double labeling revealed two patterns of Tn-X/Tn-C distribution, reciprocal and co-localization. Our results suggest that Tn-X is an essential component of normal synovial membrane, and that inflammatory mediators may increase local Tn-X production. Tn-X distribution is not always reciprocal to that of Tn-C.
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Fibroblast biology Signals targeting the synovial fibroblast in arthritis
Arthritis Research & Therapy, 2000Co-Authors: Yrjö T. Konttinen, Mika Hukkanen, Tian-fang Li, Jian Ma, Jing-wen Xu, Ismo VirtanenAbstract:Fibroblast-like cells in the synovial lining (type B lining cells), stroma and Pannus Tissue are targeted by many signals, such as the following: ligands binding to cell surface receptors; lipid soluble, small molecular weight mediators (eg nitric oxide [NO], prostaglandins, carbon monoxide); extracellular matrix (ECM)-cell interactions; and direct cell-cell contacts, including gap junctional intercellular communication. Joints are subjected to cyclic mechanical loading and shear forces. Adherence and mechanical forces affect fibroblasts via the ECM (including the hyaluronan fluid phase matrix) and the pericellular matrix (eg extracellular matrix metalloproteinase inducer [EMMPRIN]) matrices, thus modulating fibroblast migration, adherence, proliferation, programmed cell death (including anoikis), synthesis or degradation of ECM, and production of various cytokines and other mediators [ 1 ]. Aggressive, transformed or transfected mesenchymal cells containing proto-oncogenes can act in the absence of lymphocytes, but whether these cells represent regressed fibroblasts, chondrocytes or bone marrow stem cells is unclear.
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Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the Pannus-hard Tissue junction and inhibition by alendronate
Matrix biology : journal of the International Society for Matrix Biology, 1999Co-Authors: Yrjö T. Konttinen, Seppo Santavirta, Tuula Salo, R. Hanemaaijer, Heikki Valleala, Timo Sorsa, Meeri Sutinen, A. Ceponis, Olli TeronenAbstract:Abstract The hypothesis of the present work was that the Pannus Tissue overlying the articular hard Tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the Pannus-cartilage junction. Collagenase-3 mRNA ( in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the Pannus-hard Tissue junction. Inflammatory round cells associated with the critical interface contained TNF-α and IL-1β. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the Pannus-hard Tissue junction. Active collagenase-3 was inhibited with alendronate (IC 50 =500-750 μM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated Tissue destruction in rheumatoid arthritis.
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Substrate specificity and activation mechanisms of collagenase from human rheumatoid synovium.
Matrix (Stuttgart Germany), 1991Co-Authors: Yrjö T. Konttinen, Seppo Santavirta, Otso Lindy, Kimmo Suomalainen, Christopher T. Ritchlin, H. Saari, Matti Vauhkonen, Anneli Lauhio, Timo SorsaAbstract:Substrate specificity studies of collagenase extracted from human rheumatoid synovium suggest that synovial Pannus Tissue overlying articular cartilage may not be particularly active in degradation of cartilage type II collagen, which, considering the poor inherent healing capacity of the articular hyaline cartilage, may exert a protective function against inadvertant Tissue damage. Rheumatoid synovial Tissue was also used to establish synovial fibroblast cell lines. Treatment of these cells in monolayer cultures with IL-1 leads to collagenase gene activation, increased collagenase production and an almost complete autoactivation of secreted collagenase. Interleukin-1 also activated stromelysin gene suggesting this as a possible mechanism effecting autoactivation. Latent human fibroblast and macrophage collagenase purified from culture medium were efficiently activated by phenylmercuric chloride but also by gold thioglucose, gold sodium thiomalate and HCIO. These new observations support the Cys73 switch activation mechanism. In contrast to neutrophil collagenase, the activation by gold(I) compounds and HCIO was associated with a change in the apparent molecular weight of the fibroblast procollagenase. In addition, gold(I) compounds rendered collagenase more susceptible to thermal denaturation. Thus the fibroblast-type interstitial collagenase, probably derived from fibroblast- and macrophage-like synoviocytes, seems to provide the predominant collagenolytic potential in human rheumatoid synovial Tissue. Furthermore, the conditions in synovitis Tissue may be such as to favor at least initial activation of collagenase synthesized and secreted in situ.
S Baig - One of the best experts on this subject based on the ideXlab platform.
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Erythropoietin and interleukin-1β modulate nitrite production in a Swiss 3T3 cell model of rheumatoid synovial fibroblasts
Biochemical Society Transactions, 2002Co-Authors: S Baig, Y Patel, P Coussons, R GrantAbstract:Erythropoietin (EPO), a haemopoietic growth factor and a primary regulator of erythropoiesis, is widely used to treat anaemia in various chronic complications of rheumatoid arthritis (RA). Fibroblast-like cells, found in the Pannus Tissue of joints, are thought to contribute to the inflammatory pathology of RA. Thus for the current study we investigated the effects of recombinant human EPO (rHuEPO) on NO metabolism, using an interleukin-1beta (IL-1beta)-stimulated Swiss 3T3 fibroblast monolayer as a model for fibroblast activity in RA. The results show that, over 3 days, both alone and in combination with the pro-inflammatory cytokine IL-1beta (10 ng/ml), rHuEPO (25 micro-units/ml) induced significant production of nitrite in cell culture supernatants. This is an indicator of NO production by nitric oxide synthase (NOS), which is a well-documented mediator of metalloproteinase-mediated Tissue remodelling in RA. It therefore appears that, through modulation of NOS-dependent NO production, rHuEPO may influence remodelling of connective Tissue in RA, independently of its established erythropoietic role.
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Erythropoietin and interleukin-1beta modulate nitrite production in a Swiss 3T3 cell model of rheumatoid synovial fibroblasts.
Biochemical Society transactions, 2002Co-Authors: S Baig, Y Patel, P Coussons, R GrantAbstract:Erythropoietin (EPO), a haemopoietic growth factor and a primary regulator of erythropoiesis, is widely used to treat anaemia in various chronic complications of rheumatoid arthritis (RA). Fibroblast-like cells, found in the Pannus Tissue of joints, are thought to contribute to the inflammatory pathology of RA. Thus for the current study we investigated the effects of recombinant human EPO (rHuEPO) on NO metabolism, using an interleukin-1beta (IL-1beta)-stimulated Swiss 3T3 fibroblast monolayer as a model for fibroblast activity in RA. The results show that, over 3 days, both alone and in combination with the pro-inflammatory cytokine IL-1beta (10 ng/ml), rHuEPO (25 micro-units/ml) induced significant production of nitrite in cell culture supernatants. This is an indicator of NO production by nitric oxide synthase (NOS), which is a well-documented mediator of metalloproteinase-mediated Tissue remodelling in RA. It therefore appears that, through modulation of NOS-dependent NO production, rHuEPO may influence remodelling of connective Tissue in RA, independently of its established erythropoietic role.
Sohei Kitazawa - One of the best experts on this subject based on the ideXlab platform.
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RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse
Histochemistry and Cell Biology, 2002Co-Authors: Hiroyuki Mori, Riko Kitazawa, Shinichi Mizuki, Masato Nose, Sakan Maeda, Sohei KitazawaAbstract:Rheumatoid arthritis (RA) is a systemic disorder characterized by synovial inflammation and subsequent destruction and deformity of synovial joints. The articular lesions start with synovitis, focal erosion of unmineralized cartilage, and then culminate in the destruction of subarticular bone by Pannus Tissue. Periarticular osteopenia and systemic osteoporosis follow as late complications of RA. Osteoclasts, specialized cells that resorb bone, play a central role in developing these osteolytic lesions. To elucidate the mechanism of osteoclastogenesis and bone destruction in autoimmune arthritis, we investigated the expression of RANK ligand (RANKL), RANK, and osteoprotegerin (OPG) mRNA in a mouse type II collagen-induced arthritis (CIA) model by in situ hybridization. The results indicated that most of the TRAP-positive mono- and multinucleated cells in the inflamed and proliferating synovium and in the Pannus were RANK-positive authentic osteoclasts and their precursors. In the inflamed synovium and Pannus of the mouse CIA model, synovial fibroblastic cells around these RANK-positive cells were strongly positive for RANKL. Moreover, RANKL-positive osteoblasts on the endosteal bone surface, at a distance from the affected synovial joints, increased significantly in the mouse CIA model prior to periarticular osteopenia and systemic osteoporosis. These data indicated that the RANKL–RANK system plays an important role for osteoclastogenesis in both local and systemic osteolytic lesions in autoimmune arthritis, and can therefore be a good target for therapeutic intervention.
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RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse.
Histochemistry and cell biology, 2002Co-Authors: Hiroyuki Mori, Riko Kitazawa, Shinichi Mizuki, Masato Nose, Sakan Maeda, Sohei KitazawaAbstract:Rheumatoid arthritis (RA) is a systemic disorder characterized by synovial inflammation and subsequent destruction and deformity of synovial joints. The articular lesions start with synovitis, focal erosion of unmineralized cartilage, and then culminate in the destruction of subarticular bone by Pannus Tissue. Periarticular osteopenia and systemic osteoporosis follow as late complications of RA. Osteoclasts, specialized cells that resorb bone, play a central role in developing these osteolytic lesions. To elucidate the mechanism of osteoclastogenesis and bone destruction in autoimmune arthritis, we investigated the expression of RANK ligand (RANKL), RANK, and osteoprotegerin (OPG) mRNA in a mouse type II collagen-induced arthritis (CIA) model by in situ hybridization. The results indicated that most of the TRAP-positive mono- and multinucleated cells in the inflamed and proliferating synovium and in the Pannus were RANK-positive authentic osteoclasts and their precursors. In the inflamed synovium and Pannus of the mouse CIA model, synovial fibroblastic cells around these RANK-positive cells were strongly positive for RANKL. Moreover, RANKL-positive osteoblasts on the endosteal bone surface, at a distance from the affected synovial joints, increased significantly in the mouse CIA model prior to periarticular osteopenia and systemic osteoporosis. These data indicated that the RANKL–RANK system plays an important role for osteoclastogenesis in both local and systemic osteolytic lesions in autoimmune arthritis, and can therefore be a good target for therapeutic intervention.
