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Pierre Miossec - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of TNF-alpha and IL-1 beta on the control of metal metabolism and cadmium-induced cell death in chronic inflammation
PLoS ONE, 2018Co-Authors: Paola Bonaventura, Aline Lamboux, Francis Albarede, Pierre MiossecAbstract:Objective Interleukin-1-beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) are both monocyte-derived cytokines. Both cytokines have been previously described to exert a role in rheumatoid arthritis (RA) pathogenesis synergizing with other pro-inflammatory mediators, such as interleukin-17 (IL-17) on target cells, for the perpetuation of the inflammatory response (e.g. IL-6 production). In the context of experimental RA, Cd addition has an anti-proliferative and anti-inflammatory effect when associated to IL-17/TNF-alpha stimulation, due to its accumulation in Synoviocytes. The aim of this work was to evaluate if IL-1 beta interaction with IL-17 also contributes to metal-import mechanisms and its effects on cell viability and inflammation. Methods IL-17 and IL-1 beta were added to Synoviocyte cultures with or without exogenous Cd addition (0.1 ppm, 0.89 mu M). IL-6 production, Cd import kinetics, gene expression of ZIP-8 importer and metallothioneins (MTs) and cell viability were evaluated by ELISA, inductively-coupled mass spectrometry (ICP-MS), q-RT-PCR and viability assays (neutral red and annexin V) respectively. Results IL-17 and IL-1 beta acted in synergy on Synoviocytes to induce IL-6 production similarly to the IL-17/TNF-alpha combination. Metal import was lower with IL17/IL-1 beta in comparison to IL-17/ TNF-alpha exposed-Synoviocytes, as the expression of ZIP-8 and MT-1F was less induced. Monocyte and PBMCs exposure to Cd resulted in a reduced production of IL-1 beta and an increased production of TNF-alpha and this result was confirmed in co-cultures of Synoviocytes and PBMCs. The IL-17/IL-1 beta combination with Cd slightly reduced cell viability in comparison to the IL-17/TNF-alpha combination and resulted in a strong induction of IL-6 production. Conclusion IL-17/TNF-alpha combination but not IL-17/IL-1 beta combination mainly drives the accumulation of Cd in Synoviocytes and its effects on cell viability and inflammation.
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06.01 Intra-articular injection of cadmium protects arthritic joints from inflammation and destruction
Annals of the Rheumatic Diseases, 2017Co-Authors: Paola Bonaventura, Guillaume Courbon, Aline Lamboux, Fabien Lavocat, Hubert Marotte, Francis Albarede, Pierre MiossecAbstract:Background There has been no recent progress in the intra-articular treatment of joint inflammation. Rheumatoid arthritis (RA) synovium hyperplasia is sustained by the secretion of pro-inflammatory cytokines (IL-17/TNF-α), synergistically contributing to chronicity. Since inflammation up-regulates trans-membrane Zinc (Zn) importers, the effects of its binding-competitor Cadmium (Cd) were tested on Synoviocytes, synovium explants and in a rat arthritis model in order to reduce hyperplasia and inflammation. Materials and methods After exposure to IL-17/TNF-α and Cd, Cd-kinetics and Cd-cell content were measured by ICP-MS, while Zn/Cd-transporter gene expression (Zrt-Irt-like protein-8, ZIP-8, importer and metallothioneins-1, MT-1, metal homeostasis regulators) by q-RT-PCR. Synoviocyte viability and apoptosis were measured by neutral red and annexin-V staining. IL-6 levels in Synoviocyte and biopsy supernatants were measured by ELISA. Adjuvant induced arthritis rat model was used for in vivo Cd-injection into hind ankle joints. Clinical scores were evaluated. Immune cell recruitment was quantified after H and E staining. Micro-tomography and safarin-O staining were used to measure bone/cartilage loss. The potential Cd-spread was measured in different body reservoirs. Results After Synoviocyte exposure to IL-17/TNF-α combination, ZIP-8 and MT-1s gene expressions increased up to 5.3\textpm3.1 fold and 5.0\textpm0.9 fold respectively, compared to the untreated condition (p0.05). Combined Cd-cytokine exposure further enhanced MT-1s expression up to 93.3\textpm32.1 fold. Through the transporter enhanced expression, Cd content in inflammatory Synoviocytes increased two-fold. RA Synoviocytes were sensitised toward apoptosis by exposure to the Cd/cytokine combination with an 80% reduction of cell viability in comparison to control (p0.01), after 5 days of culture. Moreover, Cd-cytokines association reduced IL-6 production in vitro (up to 83%, after 5 days, p0.05) and ex-vivo (up to 94%, after 8 days, p0.01). Intra-articular Cd injection improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p0.01), inflammatory cell recruitment (up to 50%, p0.01) and bone/cartilage destruction. The use of 1 ppm of Cd provided the best risk/benefit ratio, without toxic effects on other cell types and organs. Conclusion The anti-proliferative and anti-inflammatory properties of low-dose Cd may represent a new therapeutic approach for the local treatment of synovitis and hyperplasia in arthritis and other joint diseases.
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IL-17 and TNFα combination induces a HIF-1α-dependent invasive phenotype in Synoviocytes
Annals of the Rheumatic Diseases, 2012Co-Authors: Saloua Zrioual, Vanina Lenief, Arnaud Hot, Pierre MiossecAbstract:Objectives To examine the effect of IL-17 on rheumatoid arthritis (RA) Synoviocyte migration and invasiveness. Methods IL-17A and tumour necrosis factor α (TNFα) induced mRNA expression in RA Synoviocytes was analysed using Affymetrix U133A microarrays. The capacities of IL-17 alone or in combination with TNFα to induce Synoviocyte migration and invasion were tested using Boyden and transwell Matrigel invasion chambers. A functional DNA binding assay was used to evaluate the regulation of the key hypoxia related gene HIF-1α expression and activation. The role of metalloproteinase 2 (MMP2) in IL-17 induced invasiveness was assessed using SiRNA. Hypoxia pathway gene expression was measured in blood of RA patients and healthy volunteers (HV) using Affymetrix microarrays. Results Among the genes induced by IL-17A in RA Synoviocytes, a molecular pattern of inflammation-hypoxia-related genes, including CXCR4 and MMP2 was identified. Using immunofluorence microscopy, the expression of CXCR4 on Synoviocytes was confirmed. IL-17A and TNFα induced Synoviocyte migration and invasion through a CXCR4-dependent mechanism with a synergistic effect. The combination of IL-17A and TNFα activated HIF1-α in Synoviocytes through a NFκB pathway. IL-17 enhanced invasion through MMP2 induction as demonstrated using SiRNA. Finally, hypoxia genes were over expressed in the blood of RA patients. Conclusion IL-17A, specifically when combined with TNFα may contribute to the progression of RA, notably through their effect on Synoviocyte aggressiveness. Part of this effect results from CXCR4/SDF1 and hypoxia mediated pathways.
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Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis Synoviocytes
Annals of the rheumatic diseases, 2011Co-Authors: Arnaud Hot, Pierre MiossecAbstract:Rheumatoid arthritis (RA) is a chronic inflammatory disease where the contribution of T cells is now supported by clinical results. Among the cytokines produced by T cells, interleukin (IL)-17A (previously known as IL-17) and IL-17F constitute the signature cytokines of the newly described Th17 T helper cell subset. While the effects of IL-17A on RA Synoviocytes been well described, those of IL-17F remain less studied. The present review describes the effects of IL-17A and IL-17F on Synoviocytes and their contribution to RA pathogenesis. Although IL-17F is less active than IL-17A when used alone, IL-17A and IL-17F induce in Synoviocytes a rather similar expression pattern in the presence of tumour necrosis factor α. They enhance their response by stabilising mRNA of cytokines and enhancing receptor expression. They increase the migration, chemokine gene expression and invasiveness of Synoviocytes. They contribute to disease chronicity by inhibiting Synoviocyte apoptosis. Finally, they enhance metalloprotease secretion leading to cartilage damage. These properties support the combined inhibition of IL-17A and -F to control RA inflammation and joint destruction.
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Increased AP-1 and NF-κB activation and recruitment with the combination of the proinflammatory cytokines IL-1β, tumor necrosis factor alpha and IL-17 in rheumatoid Synoviocytes
Arthritis Res Ther, 2004Co-Authors: Corinne Granet, Wova Maslinski, Pierre MiossecAbstract:To determine the contribution of IL-1β, tumor necrosis factor alpha (TNF-α) and IL-17 to AP-1, NF-κB and Egr-1 activation in rheumatoid arthritis, the effect of the cytokines used alone or in combination was measured on TF expression in rheumatoid Synoviocytes. Effects on mRNA expression were measured by RT-PCR and effects on nuclear translocation were measured by immunocytochemistry. To assess the functional consequences of cytokine induction, osteoprotegerin levels were measured in Synoviocyte supernatants. IL-1β and TNF-α alone at optimal concentration (100 pg/ml) induced the nuclear translocation of NF-κB and almost all AP-1 members, except JunB and Egr-1 for IL-1β and except Fra-2 and Egr-1 for TNF-α. IL-17 was clearly less potent since no nuclear translocation was observed, except for a weak activation of Fra-1 and NF-κB. More importantly, when these cytokines were used at low concentrations, their combination showed a synergistic effect on almost all the TFs, except for Egr-1, with a particular effect on Fra-1 and NF-κB. Increased recruitment of additional factors was induced when the three cytokines were combined. IL-1 and TNF-α induced mRNA expression of c- jun while IL-17 had no effect. A synergistic effect was seen with their combination. A similar synergistic effect was observed for osteoprotegerin production when these three cytokines were combined at low concentrations. AP-1 and NF-κB pathways were highly sensitive to the combination through synergistic mechanisms. These effects observed in rheumatoid arthritis Synoviocytes may reflect the conditions found in the rheumatoid arthritis joint and may contribute to the mode of action of cytokine inhibitors.
Gary S Firestein - One of the best experts on this subject based on the ideXlab platform.
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pi3 kinase δ is a key regulator of Synoviocyte function in rheumatoid arthritis
American Journal of Pathology, 2012Co-Authors: Beatrix Bartok, William D Bugbee, David L Boyle, Yi Liu, Pingda Ren, Scott T Ball, Christian Rommel, Gary S FiresteinAbstract:Class I phosphoinositide 3 kinase (PI3K) δ is a promising therapeutic target for rheumatoid arthritis (RA) because of its contribution to leukocyte biology. However, its contribution in fibroblasts has not been studied as a mechanism that contributes to efficacy. We investigated the expression and function of PI3Kδ in synovium and cultured fibroblast-like Synoviocytes (FLS). Immunohistochemistry demonstrated that PI3Kδ is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3Kδ mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3Kδ was also expressed in cultured FLS, along with PI3Kα and PI3Kβ, whereas PI3Kγ was not detectable. PI3Kδ mRNA expression was selectively induced by inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) but not by growth factors platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kδ inhibitor INK007, showed that PI3Kδ is required for PDGF- and TNF-induced Akt activation. PI3Kδ inhibition also diminished PDGF-mediated Synoviocyte growth and sensitized cells to H 2 O 2 -induced apoptosis. These data are the first documentation of increased PI3Kδ expression in both RA synovium and cultured Synoviocytes. Furthermore, these are the first data demonstrating that PI3Kδ is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3Kδ in RA could modulate Synoviocyte function via anti-inflammatory and disease-altering mechanisms.
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Synoviocyte innate immune responses ii pivotal role of ifn regulatory factor 3
Journal of Immunology, 2010Co-Authors: Susan E Sweeney, Trevor B Kimbler, Gary S FiresteinAbstract:Innate immune responses contribute to synovial inflammation in rheumatoid arthritis. The present study was designed to investigate the contribution of IFN regulatory factor (IRF)3 and IRF7 to type I IFN-regulated gene expression in Synoviocytes. Fibroblast-like Synoviocytes were stimulated with polyinosinic-polycytidylic acid (poly [I-C]) after transfection with IRF3 or IRF7 small interfering RNA to knockdown transcription factor expression. Western blots, luciferase assay after transfection with reporter constructs, quantitative PCR, and AP-1 DNA binding ELISA were performed to evaluate the role of IRF3 and IRF7 in poly (I-C)–induced signaling and Synoviocyte gene expression. IRF3 regulates IFN-stimulated response element (ISRE) promoter activity as well as IFN-β, IRF5, IRF7, RANTES, IFN-inducible protein-10, MCP-1, and MIP1α gene expression in response to poly (I-C). IRF7 knockdown modestly decreased a subset of genes and ISRE activity, although the results were not statistically significant. Surprisingly, IRF3 knockdown almost completely blocked expression of additional genes in which the ISRE is not traditionally considered a dominant promoter site in fibroblast-like Synoviocytes, including matrix metalloproteinase (MMP)3, MMP9, IL-6, and IL-8. Transcription factor activation studies demonstrated a role for IRF3 in regulation of c-Jun phosphorylation and AP-1 binding. IRF3 rather than IRF7 regulates poly (I-C)–induced type I IFN responses in human Synoviocytes by increasing ISRE promoter activity. IRF3 also partially regulates expression of other cytokines and MMP through activation of c-Jun and the AP-1 promoter site. Targeting Synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses.
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semi permeable membrane retention of synovial fluid lubricants hyaluronan and proteoglycan 4 for a biomimetic bioreactor
Biotechnology and Bioengineering, 2010Co-Authors: Megan E Blewis, Kyle D Jadin, William J Mccarty, William D Bugbee, Gary S FiresteinAbstract:Synovial fluid (SF) contains lubricant macromolecules, hyaluronan (HA), and proteoglycan 4 (PRG4). The synovium not only contributes lubricants to SF through secretion by Synoviocyte lining cells, but also concentrates lubricants in SF due to its semi-permeable nature. A membrane that recapitulates these synovium functions may be useful in a bioreactor system for generating a bioengineered fluid (BF) similar to native SF. The objectives were to analyze expanded polytetrafluoroethylene membranes with pore sizes of 50 nm, 90 nm, 170 nm, and 3 microm in terms of (1) HA and PRG4 secretion rates by adherent Synoviocytes, and (2) the extent of HA and PRG4 retention with or without Synoviocytes adherent on the membrane. Experiment 1: Synoviocytes were cultured on tissue culture (TC) plastic or membranes +/- IL-1beta + TGF-beta1 + TNF-alpha, a cytokine combination that stimulates lubricant synthesis. HA and PRG4 secretion rates were assessed by analysis of medium. Experiment 2: Bioreactors were fabricated to provide a BF compartment enclosed by membranes +/- adherent Synoviocytes, and an external compartment of nutrient fluid (NF). A solution with HA (1 mg/mL, MW ranging from 30 to 4,000 kDa) or PRG4 (50 microg/mL) was added to the BF compartment, and HA and PRG4 loss into the NF compartment after 2, 8, and 24 h was determined. Lubricant loss kinetics were analyzed to estimate membrane permeability. Experiment 1: Cytokine-regulated HA and PRG4 secretion rates on membranes were comparable to those on TC plastic. Experiment 2: Transport of HA and PRG4 across membranes was lowest with 50 nm membranes and highest with 3 microm membranes, and transport of high MW HA was decreased by adherent Synoviocytes (for 50 and 90 nm membranes). The permeability to HA mixtures for 50 nm membranes was approximately 20 x 10(-8) cm/s (- cells) and approximately 5 x 10(-8) cm/s (+ cells), for 90 nm membranes was approximately 35 x 10(-8) cm/s (- cells) and approximately 19 x 10(-8) cm/s (+ cells), for 170 nm membranes was approximately 74 x 10(-8) cm/s (+/- cells), and for 3 microm membranes was approximately 139 x 10(-8) cm/s (+/- cells). The permeability of 450 kDa HA was approximately 40x lower than that of 30 kDa HA for 50 nm membranes, but only approximately 2.5x lower for 3 microm membranes. The permeability of 4,000 kDa HA was approximately 250x lower than that of 30 kDa HA for 50 nm membranes, but only approximately 4x lower for 3 microm membranes. The permeability for PRG4 was approximately 4 x 10(-8) cm/s for 50 nm membranes, approximately 48 x 10(-8) cm/s for 90 nm membranes, approximately 144 x 10(-8) cm/s for 170 nm membranes, and approximately 336 x 10(-8) cm/s for 3 microm membranes. The associated loss across membranes after 24 h ranged from 3% to 92% for HA, and from 3% to 93% for PRG4. These results suggest that semi-permeable membranes may be used in a bioreactor system to modulate lubricant retention in a bioengineered SF, and that Synoviocytes adherent on the membranes may serve as both a lubricant source and a barrier for lubricant transport.
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regulation of the jnk pathway by tgf beta activated kinase 1 in rheumatoid arthritis Synoviocytes
Arthritis Research & Therapy, 2007Co-Authors: Deepa Hammaker, David L Boyle, Tomoyuki Inoue, Gary S FiresteinAbstract:c-Jun N-terminal kinase (JNK) contributes to metalloproteinase (MMP) gene expression and joint destruction in inflammatory arthritis. It is phosphorylated by at least two upstream kinases, the mitogen-activated protein kinase kinases (MEK) MKK4 and MKK7, which are, in turn, phosphorylated by MEK kinases (MEKKs). However, the MEKKs that are most relevant to JNK activation in Synoviocytes have not been determined. These studies were designed to assess the hierarchy of upstream MEKKs, MEKK1, MEKK2, MEKK3, and transforming growth factor-β activated kinase (TAK)1, in rheumatoid arthritis (RA). Using either small interfering RNA (siRNA) knockdown or knockout fibroblast-like Synoviocytes (FLSs), MEKK1, MEKK2, or MEKK3 deficiency (either alone or in combination) had no effect on IL-1β-stimulated phospho-JNK (P-JNK) induction or MMP expression. However, TAK1 deficiency significantly decreased P-JNK, P-MKK4 and P-MKK7 induction compared with scrambled control. TAK1 knockdown did not affect p38 activation. Kinase assays showed that TAK1 siRNA significantly suppressed JNK kinase function. In addition, MKK4 and MKK7 kinase activity were significantly decreased in TAK1 deficient FLSs. Electrophoretic mobility shift assays demonstrated a significant decrease in IL-1β induced AP-1 activation due to TAK1 knockdown. Quantitative PCR showed that TAK1 deficiency significantly decreased IL-1β-induced MMP3 gene expression and IL-6 protein expression. These results show that TAK1 is a critical pathway for IL-1β-induced activation of JNK and JNK-regulated gene expression in FLSs. In contrast to other cell lineages, MEKK1, MEKK2, and MEKK3 did not contribute to JNK phosphorylation in FLSs. The data identify TAK1 as a pivotal upstream kinase and potential therapeutic target to modulate Synoviocyte activation in RA.
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apoptosis in rheumatoid arthritis synovium
Journal of Clinical Investigation, 1995Co-Authors: Gary S Firestein, Nathan J ZvaiflerAbstract:RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. GenomicDNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ end labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apoptotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl2, were spared. DNA strand breaks in cultured fibroblastlike Synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-a but not by IFN-y. Fas expression was also detected on fibroblast-like Synoviocytes using flow cytometry. Therefore,DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-y) along with local oxidant injury might favor induction of apoptosis. (J. Clin. Invest. 1995.96:1631-1638.) Key words: rheumatoid arthritis * apoptosis * fas * bcl-2 * Synoviocyte
Toshio Ota - One of the best experts on this subject based on the ideXlab platform.
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cDNA macroarray analysis of gene expression in Synoviocytes stimulated with TNFα
FEBS Letters, 2002Co-Authors: Tomoyasu Sugiyama, Shizuko Ishii, Junichi Yamamoto, Ryotaro Irie, Kaoru Saito, Tetsuji Otuki, Ai Wakamatsu, Yuzuru Suzuki, Yuri Hio, Toshio OtaAbstract:Abstract Gene expression of Synoviocytes stimulated with tumor necrosis factor-α (TNFα) was studied by macroarray analysis to elucidate the cellular response and identify new biological functions of known and unknown genes. 10 035 cDNA clones were used to make cDNA macroarrays of representative genes. Synoviocytes expressed large amounts of fibronectin and collagen mRNA. Statistical analysis of the macroarray data revealed 26 genes, including six new genes, which underwent significant alteration of gene expression in response to TNFα stimulation. These findings suggest that the Synoviocyte response to TNFα stimulation forms the basis of development of various aspects of the pathophysiology of rheumatoid arthritis.
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cDNA macroarray analysis of gene expression in Synoviocytes stimulated with TNFalpha.
FEBS letters, 2002Co-Authors: Tomoyasu Sugiyama, Shizuko Ishii, Junichi Yamamoto, Ryotaro Irie, Kaoru Saito, Tetsuji Otuki, Ai Wakamatsu, Yuzuru Suzuki, Yuri Hio, Toshio OtaAbstract:Gene expression of Synoviocytes stimulated with tumor necrosis factor-alpha (TNFalpha) was studied by macroarray analysis to elucidate the cellular response and identify new biological functions of known and unknown genes. 10035 cDNA clones were used to make cDNA macroarrays of representative genes. Synoviocytes expressed large amounts of fibronectin and collagen mRNA. Statistical analysis of the macroarray data revealed 26 genes, including six new genes, which underwent significant alteration of gene expression in response to TNFalpha stimulation. These findings suggest that the Synoviocyte response to TNFalpha stimulation forms the basis of development of various aspects of the pathophysiology of rheumatoid arthritis.
Brian Johnstone - One of the best experts on this subject based on the ideXlab platform.
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CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome
Nature Genetics, 1999Co-Authors: Jose Marcelino, John D. Carpten, Wafaa M. Suwairi, Orlando M. Gutierrez, Stuart Schwartz, Christiane Robbins, Raman Sood, Izabela Makalowska, Andy Baxevanis, Brian JohnstoneAbstract:Altered growth and function of Synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases^ 1 . Hyperplasia of Synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to Synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene ( CACP ) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor'^ 2 and 'superficial zone protein'^ 3 , contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.
Wei Wei - One of the best experts on this subject based on the ideXlab platform.
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the expression change of β arrestins in fibroblast like Synoviocytes from rats with collagen induced arthritis and the effect of total glucosides of paeony
Journal of Ethnopharmacology, 2011Co-Authors: Qingtong Wang, Lingling Zhang, Wei WeiAbstract:Abstract Aim of the study To investigate the expression of β-arrestins in fibroblast-like Synoviocytes (FLS) from collagen-induced arthritis (CIA) rats and the effect of total glucosides of paeony (TGP). Materials and methods TGP and glucosides of tripterygium wilfordii (GTW) were intragastriclly administrated to collagen-induced arthritis (CIA) rats after immunization. The secondary inflammatory reaction was evaluated by hind paw swelling, polyarthritis index and histopathological changes. Antibodies to type II collagen (CII) were determined by enzyme-linked immunosorbent assay (ELISA). Synoviocyte proliferations were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. The expression of β-arrestins in Synoviocytes from CIA rats was measured by western blot. Results The administration of TGP (25, 50, 100 mg/kg) depressed hind paw swelling and decreased the arthritis scores of CIA rats. TGP improved the pathologic manifestations of CIA. Serum anti-CII antibodies level increased significantly in CIA rats, while TGP had no effect on it. Fibroblast-like Synoviocytes (FLS) proliferation was inhibited by TGP (50, 100 mg/kg). On d14, d28 after immunization, β-arrestins expression greatly up-regulated in Synoviocytes from CIA rats and then returned to baseline levels on d42 after immunization. TGP (50, 100 mg/kg) significantly reduced the expression of β-arrestins. Conclusion An inflammatory process in vivo induces an up-regulation of β-arrestins in Synoviocytes from CIA rats while TGP can inhibit this change, which might be one of the important mechanisms for TGP to produce a marked therapeutic effect on RA.
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Effect and mechanism of action of total glucosides of paeony on Synoviocytes from rats with collagen-induced arthritis
Yao xue xue bao = Acta pharmaceutica Sinica, 2006Co-Authors: Lei Zhu, Wei Wei, Yong-qiu ZhengAbstract:AIM To study the effect and mechanism of action of total glucosides of paeony (TGP) on Synoviocytes from rats with collagen-induced arthritis (CIA). METHODS Chicken type II collagen was used to induce CIA in rats. Synoviocytes were separated by incubation with collagenase and trypsin, and its ultrastructural changes were observed under transmission electron microscope. Synoviocyte proliferation was determined by 3-(4,5-dimethylthiazal-2yl) 2,5- diphenyltetrazoliumbromide (MTT) assay, and IL-1 activity in Synoviocytes supernatant was measured by thymocyte proliferation assay. TNFa and PGE, produced by Synoviocytes were determined by radioimmunoassay. RESULTS TGP was shown to protect CIA rats against the ultrastructural damages of Synoviocytes. Meanwhile, TGP also suppressed the excessive Synoviocyte proliferation and over-production of IL-1, TNFalpha and PGE2. CONCLUSION TGP has inhibitory effect on hyperfunctional Synoviocytes of CIA rats and its mechanism of action may be related with the inhibition of abnormal proliferation and secretion of Synoviocytes.
