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1.
Raza K Falciani F Curnow SJ Ross EJ Lee CY Akbar AN Lord JM Gordon C Buckley CD Salmon M 《Arthritis research & therapy》2005,7(4):R784-R795
Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to
identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis (RA) by assessing
a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early
synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months
or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients
with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid
samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory
arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range
of T cell, macrophage and stromal cell related cytokines (e.g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor
and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared
with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In
contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-γ at initiation. Early
synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The
cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required
for persistent RA. 相似文献
2.
IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. 总被引:10,自引:0,他引:10
G S Firestein A E Berger D E Tracey J G Chosay D L Chapman M M Paine C Yu N J Zvaifler 《Journal of immunology (Baltimore, Md. : 1950)》1992,149(3):1054-1062
IL-1 can participate in the perpetuation of arthritis through direct stimulation of synoviocytes and augmentation of matrix degradation. Hence, local production of the IL-1R antagonist protein (IRAP) might be an important negative feedback signal that regulates synovitis. We assessed synovial IRAP production in synovia from 30 individuals, by using a specific mAb and the immunoperoxidase staining method. IRAP was detected in 11 of 12 rheumatoid arthritis (RA) synovial tissues (ST) and was located primarily in the sublining, particularly in perivascular regions enriched for macrophages. Some staining was observed in the intimal lining of the synovium, although this was significantly less than in the sublining (p less than 0.05). Nine of 12 osteoarthritis (OA) tissues were positive for IRAP. In contrast to RA, the staining was observed primarily in the synovial lining in OA, with only minimal sublining IRAP being detected. Synovia from four patients without arthritis were negative (three autopsy specimens and one post-traumatic sample). Of the other two patients with miscellaneous diagnoses, one sample was negative (tenosynovitis) and one was positive (seronegative inflammatory arthritis) (sublining). Studies of serial sections and double-immunostaining experiments indicated that macrophages are the major cells containing immunoreactive IRAP. IRAP gene expression in vivo was determined by performing in situ hybridization on ST from 17 arthritis patients. RNA sense IRAP probes did not hybridize to any tissues. Anti-sense IRAP probes bound to two of nine RA tissues, two of six OA tissues, one of one seronegative inflammatory arthropathy tissue, and none of one flexor tenosynovitis tissue. As with immunoreactive protein, IRAP mRNA was primarily localized to cells in the synovial lining in OA but was more prominent in perivascular lymphoid aggregates in RA and seronegative inflammatory arthropathy. Northern blot analysis was performed on RNA isolated from nine ST. The appropriately sized IRAP band was identified in six of nine samples (five of six RA and one of three OA). Supernatants from cultured RA and OA ST cells contained immunoreactive and biologically active IRAP. Hence, IRAP gene expression and protein production occur in RA and OA synovium, albeit in different distributions. 相似文献
3.
Interleukin-18 induces serum amyloid A (SAA) protein production from rheumatoid synovial fibroblasts
Interleukin-18 (IL-18) is a novel proinflammatory cytokine that was recently found in synovial fluids and synovial tissues from patients with rheumatoid arthritis (RA). To investigate the role of IL-18 in rheumatoid synovitis, the levels of IL-18 and serum amyloid A (SAA) were measured in synovial fluids from 24 patients with rheumatoid arthritis (RA) and 13 patients with osteoarthritis (OA). The levels of IL-18 and SAA in the synovial fluids were elevated in RA patients. In contrast, the levels of IL-18 in synovial fluids from OA patients were significantly lower compared to those of RA patients. SAA was not detected in synovial fluids from OA patients. The expression of SAA mRNA in rheumatoid synovial cells was also examined. SAA4 mRNA, which was constitutively expressed by rheumatoid synovial cells, was not affected by IL-18 stimulation. Although acute phase SAA (A-SAA, SAA1 + 2) mRNA was not detected in unstimulated synovial cells, its expression was induced by IL-18 stimulation. By immunoblot, we demonstrated that IL-18 induced the SAA protein synthesis from rheumatoid synovial cells in a dose-dependent manner. These results indicate a novel role for IL-18 in rheumatoid inflammation through the synovial SAA production. 相似文献
4.
Baeten D Kruithof E De Rycke L Boots AM Mielants H Veys EM De Keyser F 《Arthritis research & therapy》2005,7(2):R359-R369
Considering the relation between synovial inflammation and global disease activity in rheumatoid arthritis (RA) and the distinct
but heterogeneous histology of spondyloarthropathy (SpA) synovitis, the present study analyzed whether histopathological features
of synovium reflect specific phenotypes and/or global disease activity in SpA. Synovial biopsies obtained from 99 SpA and
86 RA patients with active knee synovitis were analyzed for 15 histological and immunohistochemical markers. Correlations
with swollen joint count, serum C-reactive protein concentrations, and erythrocyte sedimentation rate were analyzed using
classical and multiparameter statistics. SpA synovitis was characterized by higher vascularity and infiltration with CD163+ macrophages and polymorphonuclear leukocytes (PMNs) and by lower values for lining-layer hyperplasia, lymphoid aggregates,
CD1a+ cells, intracellular citrullinated proteins, and MHC–HC gp39 complexes than RA synovitis. Unsupervised clustering of the
SpA samples based on synovial features identified two separate clusters that both contained different SpA subtypes but were
significantly differentiated by concentration of C-reactive protein and erythrocyte sedimentation rate. Global disease activity
in SpA correlated significantly with lining-layer hyperplasia as well as with inflammatory infiltration with macrophages,
especially the CD163+ subset, and with PMNs. Accordingly, supervised clustering using these synovial parameters identified a cluster of 20 SpA
patients with significantly higher disease activity, and this finding was confirmed in an independent SpA cohort. However,
multiparameter models based on synovial histopathology were relatively poor predictors of disease activity in individual patients.
In conclusion, these data indicate that inflammatory infiltration of the synovium with CD163+ macrophages and PMNs as well as lining-layer hyperplasia reflect global disease activity in SpA, independently of the SpA
subtype. These data support a prominent role for innate immune cells in SpA synovitis and warrant further evaluation of synovial
histopathology as a surrogate marker in early-phase therapeutic trials in SpA. 相似文献
5.
6.
Fujii K Fujii Y Hubscher S Tanaka Y 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(3):1198-1203
7.
Paulina Chalan Bart-Jan Kroesen Kornelis S. M. van der Geest Minke G. Huitema Wayel H. Abdulahad Johan Bijzet Elisabeth Brouwer Annemieke M. H. Boots 《PloS one》2013,8(11)
Improved understanding of the immune events discriminating between seropositive arthralgia and clinical synovitis is of key importance in rheumatology research. Ample evidence suggests a role for Th17 cells in rheumatoid arthritis. We hypothesized that CD4+CD161+ cells representing Th17 lineage cells may be modulated prior to or after development of clinical synovitis. Therefore, in a cross-sectional study, we investigated the occurrence of CD4+CD161+ T-cells in seropositive arthralgia patients who are at risk for developing rheumatoid arthritis and in newly diagnosed rheumatoid arthritis patients. In a prospective study, we evaluated the effect of methotrexate treatment on circulating CD4+CD161+ T-cells. Next, we assessed if these cells can be detected at the level of the RA joints. Precursor Th17 lineage cells bearing CD161 were found to be increased in seropositive arthralgia patients. In contrast, circulating CD4+CD161+T-cells were decreased in newly diagnosed rheumatoid arthritis patients. The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein and with the 66 swollen joint count. Methotrexate treatment led to normalization of CD4+CD161+ T-cells and reduced disease activity. CD4+CD161+ T cells were readily detected in synovial tissues from both early and late-stage rheumatoid arthritis. In addition, synovial fluid from late-stage disease was found to be enriched for CD4+CD161+ T-cells. Notably, synovial fluid accumulated CD4+CD161+T-cells showed skewing towards the Th1 phenotype as evidenced by increased interferon-γ expression. The changes in peripheral numbers of CD4+CD161+ T-cells in seropositive arthralgia and early rheumatoid arthritis and the enrichment of these cells at the level of the joint predict a role for CD4+CD161+ T-cells in the early immune events leading to clinical synovitis. Our findings may add to the development of RA prediction models and provide opportunities for early intervention. 相似文献
8.
Raza K Scheel-Toellner D Lee CY Pilling D Curnow SJ Falciani F Trevino V Kumar K Assi LK Lord JM Gordon C Buckley CD Salmon M 《Arthritis research & therapy》2006,8(4):R120-7
Synovial leukocyte apoptosis is inhibited in established rheumatoid arthritis (RA). In contrast, high levels of leukocyte apoptosis are seen in self-limiting crystal arthritis. The phase in the development of RA at which the inhibition of leukocyte apoptosis is first apparent, and the relationship between leukocyte apoptosis in early RA and other early arthritides, has not been defined. We measured synovial fluid leukocyte apoptosis in very early arthritis and related this to clinical outcome. Synovial fluid was obtained at presentation from 81 patients with synovitis of < or = 3 months duration. The percentages of apoptotic neutrophils and lymphocytes were assessed on cytospin preparations. Patients were assigned to diagnostic groups after 18 months follow-up. The relationship between leukocyte apoptosis and patient outcome was assessed. Patients with early RA had significantly lower levels of neutrophil apoptosis than patients who developed non-RA persistent arthritis and those with a resolving disease course. Similarly, lymphocyte apoptosis was absent in patients with early RA whereas it was seen in patients with other early arthritides. The inhibition of synovial fluid leukocyte apoptosis in the earliest clinically apparent phase of RA distinguishes this from other early arthritides. The mechanisms for this inhibition may relate to the high levels of anti-apoptotic cytokines found in the early rheumatoid joint (e.g. IL-2, IL-4, IL-15 GMCSF, GCSF). It is likely that this process contributes to an accumulation of leukocytes in the early rheumatoid lesion and is involved in the development of the microenvironment required for persistent RA. 相似文献
9.
Bramlage CP Häupl T Kaps C Ungethüm U Krenn V Pruss A Müller GA Strutz F Burmester GR 《Arthritis research & therapy》2006,8(3):R58-10
Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the
development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in
synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis
(OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression
of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation,
by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1β, TNF-α, stromelysin and collagenase I in synovial
tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA
in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed
tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less
pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial
tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed
in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact
of these factors on homeostasis and remodeling in joint physiology and pathology. 相似文献
10.
为了寻找类风湿关节炎(rheumatoid arthritis,RA)新的特异性表达标记物,应用基因芯片对RA、骨关节炎(osteoarthritis,OA)和强直性脊柱炎(ankylosing spondylitis,AS)患者关节滑膜组织的基因表达谱进行比较,并采用实时定量PCR方法对芯片结果进行验证. 全基因组表达芯片的结果显示,与OA滑膜组织及AS滑膜组织相比,在RA患者的滑膜组织中,CD38,ANKRD38,E2F2,CFDP1, CD7, ISG20 和IL2RG基因表达异常|实时定量PCR结果证实,RA患者滑膜组织中,CD38、E2F2和IL2RG基因表达明显增高. 相似文献
11.
Stefan Vordenb?umen Christoph Schleich Tim L?gters Philipp Sewerin Ellen Bleck Thomas Pauly Anja Müller-Lutz Gerald Antoch Matthias Schneider Falk Miese Benedikt Ostendorf 《Arthritis research & therapy》2014,16(5)
Introduction
Synovial inflammation and joint destruction in rheumatoid arthritis (RA) may progress despite clinical remission. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly used to detect synovial inflammation in RA. Although small joints such as metacarpophalangeal (MCP) joints are mainly affected by RA, MRI findings have never been directly compared to histological synovitis in MCP synovial tissue. The objective of the current study was therefore to analyse if DCE-MRI relates to histological signs of synovitis small RA joints.Methods
In 9 RA patients, DCE-MRI (3 Tesla, dynamic 2D T1 weighted turbo-flash sequence) of the hand was performed prior to arthroscopically-guided synovial biopsies from the second MCP of the imaged hand. Maximum enhancement (ME), rate of early enhancement, and maximum rate of enhancement were assessed in the MCP. Synovial biopsies were stained for determination of sublining CD68 and the Synovitis Score. Correlations between MRI and histological data were calculated according to Spearman.Results
ME of the MCP significantly correlated to sublining CD68 staining (r = 0.750, P = 0.02), the Synovitis Score (r = 0.743, P = 0.02), and the subscores for lining layer hypertrophy (r = 0.789, P = 0.01) and cellular density (r = 0.842; P = 0.004).Conclusions
Perfusion imaging of synovial tissue in RA finger joints employing DCE-MRI reflects histological synovial inflammation. According to our study, ME is the most closely associated parameter amongst the measures considered. 相似文献12.
Carmen A Ambarus Troy Noordenbos Maria JH de Hair Paul P Tak Dominique LP Baeten 《Arthritis research & therapy》2012,14(2):R74-14
Introduction
Synovial tissue macrophages play a key role in chronic inflammatory arthritis, but the contribution of different macrophage subsets in this process remains largely unknown. The main in vitro polarized macrophage subsets are classically (M1) and alternatively (M2) activated macrophages, the latter comprising interleukin (IL)-4 and IL-10 polarized cells. Here, we aimed to evaluate the polarization status of synovial macrophages in spondyloarthritis (SpA) and rheumatoid arthritis (RA).Methods
Expression of polarization markers on synovial macrophages, peripheral blood monocytes, and in vitro polarized monocyte-derived macrophages from SpA versus RA patients was assessed by immunohistochemistry and flow cytometry, respectively. The polarization status of the intimal lining layer and the synovial sublining macrophages was assessed by double immunofluorescence staining.Results
The expression of the IL-10 polarization marker cluster of differentiation 163 (CD163) was increased in SpA compared with RA intimal lining layer, but no differences were found in other M1 and M2 markers between the diseases. Furthermore, no significant phenotypic differences in monocytes and in vitro polarized monocyte-derived macrophages were seen between SpA, RA, and healthy controls, indicating that the differential CD163 expression does not reflect a preferential M2 polarization in SpA. More detailed analysis of intimal lining layer macrophages revealed a strong co-expression of the IL-10 polarization markers CD163 and cluster of differentiation 32 (CD32) but not any of the other markers in both SpA and RA. In contrast, synovial sublining macrophages had a more heterogeneous phenotype, with a majority of cells co-expressing M1 and M2 markers.Conclusions
The intimal lining layer but not synovial sublining macrophages display an IL-10 polarized-like phenotype, with increased CD163 expression in SpA versus RA synovitis. These differences in the distribution of the polarized macrophage subset may contribute to the outcome of chronic synovitis. 相似文献13.
Nanwei Xu Yuji Wang Dawei Li Rongbin Sun Sai Sun Guang Yang 《Biochemical and biophysical research communications》2010,401(3):417-421
Rheumatoid arthritis (RA) is a chronic autoimmune disease with features of inflammatory cell infiltration, synovial cell invasive proliferation, and ultimately, irreversible joint destruction. It has been reported that the p53 pathway is involved in RA pathogenesis. MDM4/MDMX is a major negative regulator of p53. To determine whether MDM4 contributes to RA pathogenesis, MDM4 mRNA and protein expression were assessed in fibroblast-like synoviocytes (FLS) by real-time PCR, western blotting, and in synovial tissues by immunohistochemistry. Furthermore, MDM4 was knocked down and overexpressed by lentivirus-mediated expression, and the proliferative capacity of FLS was determined by MTS assay. We found that cultured FLS from RA and osteoarthritis (OA) patients exhibited higher levels of MDM4 mRNA and protein expression than those from trauma controls. MDM4 protein was highly expressed in the synovial lining and sublining cells from both types of arthritis. Finally, MDM4 knockdown inhibited the proliferation of RA FLS by enhancing functional p53 levels while MDM4 overexpression promoted the growth of RA FLS by inhibiting p53 effects. Taken together, our results suggest that the abundant expression of MDM4 in FLS may contribute to the hyperplasia phenotype of RA synovial tissues. 相似文献
14.
J Itoh K Kinjoh A Ohyama M Nose M Kyogoku 《The journal of histochemistry and cytochemistry》1992,40(11):1675-1683
We studied the localization of T-cells and HLA-DR antigen-bearing (DR+) cells in rheumatoid synovitis by employing an improved two-color immunofluorescent staining (TCIF) technique. With this technique we have successfully identified DR+ activated T-cells in the inflammatory synovium. T-cells expressed HLA-DR antigen when they were in contact with DR+ antigen-presenting cells (APC). In addition, activated T-cells showed characteristic distribution within the synovium: they were found around high endothelial venules, within lymphoid follicles, and in hyperplastic synovial lining, suggesting their involvement in the development of rheumatoid synovial lesions via interaction with synovial DR+ APC lineage cells. These findings may contribute to better understanding of the role of activated T-cells in the histogenesis of rheumatoid synovitis, a typical chronic inflammatory lesion. 相似文献
15.
Kruithof E Baeten D De Rycke L Vandooren B Foell D Roth J Cañete JD Boots AM Veys EM De Keyser F 《Arthritis research & therapy》2005,7(3):R569-R580
At present only few biological data are available to indicate whether psoriatic arthritis (PsA) is part of the spondyloarthropathy
(SpA) concept, whether it is a separate disease entity or a heterogeneous disease group with oligoarticular/axial forms belonging
to SpA and polyarticular forms resembling rheumatoid arthritis (RA). To address this issue with regard to peripheral synovitis,
we compared the synovial characteristics of PsA with those of ankylosing spondylitis (AS)/undifferentiated SpA (USpA) and
RA, and compared the synovium of oligoarticular versus polyarticular PsA. Synovial biopsies were obtained from patients with
RA, nonpsoriatic SpA (AS + USpA), and oligoarticular and polyarticular PsA. The histological analysis included examination(s)
of the lining layer thickness, vascularity, cellular infiltration, lymphoid aggregates, plasma cells and neutrophils. Also,
we performed immunohistochemical assessments of CD3, CD4, CD8, CD20, CD38, CD138, CD68, CD163, CD83, CD1a, CD146, αVβ3, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, S100A12, intracellular citrullinated proteins
and major histocompatibility complex (MHC)–human cartilage (HC) gp39 peptide complexes. Comparing SpA (PsA + AS + USpA) with
RA, vascularity, and neutrophil and CD163+ macrophage counts were greater in SpA (P < 0.05), whereas lining layer thickness and the number of CD83+ dendritic cells were greater in RA (P < 0.05). In RA, 44% of samples exhibited positive staining for intracellular citrullinated proteins and 46% for MHC–HC gp39
peptide complexes, whereas no staining for these markers was observed in SpA samples. We excluded influences of disease-modifying
antirheumatic drug and/or corticosteroid treatment by conducting systematic analyses of treated and untreated subgroups. Focusing
on PsA, no significant differences were observed between PsA and nonpsoriatic SpA. In contrast, vascularity (P < 0.001) and neutrophils were increased in PsA as compared with RA (P = 0.010), whereas staining for intracellular citrullinated proteins and MHC–HC gp39 peptide complexes was exclusively observed
in RA (both P = 0.001), indicating that the same discriminating features are found in PsA and other SpA subtypes compared with RA. Exploring
synovial histopathology between oligoarticular and polyarticular PsA, no significant differences were noted. Moreover, intracellular
citrullinated proteins and MHC–HC gp39 peptide complexes, which are specific markers for RA, were observed in neither oligoarticular
nor polyarticular PsA. Taken together, these data indicate that the synovial histopathology of PsA, either oligoarticular
or polyarticular, resembles that of other SpA subtypes, whereas both groups can be differentiated from RA on the basis of
these same synovial features, suggesting that peripheral synovitis in PsA belongs to the SpA concept. 相似文献
16.
Helmchen B Weckauf H Ehemann V Wittmann I Meyer-Scholten C Berger I 《Histology and histopathology》2005,20(2):365-372
OBJECTIVE: To investigate the expression pattern of cell cycle related gene products in active and quiescent Rheumatoid arthritis (RA). METHODS: Synovial tissue from 20 patients with active proliferative RA and 28 patients with RA in remission was immunohistochemically examined for expression of p53, p63, p21, p27, p16, cyclin D1, CDK4, RB, E2F, Ki-67 on tissue microarrays and by DNA flow cytometry for cell cycle phases. RESULTS: Elevated expression of p53 and p27 was found in synovial lining and in stromal cells in proliferative active RA. In the remission stage this finding was confined to the synovial lining. Most of the cells were in the G0-phase. Ki-67 proliferation index was maximum 10% in synovial cells. CONCLUSION: The p53 pathway is activated in synovial cells in active RA as well as in quiescent stage of disease. Differences in the spatial expression pattern of proteins involved in the p53 pathway in RA in remission compared to actively proliferating RA reflect the phasic nature of the disease and support in our opinion the concept of adaptive role of p53 pathway in RA. 相似文献
17.
Peter Fritz Anette Mischlinski Cornelia Wicherek Johannes Saal 《The Histochemical journal》1994,26(10):804-816
Summary A two-dimensional electrophoresis technique for analysing sections of human tissue is described. Cryostat sections, 10 μm
thick, are placed on an isoelectric focusing gel and then transfered to an SDS gel in the second dimension. The protein pattern
is visualized by silver staining and is thought to represent soluble proteins. The silver-stained proteins were found to be
both reproducible and, to the extent tested, organ-specific. This method was used to analyse 43 synovial membranes from patients
suffering from rheumatoid arthritis or degenerative joint diseases. The analysis did not reveal any specific protein pattern
for rheumatoid arthritis. The protein spot number was not related to the cause of arthritis. However, the total protein spot
number was related to the histomorphological synovitis type, with those exhibiting either an exudative or proliferative synovitis
pattern possessing significantly higher protein spot numbers than those specimens exhibiting a sero-fibrous or lympho-plasmacytic
pattern of synovitis. 相似文献
18.
Involvement of PDCD5 in the regulation of apoptosis in fibroblast-like synoviocytes of rheumatoid arthritis 总被引:1,自引:0,他引:1
Wang N Lu HS Guan ZP Sun TZ Chen YY Ruan GR Chen ZK Jiang J Bai CJ 《Apoptosis : an international journal on programmed cell death》2007,12(8):1433-1441
Apoptosis is reduced in the synovial tissue of patients with rheumatoid arthritis (RA), possibly due to decreased expression
of pro-apoptotic genes. Programmed Cell Death 5 (PDCD5) has been recently identified as a protein that mediates apoptosis.
Although PDCD5 is down-regulated in many human tumors, the role of PDCD5 in RA has not been investigated. Here we report that
reduced levels of PDCD5 mRNA and protein are detected in RA synovial tissue (ST) and fibroblast-like synoviocytes (FLS) than
in tissue and cells from patients with osteoarthritis (OA). We also report differences in the PDCD5 expression pattern in
tissues from patients with these two types of arthritis. PDCD5 showed a scattered pattern in rheumatoid synovium compared
with OA, in which the protein labeling was stronger in the synovial lining layer than in the sublining. We also observed increased
expression and nuclear translocation of PDCD5 in RA patient-derived FLS undergoing apoptosis. Finally, overexpression of PDCD5
led to enhanced apoptosis and activation of caspase-3 in triptolide-treated FLS. We propose that PDCD5 may be involved in
the pathogenesis of RA. These data also suggest that PDCD5 may serve as a therapeutic target to enhance sensitivity to antirheumatic
drug-induced apoptosis in RA. 相似文献
19.
Ichikawa K Liu W Fleck M Zhang H Zhao L Ohtsuka T Wang Z Liu D Mountz JD Ohtsuki M Koopman WJ Kimberly R Zhou T 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(2):1061-1069
TRAIL has been proposed as an anti-inflammatory cytokine in animal models of rheumatoid arthritis (RA). Using two agonistic mAbs specific for TRAIL-R1 (DR4) and TRAIL-R2 (DR5), we examined the expression and function of these death receptors in RA synovial fibroblast cells. The synovial tissues and primary synovial fibroblast cells isolated from patients with RA, but not those isolated from patients with osteoarthritis, selectively expressed high levels of cell surface DR5 and were highly susceptible to anti-DR5 Ab (TRA-8)-mediated apoptosis. In contrast, RA synoviocytes did not show increased expression of TRAIL-R1 (DR4), nor was there any difference in expression of Fas between RA and osteoarthritis synovial cells. In vitro TRA-8 induced apoptosis of RA synovial cells and inhibited production of matrix metalloproteinases induced by pro-inflammatory cytokines. In vivo TRA-8 effectively inhibited hypercellularity of a SV40-transformed RA synovial cell line and completely prevented bone erosion and cartilage destruction induced by these cells. These results indicate that increased DR5 expression and susceptibility to DR5-mediated apoptosis are characteristic of the proliferating synovial cells in RA. As highly proliferative transformed-appearing RA synovial cells play a crucial role in bone erosion and cartilage destruction in RA, the specific targeting of DR5 on RA synovial cells with an agonistic anti-DR5 Ab may be a potential therapy for RA. 相似文献
20.
Surgical synovectomy to remove the inflammatory synovium can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction. An efficient medically induced programmed cell death (apoptosis) in the rheumatoid synovium might play a role similar to synovectomy but without surgical tissue damage. Gene transfer of Fas ligand (FasL) has increased the frequency of apoptotic cells in mouse and rabbit arthritic synovium. In this study, we investigated whether repeated FasL gene transfer could remove human inflammatory synovial tissue in situ and function as a molecular synovectomy. Briefly, specimens of human synovium from joint replacement surgeries and synovectomies of rheumatoid arthritis (RA) patients were grafted subcutaneously into male C.B-17 severe combined immunodeficiency (SCID) mice. Injections of a recombinant FasL adenovirus (Ad-FasL) into the grafted synovial tissue at the dosage of 10(11) particles per mouse were performed every two weeks. Three days after the fifth virus injection, the mice were euthanized by CO2 inhalation and the human synovial tissues were collected, weighed and further examined. Compared to the control adenovirus-LacZ (Ad-LacZ) and phosphate buffered saline (PBS) injected RA synovium, the Ad-FasL injected RA synovium was dramatically reduced in size and weight (P < 0.005). The number of both synoviocytes & mononuclear cells was significantly reduced. Interestingly, an approximate 15-fold increased frequency of apoptotic cells was observed in RA synovium three days after Ad-FasL injection, compared with control tissues. In summary, our in vivo investigation of gene transfer to human synovium in SCID mice suggests that repeated intra-articular gene transfer of an apoptosis inducer, such as FasL, may function as a 'gene scalpel' for molecular synovectomy to arrest inflammatory synovium at an early stage of RA. 相似文献