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1.
Schmutz C Hulme A Burman A Salmon M Ashton B Buckley C Middleton J 《Arthritis research & therapy》2005,7(2):R217-R229
In patients with rheumatoid arthritis (RA), chemokine and chemokine receptor interactions play a central role in the recruitment
of leukocytes into inflamed joints. This study was undertaken to characterize the expression of chemokine receptors in the
synovial tissue of RA and non-RA patients. RA synovia (n = 8) were obtained from knee joint replacement operations and control non-RA synovia (n = 9) were obtained from arthroscopic knee biopsies sampled from patients with recent meniscal or articular cartilage damage
or degeneration. The mRNA expression of chemokine receptors and their ligands was determined using gene microarrays and PCR.
The protein expression of these genes was demonstrated by single-label and double-label immunohistochemistry. Microarray analysis
showed the mRNA for CXCR5 to be more abundant in RA than non-RA synovial tissue, and of the chemokine receptors studied CXCR5 showed the greatest upregulation.
PCR experiments confirmed the differential expression of CXCR5. By immunohistochemistry we were able to detect CXCR5 in all RA and non-RA samples. In the RA samples the presence of CXCR5
was observed on B cells and T cells in the infiltrates but also on macrophages and endothelial cells. In the non-RA samples
the presence of CXCR5 was limited to macrophages and endothelial cells. CXCR5 expression in synovial fluid macrophages and peripheral blood monocytes from RA patients was confirmed by PCR. The present
study shows that CXCR5 is upregulated in RA synovial tissue and is expressed in a variety of cell types. This receptor may
be involved in the recruitment and positioning of B cells, T cells and monocytes/macrophages in the RA synovium. More importantly,
the increased level of CXCR5, a homeostatic chemokine receptor, in the RA synovium suggests that non-inflammatory receptor–ligand
pairs might play an important role in the pathogenesis of RA. 相似文献
2.
De Klerck B Geboes L Hatse S Kelchtermans H Meyvis Y Vermeire K Bridger G Billiau A Schols D Matthys P 《Arthritis research & therapy》2005,7(6):R1208-R1220
CXCL12 (stromal cell-derived factor 1) is a unique biological ligand for the chemokine receptor CXCR4. We previously reported
that treatment with a specific CXCR4 antagonist, AMD3100, exerts a beneficial effect on the development of collagen-induced
arthritis (CIA) in the highly susceptible IFN-γ receptor-deficient (IFN-γR KO) mouse. We concluded that CXCL12 plays a central
role in the pathogenesis of CIA in IFN-γR KO mice by promoting delayed type hypersensitivity against the auto-antigen and
by interfering with chemotaxis of CXCR4+ cells to the inflamed joints. Here, we investigated whether AMD3100 can likewise inhibit CIA in wild-type mice and analysed
the underlying mechanism. Parenteral treatment with the drug at the time of onset of arthritis reduced disease incidence and
modestly inhibited severity in affected mice. This beneficial effect was associated with reduced serum concentrations of IL-6.
AMD3100 did not affect anti-collagen type II antibodies and, in contrast with its action in IFN-γR KO mice, did not inhibit
the delayed type hypersensitivity response against collagen type II, suggesting that the beneficial effect cannot be explained
by inhibition of humoral or cellular autoimmune responses. AMD3100 inhibited the in vitro chemotactic effect of CXCL12 on splenocytes, as well as in vivo leukocyte infiltration in CXCL12-containing subcutaneous air pouches. We also demonstrate that, in addition to its effect
on cell infiltration, CXCL12 potentiates receptor activator of NF-κB ligand-induced osteoclast differentiation from splenocytes
and increases the calcium phosphate-resorbing capacity of these osteoclasts, both processes being potently counteracted by
AMD3100. Our observations indicate that CXCL12 acts as a pro-inflammatory factor in the pathogenesis of autoimmune arthritis
by attracting inflammatory cells to joints and by stimulating the differentiation and activation of osteoclasts. 相似文献
3.
Collagen-induced arthritis (CIA) is a widely used model of human rheumatoid arthritis (RA) characterized by chronic inflammation of the synovial joints. The pathogenesis of RA and CIA has not been completely defined, but both involve the recruitment of leukocytes and lymphocytes to the joints and Th1-type cell mediated autoimmune responses. The C-C chemokine receptor 5 (CCR5) is preferentially expressed on Th1 cells and has been strongly implicated in inflammatory process through trafficking of leukocytes and lymphocytes into the sites of inflammation. We investigated the role of the CCR5 in CIA using CCR5 knockout mice (CCR5-/-) in which we analyzed the consequences of CCR5 deficiency for the immune response and inflammation. We found that CCR5-/- mice showed a significant reduction in the incidence of CIA after collagen II (CII)-immunization as compared to wild-type (CCR5+/+) mice. The reduced incidence seen in CCR5-/- mice was associated with these animals having significantly lower IgG levels, especially IgG2a and IgG2b antibodies against CII, as well as an obviously augmented IL-10 production in splenocytes. Overproduction of MIP-1beta in CCR5-deficient mice after CII-immunization may contribute partially to the occurrence of arthritis. 相似文献
4.
Background
Human T-cell leukemia virus type I (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATL) as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A transgenic mouse that expresses HTLV-1 Tax also develops T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. The aim of this study was to identify the primary T-cell subsets involved in the development of arthropathy in Tax transgenic mice.Principal Findings
By 24 months of age, Tax transgenic mice developed severe arthropathy with a cumulative incidence of 22.8%. The pathological findings of arthropathy in Tax transgenic mice were similar to those seen in human rheumatoid arthritis or mouse models of rheumatoid arthritis, with synovial proliferation and a positive rheumatoid factor. Before the onset of spontaneous arthropathy, young and old Tax transgenic mice were not sensitive to collagen and did not develop arthritis after immunization with type II collagen. The arthropathic Tax transgenic mice showed a significantly decreased proportion of splenic CD4+ T cells, whereas the proportion of splenic CD8+ T cells was increased. Regulatory T cells (CD4+CD25+Foxp3+) were significantly decreased and CD8+ T cells that expressed the chemokine receptor CCR4 (CD8+CCR4+) were significantly increased in arthropathic Tax transgenic mice. The expression of tax mRNA was strong in the spleen and joints of arthropathic mice, with a 40-fold increase compared with healthy transgenic mice.Conclusions
Our findings reveal that Tax transgenic mice develop rheumatoid-like arthritis with proliferating synovial cells in the joints; however, the proportion of different splenic T-cell subsets in these mice was completely different from other commonly used animal models of rheumatoid arthritis. The crucial T-cell subsets in arthropathic Tax transgenic mice appear to resemble those in HAM/TSP patients rather than those in rheumatoid arthritis patients. 相似文献5.
Hamer ER Apfel MI Carvalho JJ Pereira MJ Levy RA 《Journal of cellular and molecular medicine》2002,6(3):407-414
In order to verify the cholesterol influence in RA severity in DBA/1J mice, we quantified the cholesterol present in the knee joints of normal (N) and with collagen II induced arthritis (CIA). Forty male DBA/1J mice, were divided in normal (n=20) and CIA group (n=20). Mice in CIA group were injected with 100 μg of collagen II emulsified in Freund's complete adjuvant. Sixteen DBA/1J (8 N and 8 CIA) received an injection of 2.96 × 106 Bq of 3H-cholesterol and were anesthetized and sacrificed. Semi-fine sections were covered with LM-1 emulsion, exposed for six weeks and developed. Collagen induced edema, erythema and dysfunction of knee joints in CIA group. Radioactive cholesterol was located more on the synovial membrane, where we found the greatest density of silver grains, significantly ( P <0.0001) higher in group CIA vs. controls (61±2.3 × 18±0.7). We conclude that the cholesterol deposits on the synovial membrane is related to CIA severity. 相似文献
6.
Apigenin,a potent suppressor of dendritic cell maturation and migration,protects against collagen‐induced arthritis
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Qingyou Zhou Hongyu Jie Yi He Jiaochan Han Juan He Yong Jiang Erwei Sun 《Journal of cellular and molecular medicine》2016,20(1):170-180
This study aimed to investigate whether apigenin (API) suppresses arthritis development through the modulation of dendritic cell functions. Bone marrow‐derived dendritic cells (BMDCs) were stimulated in vitro with lipopolysaccharide (LPS) and treated with API for 24 hrs; DC functions, including phenotype expressions, cytokine secretion, phagocytosis and chemotaxis, were then investigated. The effects of API on collagen‐induced arthritis (CIA) were examined in vivo, and purified DCs from the lymph nodes (LNs) of API‐treated CIA mice were analysed for phenotypes and subsets. In in vitro, API efficiently restrained the phenotypic and functional maturation of LPS‐stimulated BMDCs while maintaining phagocytotic capabilities. Moreover, API inhibited the chemotactic responses of LPS‐stimulated BMDCs, which may be related to the depressive effect on chemokine receptor 4 (CXCR4). In in vivo, API treatment delayed the onset and reduced the severity of arthritis in CIA mice, and diminished secretion of pro‐inflammatory cytokines in the serum and supernatants from the LN cells of the CIA mice. Similar to the in vitro findings, the API‐treated mice exhibited reduced expression of co‐stimulatory molecules and major histocompatibility complex II on DCs. Furthermore, API treatment strongly down‐regulated the number of Langerhans cells, but not plasmacytoid DCs (pDCs) in LNs, which may be related to the depressive effect of API on the expression of CXCR4 on DCs of peripheral blood. These data provide new insight into the mechanism of action of API on arthritis and indicate that the inhibition of maturation and migration of DCs by API may contribute to its immunosuppressive effects. 相似文献
7.
Kyoko Wakamatsu Toshihiro Nanki Nobuyuki Miyasaka Kazuo Umezawa Tetsuo Kubota 《Arthritis research & therapy》2005,7(6):R1348
A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation
of IκB (inhibitor of nuclear factor-κB [NF-κB]) but selectively inhibits nuclear translocation of activated NF-κB. This study
aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-κB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated
with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with
rheumatoid arthritis (RA), NF-κB activity was examined by electrophoretic mobility shift assays. The expression of molecules
involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was
estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis
exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic
and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis
factor-α, activities of NF-κB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key
inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and
vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration
of an inhibitor of NF-κB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression
of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect. 相似文献
8.
Masako Kono Morimasa Yoshioka Miki Imai Shunichi Hirose 《Microbiology and immunology》1985,29(7):645-657
Mycoplasma pulmonis m53 was inoculated intraarticularly in the bilateral hind footpads and bilateral knee joints of BALB/c mice. Mycoplasmas were recovered from the affected joints over 20 weeks accompanying acute or subacute inflammation. Intensive deposition of immunoglobulins, a complement (C3) and mycoplasma cell antigens occurred in synovial and adjacent connective tissues. The histopathologically intact kidneys, brain, and lungs showed deposition of IgG and the complement on the endothelial cells of blood vessels. An IgG-rheumatoid factor like substance (RFLS) was detected in the serum of the mice by an enzyme-linked immunoabsorbent assay. Persistence of mycoplasma cells and immune complexes in the articular tissues might cause the prolongation of inflammatory responses in murine mycoplasmal arthritis. 相似文献
9.
Joint cartilage is attacked in both autoimmune inflammatory and osteoarthritic processes. Type IX collagen (CIX) is a protein
of importance for cartilage integrity and stability. In this study we have backcrossed a transgenic disruption of the col9a1 gene, which leads to an absence of CIX, into two different inbred mouse strains, DBA/1 and B10.Q. None of the CIX-deficient
mice developed observable clinical or microscopic osteoarthritis, but DBA/1 male mice had more pronounced enthesopathic arthritis,
the so-called stress-induced arthritis. Both DBA/1 and B10.Q strains are susceptible to the induction of collagen-induced
arthritis, and CIX deficiency in both strains led to the development of a more severe arthritis than in the controls. Induction
of arthritis with monoclonal antibodies against type II collagen (CII) led to an earlier arthritis in the paws that also involved
the knee joints. The antibodies used, which were specific for the J1 and the C1I epitopes of CII, initiate their arthritogenic attack by binding to cartilage. The C1I-specific antibodies bound to cartilage better in CIX-deficient mice than in wild-type animals, demonstrating that the lack
of CIX in cartilage leads to an increased accessibility of structures for antibody binding and thus making the joints more
vulnerable to inflammatory attack. These findings accentuate the importance of cartilage stability; cartilage disrupted as
a result of genetic disorders could be more accessible and vulnerable to an autoimmune attack by pathogenic antibodies. 相似文献
10.
Tu-Rapp H Hammermüller A Mix E Kreutzer HJ Goerlich R Köhler H Nizze H Thiesen HJ Ibrahim SM 《Arthritis research & therapy》2004,6(5):R404-R414
Collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis, e.g.
polyarthritis, synovitis, and subsequent cartilage/bone erosions. One feature of the disease contributing to joint damage
is synovial hyperplasia. The factors responsible for the hyperplasia are unknown; however, an imbalance between rates of cell
proliferation and cell death (apoptosis) has been suggested. To evaluate the role of a major pathway of cell death – Fas (CD95)/FasL
– in the pathogenesis of CIA, DBA/1J mice with a mutation of the Fas gene (lpr) were generated. The susceptibility of the mutant DBA-lpr/lpr mice to arthritis induced by collagen type II was evaluated.
Contrary to expectations, the DBA-lpr/lpr mice developed significantly milder disease than the control littermates. The incidence
of disease was also significantly lower in the lpr/lpr mice than in the controls (40% versus 81%; P < 0.05). However DBA-lpr/lpr mice mounted a robust immune response to collagen, and the expression of local proinflammatory
cytokines such as, e.g., tumor necrosis factor α (TNF-α) and IL-6 were increased at the onset of disease. Since the contribution
of synovial fibroblasts to inflammation and joint destruction is crucial, the potential activating effect of Fas on mouse
fibroblast cell line NIH3T3 was investigated. On treatment with anti-Fas in vitro, the cell death of NIH3T3 fibroblasts was reduced and the expression of proinflammatory cytokines TNF-α and IL-6 was increased.
These findings suggest that impairment of immune tolerance by increased T-cell reactivity does not lead to enhanced susceptibility
to CIA and point to a role of Fas in joint destruction. 相似文献
11.
Xiangli Li Blair U Bradford Frederick Dalldorf Sanna M Goyert Stephen A Stimpson Ronald G Thurman Sergei S Makarov 《Arthritis research & therapy》2004,6(3):R273
Bacterial infections play an important role in the multifactorial etiology of rheumatoid arthritis. The arthropathic properties
of Gram-positive bacteria have been associated with peptidoglycan–polysaccharide complexes (PG-PS), which are major structural
components of bacterial cell walls. There is little agreement as to the identity of cellular receptors that mediate innate
immune responses to PG-PS. A glycosylphosphatidylinositol-linked cell surface protein, CD14, the lipopolysaccharide receptor,
has been proposed as a PG-PS receptor, but contradictory data have been reported. Here, we examined the inflammatory and pathogenic
responses to PG-PS in CD14 knockout mice in order to examine the role for CD14 in PG-PS-induced signaling. We found that PG-PS-induced
responses in vitro, including transient increase in intracellular calcium, activation of nuclear factor-κB, and secretion of the cytokines tumor
necrosis factor-α and interleukin-6, were all strongly inhibited in CD14 knockout macrophages. In vivo, the incidence and severity of PG-PS induced acute polyarthritis were significantly reduced in CD14 knockout mice as compared
with their wild-type counterparts. Consistent with these findings, CD14 knockout mice had significantly inhibited inflammatory
cell infiltration and synovial hyperplasia, and reduced expression of inflammatory cytokines in PG-PS arthritic joints. These
results support an essential role for CD14 in the innate immune responses to PG-PS and indicate an important role for CD14
in PG-PS induced arthropathy. 相似文献
12.
Szántó S Gál I Gonda A Glant TT Mikecz K 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(11):6723-6734
L (leukocyte)-selectin (CD62L) and CD44 are major adhesion receptors that support the rolling of leukocytes on endothelium, the first step of leukocyte entry into inflamed tissue. The specific contribution of L-selectin or CD44 to the regulation of cell traffic to joints in arthritis has not been investigated. We used CD44-deficient, L-selectin-deficient, and CD44/L-selectin double knockout mice to determine the requirement for these receptors for inflammatory cell recruitment during Ag-induced arthritis. Intraperitoneal immunization resulted in similar activation status and Ag-specific responses in wild-type and gene-targeted mice. However, extravasation of neutrophil granulocytes, but not the emigration of T cells, into the knee joints after intra-articular Ag injection was significantly delayed in L-selectin-deficient and double knockout mice. Intravital videomicroscopy on the synovial microcirculation revealed enhanced leukocyte rolling and diminished adherence in mice lacking either CD44 or L-selectin, but CD44 deficiency had no significant effect on the recruitment of L-selectin-null cells. Compared with wild-type leukocytes, expression of L-selectin was down-regulated in CD44-deficient cells in the spleen, peripheral blood, and inflamed joints, suggesting that reduced expression of L-selectin, rather than the lack of CD44, could be responsible for the delayed influx of granulocytes into the joints of CD44-deficient mice. In conclusion, there is a greater requirement for L-selectin than for CD44 for neutrophil extravasation during the early phase of Ag-induced arthritis. 相似文献
13.
Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1beta and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation. 相似文献
14.
15.
THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent anti-diabetic properties.
Because of the proposed role of PPARγ in inflammation, we investigated the potential of orally active THR0921 to inhibit the
pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen
in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster
injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores
of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of
isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover,
spleen cell production of IFN-γ, tumor necrosis factor (TNF)-α and IL-1β in response to exposure to lipopolysaccharide or
type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-α, IL-1β, monocyte chemotactic protein-1 and receptor activator of
nuclear factor κB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited
osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In
conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARγ may be an
important therapeutic target for rheumatoid arthritis. 相似文献
16.
In this study we investigated mechanisms involved in the chronic character of experimental collagen type II induced arthritis (CIA). We compared the knee joints of mouse strains which are prone to develop this autoimmune disease (DBA/1,B10RIII) with other nonsusceptible mouse strains (C57Bl/6,BALB/c) in their reaction to different stimuli: immune complexes (IC), zymosan and streptococcal cell walls (SCW). Inflammation was evaluated by(99m)Tc uptake measurements and in haematoxylin- and eosin-stained knee-joint sections. Passively induced immune complex mediated arthritis (ICA) in knee joints of C57Bl/6 and BALB/c mice, showed moderate cell influx at day 3, whereas at day 7 only minor amounts of inflammatory cells were observed. In contrast, in arthritic DBA/1 and, to a lesser extent, in B10.RIII joints, a tremendous cell influx was observed at day 3 and even at day 14 there was still significant synovitis. In contrast, if arthritis was elicited by intra-articular injection of zymosan or SCW in C57Bl/6 and DBA/1, the course of inflammation was similar in both strains and no chronic inflammation developed. In line with severe arthritis, chemotactic factor production was dramatically enhanced in ICA in DBA/1 mice, and a prolonged production of IL-1 was evident. When IL-1 was neutralized before or during the ICA using specific anti-IL-1alpha,beta antibodies, inflammation could be blocked completely. Single or multiple injection of IL-1 in the knee joint of C57Bl/6 or DBA/1 showed comparable inflammation, indicating that the chemotactic response per se is comparable in both strains. No prolonged production of IL-1 was found during zymosan or SCW arthritis. Selective removal of macrophages from the synovial intima prior to ICA induction (using clodronate-containing liposomes) prevented the onset of inflammation in C57Bl/6 and DBA/1 mice. It can be concluded that immune complexes, but not zymosan or SCW, cause a more severe and chronic arthritis in mouse strains which are susceptible for collagen type II autoimmune arthritis. This is due to higher and prolonged expression of IL-1 and chemotactic factors, caused by stimulation with immune complexes. The interaction of IC with lining macrophages probably plays a dominant role in development of chronicity. 相似文献
17.
18.
Oncostatin M is a pro-inflammatory cytokine previously shown to promote marked cartilage destruction both in vitro and in vivo when in combination with IL-1 or tumour necrosis factor alpha. However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown. Using adenoviral gene transfer, we have overexpressed
oncostatin M in combination with either IL-1 or tumour necrosis factor alpha intra-articularly in the knees of C57BL/6 mice.
Both of these combinations induced marked bone damage and markedly increased tartrate-resistant acid phosphatase-positive
multinucleate cell staining in the synovium and at the front of bone erosions. Furthermore, there was increased expression
of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated
with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control. This model
of inflammatory arthritis demonstrates that, in vivo, oncostatin M in combination with either IL-1 or tumour necrosis factor alpha represents cytokine combinations that promote
bone destruction. The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive
staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction. 相似文献
19.
Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1β and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation. 相似文献
20.
AimSulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti-inflammatory effect of sulfuretin on rheumatoid arthritis have not been elucidated. In this study we investigated whether sulfuretin treatment modulates the severity of arthritis in an experimental model.Main methodsWe evaluated the effects of sulfuretin on tumor necrosis factor-α (TNF-α)-treated human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and on collagen-induced arthritis (CIA) mice in vivo.Key findingsIn vitro experiments demonstrated that sulfuretin suppressed the chemokine production, matrix metalloproteinase secretion, and cell proliferation induced by tumor necrosis factor-α in rheumatoid FLS. In addition, sulfuretin inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand in bone marrow macrophages. In mice with CIA, early intervention with sulfuretin prevented joint destruction, as evidenced by a lower cumulative disease incidence and an absence of diverse disease features based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels. In mice with established arthritis, sulfuretin treatment significantly reduced synovial inflammation and joint destruction. The in vitro and in vivo protective effects of sulfuretin were mediated by inhibition of the NF-κB signaling pathway.SignificanceThese results suggest that using sulfuretin to block the NF-κB pathway in rheumatoid joints reduces both inflammatory responses and joint destruction. Therefore, sulfuretin may have therapeutic value in preventing or delaying the progression of rheumatoid arthritis. 相似文献