Home About us Contact
|
Home About us Contact | ||
|
|
||
Induced Arthritis (induced + arthritis)
Selected AbstractsAddition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus -induced arthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2007Margareta Verdrengh Abstract Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus -induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] The anti-arthritic effect of ursolic acid on zymosan-induced acute inflammation and adjuvant-induced chronic arthritis modelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2008Suk-Yun Kang Ursolic acid (UA) is pentacyclic triterpenoic acid that naturally occurs in many medicinal herbs and plants. In this study, we examined the possible suppressive effect of UA extracted from Oldenlandia diffusa on zymosan-induced acute inflammation in mice and complete Freund's adjuvant (CFA)-induced arthritis in rats. UA treatment (per oral) dose-dependently (25,200 mg kg,1) suppressed zymosan-induced leucocyte migration and prostaglandin E2 (PGE2) production in the air pouch exudates. Since the maximal effective dose of UA was 50 mg kg,1 in the zymosan experiment, we used this dose of UA in a subsequent study using an adjuvant-induced rheumatoid arthritis model. UA treatment (50 mg kg,1, per oral, once a day for 10 days) was started from day 12 after adjuvant injection. UA dramatically inhibited paw swelling, plasma PGE2 production and radiological changes in the joint caused by CFA injection. Moreover, UA significantly suppressed the arthritis-induced mechanical and thermal hyperalgesia as well as the spinal Fos expression, as determined by immunohistochemistry, which was increased by CFA injection. In addition, overall anti-arthritic potency of UA was comparable with ibuprofen (100 mg kg,1, oral) while UA did not induce significant gastric lesions as compared with the ibuprofen treatment group. These findings strongly suggest that UA is a useful suppressive compound for rheumatoid arthritis treatment with low risk of gastric problems. [source] CTLA-4Ig blocks the development and progression of citrullinated fibrinogen,induced arthritis in DR4-transgenic miceARTHRITIS & RHEUMATISM, Issue 10 2010David Yue Objective To assess the role of T cells in the mouse model of citrullinated human fibrinogen,induced rheumatoid arthritis (RA) using CTLA-4Ig, an agent that blocks T cell costimulation, which is required for T cell activation. Methods Humanized HLA,DR,1*0401,transgenic (DR4-Tg) mice were immunized with Cit,human fibrinogen to induce arthritis. Prior to, and at the onset or peak of, arthritis, the DR4-Tg mice were treated with CTLA-4Ig or control human IgG1 or were left untreated. Arthritis development and progression were monitored by measuring ankle swelling with calipers and by assessing histopathologic changes. The immune responses to the citrullinated antigens and the corresponding unmodified antigens, as well as the arthritogenicity of lymphocytes from these mice, were examined. The latter was performed using lymphocyte transfers from CTLA-4Ig,treated or control mice via intraperitoneal injection into naive DR4-Tg mice. Recipient mice also received an intraarticular injection of Cit,human fibrinogen, unmodified human fibrinogen, or vehicle. Results CTLA-4Ig,treated, but not human IgG1-treated, arthritic mice had significantly reduced ankle swelling and pathologic joint damage. Treatment with CTLA-4Ig, but not human IgG1, suppressed Cit,human fibrinogen,induced T cell activation, including citrulline-specific T cell activation, when given prior to disease onset. Transfer of splenic lymphocytes from untreated or human IgG1,treated arthritic mice caused arthritis in recipients, and this occurred when Cit,human fibrinogen, but not unmodified fibrinogen, was deposited into the joint. Splenocytes from CTLA-4Ig,treated mice were unable to transfer arthritis. Conclusion Activated citrulline-specific T cells play a direct role in the development and progression of arthritis in this model of Cit,human fibrinogen,induced RA. [source] SIGIRR/TIR-8 is an inhibitor of toll-like receptor signaling in primary human cells and regulates inflammation in models of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2010Stefan K. Drexler Objective Single-immunoglobulin interleukin-1 receptor,related (SIGIRR), which is also known as Toll/interleukin-1 receptor 8 (TIR-8), is a member of the TIR domain,containing family of receptors and was first characterized as an inhibitor of interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling. In the Dextran sulfate sodium,induced colitis model, SIGIRR,/, mice were shown to have increased inflammation and to be more susceptible to endotoxin challenge. Increasing evidence implicates TLR and IL-1R signaling in the pathology of rheumatoid arthritis (RA). Therefore, the purpose of this study was to investigate the involvement of SIGIRR in regulating inflammation in disease-relevant models. Methods Primary human monocyte-derived macrophages and dendritic cells (DCs) were used to overexpress SIGIRR as well as to knock down endogenously expressed SIGIRR using small interfering RNAs. SIGIRR was also overexpressed in synovial cells derived from RA patients. To investigate the role of SIGIRR in vivo, zymosan-induced arthritis (ZIA) and collagen antibody,induced arthritis (CAIA) were induced in SIGIRR-knockout mice. Results SIGIRR overexpression inhibited TLR-induced cytokine production in macrophages and DCs, while SIGIRR knockdown resulted in increased cytokine production following TLR stimulation. Moreover, SIGIRR overexpression inhibited the spontaneous release of cytokines by human RA synovial cells. The role of SIGIRR as an inhibitor of inflammation was confirmed in vivo, since SIGIRR,/, mice developed a more severe disease in both the ZIA and CAIA models. Conclusion Our study is the first to show the expression pattern and function of SIGIRR in primary human cells. Furthermore, this investigation defines the role of SIGIRR in disease-relevant cell types and demonstrates that SIGIRR is a potential therapeutic target for RA. [source] Combination antibiotics for Chlamydia -induced arthritis: Breakthrough to a cure?ARTHRITIS & RHEUMATISM, Issue 5 2010Markus Rihl First page of article [source] Mediation of nonerosive arthritis in a mouse model of lupus by interferon-,,stimulated monocyte differentiation that is nonpermissive of osteoclastogenesisARTHRITIS & RHEUMATISM, Issue 4 2010Kofi A. Mensah Objective In contrast to rheumatoid arthritis (RA), the joint inflammation referred to as Jaccoud's arthritis that occurs in systemic lupus erythematosus (SLE) is nonerosive. Although the mechanism responsible is unknown, the antiosteoclastogenic cytokine interferon-, (IFN,), whose transcriptome is present in SLE monocytes, may be responsible. This study was undertaken to examine the effects of IFN, and lupus on osteoclasts and erosion in the (NZB × NZW)F1 mouse model of SLE with K/BxN serum,induced arthritis. Methods Systemic IFN, levels in (NZB × NZW)F1 mice were elevated by administration of AdIFN,. SLE disease was marked by anti,double-stranded DNA (anti-dsDNA) antibody titer and proteinuria, and Ifi202 and Mx1 expression represented the IFN, transcriptome. Microfocal computed tomography was used to evaluate bone erosions. Flow cytometry for CD11b and CD11c was used to evaluate the frequency of circulating osteoclast precursors (OCPs) and myeloid dendritic cells (DCs) in blood. Results Administration of AdIFN, to (NZB × NZW)F1 mice induced osteopetrosis. (NZB × NZW)F1 mice without autoimmune disease were fully susceptible to focal erosions in the setting of serum-induced arthritis. However, (NZB × NZW)F1 mice with high anti-dsDNA antibody titers and the IFN, transcriptome were protected against bone erosions. AdIFN, pretreatment of NZW mice before K/BxN serum administration also resulted in protection against bone erosion (r2 = 0.4720, P < 0.01), which was associated with a decrease in the frequency of circulating CD11b+CD11c, OCPs and a concomitant increase in the percentage of CD11b+CD11c+ cells (r2 = 0.6330, P < 0.05), which are phenotypic of myeloid DCs. Conclusion These findings suggest that IFN, in SLE shifts monocyte development toward myeloid DCs at the expense of osteoclastogenesis, thereby resulting in decreased bone erosion. [source] Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor ,, and not estrogen receptor , or G protein,coupled receptor 30ARTHRITIS & RHEUMATISM, Issue 2 2010Cecilia Engdahl Objective The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ER, or ER, or via the recently proposed transmembrane estrogen receptor G protein,coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA). Methods Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen,induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ER,), diarylpropionitrile (DPN; for ER,), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting. Results Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment. Conclusion In a well-established model of postmenopausal RA, ER,, but not ER, or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA. [source] Inhibition of synovial hyperplasia, rheumatoid T cell activation, and experimental arthritis in mice by sulforaphane, a naturally occurring isothiocyanateARTHRITIS & RHEUMATISM, Issue 1 2010Jin-Sun Kong Objective To investigate whether sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables such as broccoli, regulates synoviocyte hyperplasia and T cell activation in rheumatoid arthritis (RA). Methods Synoviocyte survival was assessed by MTT assay. The levels of Bcl-2, Bax, p53, and pAkt were determined by Western blot analysis. Cytokine concentrations in culture supernatants from mononuclear cells were analyzed by enzyme-linked immunosorbent assay. The in vivo effects of SFN were examined in mice with experimentally induced arthritis. Results SFN induced synoviocyte apoptosis by modulating the expression of Bcl-2/Bax, p53, and pAkt. In addition, nonapoptotic doses of SFN inhibited T cell proliferation and the production of interleukin-17 (IL-17) and tumor necrosis factor , (TNF,) by RA CD4+ T cells stimulated with anti-CD3 antibody. Anti-CD3 antibody,induced increases in the expression of retinoic acid,related orphan receptor ,t and T-bet were also repressed by SFN. Moreover, the intraperitoneal administration of SFN to mice suppressed the clinical severity of arthritis induced by injection of type II collagen (CII), the anti-CII antibody levels, and the T cell responses to CII. The production of IL-17, TNF,, IL-6, and interferon-, by lymph node cells and spleen cells from these mice was markedly reduced by treatment with SFN. Anti-CII antibody,induced arthritis in mice was also alleviated by SFN injection. Conclusion SFN was found to inhibit synovial hyperplasia, activated T cell proliferation, and the production of IL-17 and TNF, by rheumatoid T cells in vitro. The antiarthritic and immune regulatory effects of SFN, which were confirmed in vivo, suggest that SFN may offer a possible treatment option for RA. [source] Caspase 1,independent activation of interleukin-1, in neutrophil-predominant inflammationARTHRITIS & RHEUMATISM, Issue 12 2009Monica Guma Objective Interleukin-1, (IL-1,) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL-1, to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis. Methods Caspase 1,deficient (Casp1,/,) and wild-type (WT) mice were tested for their response to arthritogenic K/BxN serum transfer for induction of arthritis or injection of monosodium urate monohydrate (MSU) crystals for induction of peritonitis. All mice were prophylactically treated with inhibitors of neutrophil elastase or chymase. Arthritic paws were tested for the presence of IL-1, protein by enzyme-linked immunosorbent assay and Western blotting. Neutrophils and mast cells from WT and mutant mice were tested for their ability to secrete IL-1, after in vitro stimulation, in the presence of protease inhibitors. Results Casp1,/, and WT mice developed paw swelling to the same extent in the K/BxN serum transfer,induced arthritis model. MSU crystal injection into Casp1,/, mice also resulted in neutrophil influx and production of measurable peritoneal IL-1, protein. Both of these responses were attenuated with neutrophil elastase inhibitors. K/BxN serum transfer,induced arthritis was also reduced by treatment with a chymase inhibitor. Casp1,/, neutrophils and mast cells, when exposed to MSU crystals, secreted similar amounts of IL-1, protein upon in vitro stimulation with lipopolysaccharide, albeit at lower levels than that secreted by WT cells. Elastase and chymase inhibitors reduced the amount of IL-1, released by these cells. Conclusion The production of IL-1, by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1,targeted therapies in neutrophil-predominant arthritis. [source] Gadd45, deficiency in rheumatoid arthritis: Enhanced synovitis through JNK signalingARTHRITIS & RHEUMATISM, Issue 11 2009Camilla I. Svensson Objective JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45,, which is an NF-,B,regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45, expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45, deficiency increases arthritis severity in passive K/BxN murine arthritis. Methods Activation of the NF-,B and JNK pathways and Gadd45, expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45,,/, and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed. Results Expression levels of the Gadd45, gene and protein were unexpectedly low in human RA synovium despite abundant NF-,B activity. Forced Gadd45, expression in human FLS attenuated tumor necrosis factor,induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45, deficiency exacerbated K/BxN serum,induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts. Conclusion Deficient Gadd45, expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45, expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7. [source] Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritisARTHRITIS & RHEUMATISM, Issue 10 2009Alexander Fassold Objective In inflammatory lesions, sympathetic nerve fibers disappear soon after the start of inflammation. We identified sympathetic nerve repellents as possible causal agents in rheumatoid arthritis (RA). On nerve terminals, repellent factors bind to neuropilin-2 and its coreceptor. The aim of this study was to investigate the role of neuropilin-2 in the synovial tissue of patients with RA and patients with osteoarthritis (OA) and in experimental arthritis. Methods The density of neuropilin-2,positive fibers and cells positive for semaphorin 3F (a sympathetic repellent) was investigated using immunofluorescence staining. Enzyme-linked immunosorbent assay was used to detect soluble neuropilin-2 in body fluids from patients with RA and patients with OA. An axon outgrowth assay and a neuropilin-2 Fc fusion construct (neuropilin-2Fc) were used to investigate semaphorin 3F,induced sympathetic nerve repulsion. In an animal model of type II collagen,induced arthritis, soluble neuropilin-2Fc was studied in vivo. Results The synovial density of neuropilin-2,positive sympathetic nerve fibers was lower in RA than in OA, but the density of cells positive for semaphorin 3F was similar. In synovial fluid, the level of soluble neuropilin-2 was markedly higher in RA compared with OA. Mouse sympathetic ganglia served as an excellent model with which to study semaphorin 3F,induced nerve fiber repulsion. Neuropilin-2 and its coreceptor were present on sympathetic neurons, and semaphorin 3F bound to neuropilin-2Fc (binding constant 96 nmoles/liter). Semaphorin 3F dose-dependently increased sympathetic nerve fiber repulsion (at a 50% maximum response concentration of 160,210 nmoles/liter). In contrast to our expectations, soluble neuropilin-2Fc did not inhibit repulsion but increased the repellent effect of semaphorin 3F. In experimental arthritis, therapy with neuropilin-2Fc aggravated arthritis. Conclusion Soluble neuropilin-2 has no antirepellent activity but aggravates sympathetic nerve fiber repulsion and arthritis. Increased shedding of neuropilin-2 is probably an unfavorable sign in RA. [source] CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritisARTHRITIS & RHEUMATISM, Issue 10 2009Paul D. Doodes Objective CCR5 and its ligands (CCL3, CCL4, and CCL5) may play a role in inflammatory cell recruitment into the joint. However, it was recently reported that CCR5 on T cells and neutrophils acts as a decoy receptor for CCL3 and CCL5 to assist in the resolution of inflammation. The aim of this study was to determine whether CCR5 functions as a proinflammatory or antiinflammatory mediator in arthritis, by examining the role of CCR5 in proteoglycan (PG),induced arthritis (PGIA). Methods Arthritis was induced by immunizing wild-type (WT) and CCR5-deficient (CCR5,/,) BALB/c mice with human PG in adjuvant. The onset and severity of PGIA were monitored over time. Met-RANTES was used to block CCR5 in vivo. Arthritis was transferred to SCID mice, using spleen cells from arthritic WT and CCR5,/, mice. The expression of cytokines and chemokines was measured by enzyme-linked immunosorbent assay. Results In CCR5,/, mice and WT mice treated with the CCR5 inhibitor Met-RANTES, exacerbated arthritis developed late in the disease course. The increase in arthritis severity in CCR5,/, mice correlated with elevated serum levels of CCL5. However, exacerbated arthritis was not intrinsic to the CCR5,/, lymphoid cells, because the arthritis that developed in SCID mouse recipients was similar to that in WT and CCR5,/, mice. CCR5 expression in the SCID mouse was sufficient to clear CCL5, because serum levels of CCL5 were the same in SCID mouse recipients receiving cells from either WT or CCR5,/, mice. Conclusion These data demonstrate that CCR5 is a key player in controlling the resolution of inflammation in experimental arthritis. [source] Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum,induced arthritis in vivoARTHRITIS & RHEUMATISM, Issue 7 2009Frank Buttgereit Objective Endogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast-targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis. Methods Intracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11,-hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5-week-old male transgenic mice and their wild-type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone. Results Acute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice. Conclusion Disruption of GC signaling in osteoblasts significantly attenuates K/BxN mouse serum,induced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune-mediated inflammatory response via a GC-dependent pathway. [source] Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: A link between angiogenesis and inflammationARTHRITIS & RHEUMATISM, Issue 2 2009Seung-Ah Yoo Objective To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA). Methods Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor , (TNF,), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody. Results PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1,, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNF, and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1, and TNF,. A novel anti,flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNF, and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody,induced arthritis in mice. Conclusion Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti,flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA. [source] Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus,induced arthritisARTHRITIS & RHEUMATISM, Issue 3 2008Yongzhi Guo Objective To assess the functional roles of plasmin in a murine model of Staphylococcus aureus,induced bacterial arthritis. Methods Bacterial arthritis was induced in plasminogen-deficient (Plg,/,) and wild-type (Plg+/+) littermates by local injection of 1 × 106 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg,/, mice on days 0,7 or days 7,14. Antibiotic treatment was administered to Plg,/, mice on days 7,14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed. Results In Plg+/+ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg,/, mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg+/+ and Plg,/, mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg,/, mice, however. Treatment of Plg,/, mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg,/, mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg+/+ mice than in Plg,/, mice during bacterial arthritis. Conclusion Our findings indicate that plasmin plays a pluripotent role in protecting against S aureus,induced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression. [source] Suppressive role of leukocyte cell,derived chemotaxin 2 in mouse anti,type II collagen antibody,induced arthritisARTHRITIS & RHEUMATISM, Issue 2 2008Akinori Okumura Objective We previously reported that the Val58Ile polymorphism of the leukocyte cell,derived chemotaxin 2 gene (LECT2) is associated with the severity of rheumatoid arthritis (RA). To define the role of LECT2 in inflammatory arthritides, we investigated the development of collagen antibody,induced arthritis (CAIA) in LECT2-deficient (LECT2,/,) mice. Methods CAIA was induced in mice by administering anti,type II collagen antibodies followed by lipopolysaccharide. Daily assessment of hind paw swelling was used to monitor the development of arthritis. The histopathologic features and expression of inflammatory cytokines were also analyzed. We confirmed the role of LECT2 by introducing a LECT2 expression vector into LECT2,/, mice, using a hydrodynamic gene transfer method. Results Arthritis in LECT2,/, mice was significantly exacerbated compared with that in wild-type (WT) controls. Histopathologic assessment of the tarsal joints showed that inflammation and erosion of cartilage and bone in LECT2,/, mice were more severe than that in controls. Interleukin-1, (IL-1,), IL-6, and certain chemokines were present at significantly higher levels in the arthritic hind paws of LECT2,/, mice. In contrast, the amount of LECT2 in the serum and locally in the hind paws was higher in arthritic WT mice. Finally, hydrodynamic gene transfer experiments revealed that the severity of arthritis was reduced by the systemic expression of exogenous mouse LECT2 protein in LECT2,/, mice. Conclusion These results strongly suggest that LECT2 directly suppresses the development of CAIA. Manipulation of LECT2 might provide a rationale for novel therapeutic approaches to the treatment of inflammatory arthritides such as RA. [source] Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in miceARTHRITIS & RHEUMATISM, Issue 6 2007Manfred Kneilling Objective Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. Methods Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse,derived serum or control serum in wild-type Kit+/Kit+ mice, congenic mast cell,deficient KitW/KitW - v mice, or mast cell,deficient KitW/KitW - v mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated ,v,3 integrin using 18F,galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, ,3, and ,-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. Results Comparing wild-type mice, mast cell,deficient KitW/KitW - v mice, and mast cell,reconstituted KitW/KitW - v mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and ,v,3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented ,v,3 integrin activation, angiogenesis, and joint destruction. Conclusion Mast cell engraftment fully restores susceptibility to ,v,3 integrin activation, angiogenesis, and joint destruction in GPI antibody,induced arthritis. Importantly, selective mast cell stabilization prevents ,v,3 integrin activation, angiogenesis, and joint destruction. [source] Acceleration of the onset of collagen-induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1ARTHRITIS & RHEUMATISM, Issue 11 2003Yoshifumi Tada Objective Platelet endothelial cell adhesion molecule 1 (PECAM-1; CD31) is a member of the immunoglobulin superfamily that is expressed in platelets, leukocytes, and endothelial cells. PECAM-1 has been shown to play a role in transendothelial migration of leukocytes and contains immunoreceptor tyrosine-based inhibitory motifs in its cytoplasmic tail and inhibits cellular responses. We examined the role of PECAM-1 in the development of collagen-induced arthritis (CIA). Methods CIA was induced in PECAM-1,deficient DBA/1 mice. The incidence of arthritis and the arthritis index were examined. Anti,type II collagen (anti-CII) antibody levels and interferon-, (IFN,) production by lymph node cells and spleen cells were determined. Lymphocytes from arthritic PECAM-1,deficient and wild-type mice were labeled with dye, transferred to arthritic PECAM-1+/, mice, and cell migration to inflamed joints was examined. Results PECAM-1,deficient mice showed accelerated onset of arthritis and increased severity only during the early phase. Anti-CII antibody levels were also increased during the early phase. IFN, production by lymph node cells and spleen cells from PECAM-1,deficient mice in response to CII was higher than that in wild-type mice. Lymphocytes from arthritic PECAM-1,deficient mice showed accelerated migration to inflamed joints, but not lymph nodes or spleen. The development of anti-CII antibody,induced arthritis was similar in PECAM-1,deficient and wild-type mice. Conclusion These results indicate that PECAM-1 negatively regulates humoral and cell-mediated immune responses and lymphocyte migration into joints and, consequently, the development of CIA. In addition, the role of PECAM-1 in the transendothelial migration of leukocytes appears to be redundant in this model. [source] Blockade of parathyroid hormone,related protein prevents joint destruction and granuloma formation in streptococcal cell wall,induced arthritisARTHRITIS & RHEUMATISM, Issue 6 2003J. L. Funk Objective To determine whether parathyroid hormone,related protein (PTHrP), an interleukin-1,,inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. Methods PTHrP expression and the effect of PTHrP 1,34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW),induced arthritis, an animal model of RA. Results As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor,positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1,34. Conclusion These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders. [source] | ||||||||||