Science.gov

Sample records for collagen ii-induced arthritis

  1. Changes and significance of IL-25 in chicken collagen II-induced experimental arthritis (CIA).

    PubMed

    Kaiwen, Wang; Zhaoliang, Su; Yinxia, Zhao; Siamak, Sandoghchian Shotorbani; Zhijun, Jiao; Yuan, Xue; Heng, Yang; Dong, Zheng; Yanfang, Liu; Pei, Shen; Shengjun, Wang; Qixiang, Shao; Xinxiang, Huang; Liwei, Lu; Huaxi, Xu

    2012-08-01

    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. It is a systemic inflammatory disease, characterized by chronic, symmetrical, multi-articular synovial arthritis. IL-25 (IL-17E) is a member of the recently emerged cytokine family (IL-17s), which is expressed in Th2 cells and bone marrow-derived mast cells. Unlike the other members of this family, IL-25 is capable of inducing Th2-associated cytokines (IL-4, IL-5, and IL-13) and also promotes the release of some pro-immune factors (IL-6 and IL-8). IL-25 is also a pleiotropic factor, which constitutes a tissue-specific pathological injury and chronic inflammation. In this study, we used chicken collagen II-induced experimental arthritis (CIA) model in DBA/1 mice to investigate the relationship between IL-25 and other inflammatory factors, revealing the possible mechanism in CIA. Our results showed that the expression level of IL-25 was enhanced in the late stage of CIA, and IL-17 was increased in the early stage of the disease. It is well known that IL-17 has a crucial role in the development of RA pathogenesis, and IL-25 plays a significant role in humoral immune. For reasons given above, we suggested that the IL-25 inhibited IL-17 expression to some extent, while enhancing the production of IL-4. It was confirmed that IL-25 not only regulated the cellular immune, but also involved the humoral immune in rheumatoid arthritis.

  2. Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis

    PubMed Central

    Östberg, Therese; Wähämaa, Heidi; Palmblad, Karin; Ito, Norimasa; Stridh, Pernilla; Shoshan, Maria; Lotze, Michael T; Harris, Helena Erlandsson; Andersson, Ulf

    2008-01-01

    Introduction High mobility group box chromosomal protein 1 (HMGB1) is a nuclear protein that acts as a pro-inflammatory mediator following extracellular release. The protein is aberrantly expressed extracellularly in the settings of clinical and experimental synovitis. Therapy based on HMGB1 antagonists has shown encouraging results in experimental arthritis and warrants further scientific exploration using independent methods. In the present study we asked whether nuclear sequestration of HMGB1 preventing HMGB1 release would be beneficial for synovitis treatment. Methods Oxaliplatin-based therapy was evaluated in collagen type II-induced arthritis in DBA/1 mice by clinical scoring and immunostaining of articular tissue. Oxaliplatin is an antineoplastic platinum-based compound that generates DNA adducts which tightly bind HMGB1. Secretion and intracellular location of HMGB1 were assessed by a novel HMGB1-specific ELISPOT assay and immunofluorescent staining. Results Intraperitoneal injections of oxaliplatin in early collagen type II-induced arthritis trapped HMGB1 with a distinct biphasic response pattern. Oxaliplatin therapy showed beneficial results for approximately 1 week. Microscopic evaluation of synovitis during this period showed strong nuclear HMGB1 staining in the oxaliplatin treated animals with much lower quantities of extracellular HMGB1 when compared to control treated animals. Furthermore, cellular infiltration, as well as cartilage and bone damage, were all reduced in the oxaliplatin treated group. A dramatic and as yet unexplained clinical relapse occurred later in the oxaliplatin exposed animals, which coincided with a massive synovial tissue expression of extracellular HMGB1 in all treated animals. This rebound-like reaction was also accompanied by a significantly increased incidence of arthritis in the oxaliplatin treated group. These results indicate a distinct temporal and spatial relationship between the clinical course of disease and the

  3. Phellinus baumii ethyl acetate extract alleviated collagen type II induced arthritis in DBA/1 mice.

    PubMed

    Yayeh, Taddesse; Lee, Whi Min; Ko, Dukhwan; Park, Seung-Choon; Cho, Jae Youl; Park, Hwa-Jin; Lee, In-Kyoung; Kim, Seung-Hyung; Hong, Seung-Bok; Kim, Suk; Yun, Bong-Sik; Rhee, Man Hee

    2013-10-01

    Mushrooms have a long history of dietary benefits in Asia due to their health-promoting effects. Phellinus baumii, a wild mushroom, has been reported to have anti-platelet, anti-inflammatory, anti-obesity and free radical scavenging activities. However, its anti-rheumatoid arthritis (RA) property remains poorly understood. Hence, we investigated the protective effect of Phellinus baumii ethyl acetate extract (PBEAE) against bovine collagen type II induced arthritis (CIA) in DBA/1 mice. PBEAE (50 and 150 mg/kg) reduced the CIA score and leukocyte count in draining lymph nodes (DLNs) and inflamed joints. PBEAE also attenuated the expressions of CD3⁺ (T cells), CD19⁺ (B cells), CD4⁺ (T-helper), CD8⁺ (T-cytotoxic), MHC class II/CD11c⁺ (antigen-presenting cells), double positives (B220⁺/CD23⁺ and CD3⁺/CD69⁺: early lymphocyte activation markers) and CD4⁺/CD25⁺ (activated T-helper) leukocyte subpopulations in DLNs. Likewise, CD3⁺ and Gr-1⁺CD11b⁺ (neutrophil) counts in inflamed joints were also decreased. Furthermore, PBEAE reduced the serum levels of anti-collagen type immunoglobulin G, tumor necrosis factor-α and interleukin (IL)-1β and IL-6. Taken together, PBEAE impaired cellular recruitment to the inflamed joint and alleviated CIA, and thus could be considered as a potential agent against rheumatoid arthritis.

  4. Mice Deficient in CD38 Develop an Attenuated Form of Collagen Type II-Induced Arthritis

    PubMed Central

    Postigo, Jorge; Iglesias, Marcos; Cerezo-Wallis, Daniela; Rosal-Vela, Antonio; García-Rodríguez, Sonia; Zubiaur, Mercedes; Sancho, Jaime

    2012-01-01

    CD38, a type II transmembrane glycoprotein expressed in many cells of the immune system, is involved in cell signaling, migration and differentiation. Studies in CD38 deficient mice (CD38 KO mice) indicate that this molecule controls inflammatory immune responses, although its involvement in these responses depends on the disease model analyzed. Here, we explored the role of CD38 in the control of autoimmune responses using chicken collagen type II (col II) immunized C57BL/6-CD38 KO mice as a model of collagen-induced arthritis (CIA). We demonstrate that CD38 KO mice develop an attenuated CIA that is accompanied by a limited joint induction of IL-1β and IL-6 expression, by the lack of induction of IFNγ expression in the joints and by a reduction in the percentages of invariant NKT (iNKT) cells in the spleen. Immunized CD38 KO mice produce high levels of circulating IgG1 and low of IgG2a anti-col II antibodies in association with reduced percentages of Th1 cells in the draining lymph nodes. Altogether, our results show that CD38 participates in the pathogenesis of CIA controlling the number of iNKT cells and promoting Th1 inflammatory responses. PMID:22438945

  5. The Predicted Proteomic Network Associated with the Antiarthritic Action of Qingfu Guanjieshu in Collagen-II-Induced Arthritis in Rats

    PubMed Central

    Wang, Ting Yu; Zhou, Hua; Wong, Yuen Fan; Wu, Pui Kei; Hsiao, Wen-Luan Wendy; Leung, Elaine Lai-Han; Liu, Liang

    2013-01-01

    Qingfu Guanjieshu (QFGJS) is an herbal preparation for treating rheumatoid arthritis (RA). Previous studies revealed that QFGJS significantly inhibited experimental arthritis and acute inflammation, accompanied by reduction of proinflammatory cytokines and elevation of anti-inflammatory cytokines. This study aims to identify the targeted proteins and predict the proteomic network associated with the drug action of QFGJS by using 2D gel and MALDI-TOF-MS/MS techniques. Thirty female Wistar rats were evenly grouped as normal and vehicle- and QFGJS-treated CIA rats. The antiarthritic effect of QFGJS was examined with a 19-day treatment course, and the knee synovial tissues of animals from each group were obtained for 2D gel and MALDI-TOF-MS/MS analysis. Results showed that QFGJS significantly ameliorated collagen II-induced arthritis when administrated at 2.8 g/kg body weight for 19 days. 2D gel image analysis revealed 89 differentially expressed proteins in the synovial tissues among the normal and vehicle- and QFGJS-treated CIA rats from over 1000 proteins of which 63 proteins were identified by MALDI-TOF-MS/MS analysis, and 32 proteins were included for classification of functions using Gene Ontology (GO) method. Finally, 14 proteins were analyzed using bioinformatics, and a predicted proteomic network related to the anti-arthritic effect of QFGJS was established, and Pgk1 plays a central role. PMID:23781264

  6. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

    SciTech Connect

    Hong, Hyun Sook; Son, Youngsook

    2014-10-10

    Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel ability to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.

  7. [Immunomodulatory effect of UC-MSC on function of immunocytes of rats with collagen type II induced arthritis].

    PubMed

    Gu, Jian; Lin, Chuan-Ming; Gu, Wei; Cai, Xin-Zhen; Li, Zou; Ren, Min-Min; Sun, Xing; Ni, Jun; Shen, Lian-Jun; Wu, Wei; He, Bin; Sun, Mei; Zhang, Yu

    2014-02-01

    This study was purposed to observe the influence of umbilical cord mesenchymal stem cells (UC-MSC) on the peripheral blood CD4(+)CD25(+)regulatory T cells (Treg), Th17 cells and neutrophils in rats with collagen type II-induced arthritis(CIA), and to explore the regulating effect of UC-MSC transplantation on immunocyte subgroup. The rats wee divided into 3 groups: CIA group (model group), UC-MSC treated group and blank control group. The CIA rats were injected with UC-MSC via tail vein. The percentage of CD4(+)CD25(+) cells in peripheral blood and the expression of NCD11b on neutrophil surface in CIA rates was detected by flow cytometry (FCM), and the serum interleukin-17 (IL-17) was observed by enzyme-linked immunosorbent assay (ELISA). The results showed that the mean fluorescence intensity(MFI) of NCD11b and the level of IL-17 in the model group were significantly higher than those in the blank control group, and the ratio of CD4(+)CD25(+) cells were significantly lower (P < 0.05). The MIF of NCD11b and the level of IL-17 in the UC-MSC treated group were significantly lower than that in the model group (P < 0.05), while the proportion of CD4(+)CD25(+) Treg increased (P < 0.05). Since the fifth week, the above indicators in the UC-MSC group have almostly approached the control group. It is concluded that the UC-MSC can increase peripheral blood Treg proportion in CIA rat, inhibit the secretion of Th17 and the activity of neutrophils, reduce the immune inflammation reaction, decrease the release of proinflammatory factor, and induce immune reconstruction.

  8. Epicutaneous (EC) immunization with type II collagen (COLL II) induces CD4(+) CD8(+) T suppressor cells that protect from collagen-induced arthritis (CIA).

    PubMed

    Marcińska, Katarzyna; Majewska-Szczepanik, Monika; Lazar, Agata; Kowalczyk, Paulina; Biała, Dominika; Woźniak, Dorota; Szczepanik, Marian

    2016-04-01

    We have shown previously that epicutaneous (EC) immunization with protein antigen induces T suppressor cells that alleviate inflammatory response in contact hypersensitivity reactions, in an animal model of multiple sclerosis, and in TNBS-induced colitis. DBA/1 mice were EC immunized with type II collagen (COLL II) spread over a gauze patch on days 0 and 4. On day 7, patches were removed and mice were intradermally (id) immunized with COLL II in CFA to induce collagen-induced arthritis (CIA). Our work shows that EC immunization with 100μg of COLL II prior to CIA induction reduces disease severity as determined by macroscopic evaluation. Reduced disease severity after EC immunization with COLL II correlates with milder histological changes found in joint sections. Experiments with the three non-cross-reacting antigens COLL II, ovalbumin (OVA) and myelin basic protein (MBP) showed that skin-induced suppression is antigen non-specific. Transfer experiments show that EC immunization with COLL II induces suppressor cells that belong to the population of CD4(+) CD8(+) double positive lymphocytes. Flow cytometry experiments showed increased percentage of CD4(+) CD8(+) RORγt(+) cells in axillary and inguinal lymph nodes isolated from mice patched with COLL II. Maneuver of EC immunization with a protein antigen that induces suppressor cells to inhibit inflammatory responses may become an attractive, noninvasive, needle-free therapeutic method for different clinical situations. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Mimicking disruption of brain-immune system-joint communication results in collagen type II-induced arthritis in non-susceptible PVG rats.

    PubMed

    Wolff, Christine; Straub, Rainer H; Hahnel, Anja; Randolf, Anke; Wildmann, Johannes; Besedovsky, Hugo O; del Rey, Adriana

    2015-11-05

    The brain-immune system-joint communication is disrupted during collagen type II (CII) arthritis in DA rats. Since PVG rats are not susceptible to arthritis induction, comparison of hypothalamic and peripheral neuro-endocrine and immune responses between immunized DA and PVG rats might help to explain their different susceptibility to develop the disease. PVG and DA rats were immunized with CII. Corticosterone, neurotransmitters, anti-CII antibodies, and cytokine concentrations in plasma, and hypothalamic neurotransmitters and cytokines were determined by ELISA, Luminex, HPLC and RT-qPCR. Adrenalectomy or sham-operation was performed in PVG and DA rats 14 days before immunization. Basal plasma corticosterone and adrenaline concentrations were significantly higher, and plasma cytokines and hypothalamic noradrenaline were lower in PVG rats than in DA rats. While DA rats developed severe arthritis upon immunization (maximum score 16), only 12 out of 28 PVG rats showed minimal symptoms (score 1-2). The density of sympathetic nerve fibers in arthritic joints of DA rats markedly decreased, but it remained stable in immunized PVG rats. The ratio corticosterone to IL-1β levels in plasma was markedly higher in immunized PVG rats than in arthritic DA rats. Adrenalectomy resulted in severe arthritis in PVG rats upon immunization with CII. While DA rats show an altered immune-brain communication that favors the development of arthritis, PVG rats express a protective neuro-endocrine milieu, particularly linked to the basal tone of the HPA axis. Mimicking disruption of this axis elicits arthritis in non-susceptible PVG rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and alters serum cytokine/chemokine patterns in the bovine collagen type II induced arthritis in the DBA mouse model.

    PubMed

    Zimmerman, Daniel H; Taylor, Patricia; Bendele, Alison; Carambula, Roy; Duzant, Yvonne; Lowe, Valeria; O'Neill, Sean P; Talor, Eyal; Rosenthal, Kenneth S

    2010-04-01

    The mouse model of collagen induced arthritis (CIA) effectively mimics human disease and thus is useful for testing and development of rheumatoid arthritis (RA) therapies. We developed a Ligand Epitope Antigen Presentation System (LEAPS) peptide hetero-conjugate vaccine containing an epitope of human collagen type II (CEL-2000) that acted as a therapeutic vaccine in the collagen induced arthritis (CIA) mouse model. LEAPS technology converts a small peptide containing a disease specific epitope into an immunogen by attaching it to an immune or T cell binding peptide (I/TCBL). For CEL-2000, a peptide from human collagen type II (254-273) is attached to the I/TCBL peptide from human beta2 microglobulin (J). Treatment with CEL-2000 limited disease (CIA) progression, as demonstrated by reduced Arthritic Index (AI) score, and footpad swelling. Efficacy was confirmed by histopathological microscopic examination of tissues at the end of the study. CEL-2000 limited disease progression as well or better than the etanercept (Enbrel) therapeutic control with significantly better histopathological results than the etanercept treated mice. Most interestingly, CEL-2000 therapy modulated serum cytokine levels with an increase in IL-12p70 and IL-10, which are not seen with etanercept therapy, and reduced IL-17 and TNF-alpha, also seen with etanercept, among other cytokines studied. CEL-2000 was safe and well tolerated for the mice that received 5 injections given every 2weeks in a 90day study supporting its potential usage for long term therapy. These studies demonstrate that fewer treatments with CEL-2000 provide therapy at least as effective as etanercept by specifically modulating the disease producing autoimmune response.

  11. Pathogenetic difference between collagen arthritis and adjuvant arthritis

    PubMed Central

    1984-01-01

    Daily treatment with cyclosporin at a dose of 25 mg/kg for 14 d gave complete suppression of the development of collagen arthritis and adjuvant arthritis in Sprague-Dawley rats during an observation period of 45 d. To study whether the immunologic unresponsiveness produced by cyclosporin is antigen specific, we rechallenged the cyclosporin- protected rats with either type II collagen or complete Freund's adjuvant (CFA) after discontinuation of cyclosporin treatment. Type II collagen-immunized, cyclosporin-protected rats did not develop arthritis in response to reimmunization with type II collagen, but, they did develop arthritis in response to a subsequent injection of CFA. Similarly, CFA-injected, cyclosporin-protected rats showed a suppressed arthritogenic reaction in response to reinjection of CFA, whereas their response to a subsequent immunization with type II collagen was unaffected. On the other hand, the rats that were treated with cyclosporin without any prior antigenic challenge could develop arthritis in response to a subsequent injection of CFA or type II collagen after cessation of cyclosporin treatment. These results indicate that specific immunologic unresponsiveness can be induced by cyclosporin in the two experimental models of polyarthritis, collagen arthritis and adjuvant arthritis, and that there is no cross-reactivity between type II collagen and the mycobacterial cell wall components. The results further indicate that immunity to type II collagen plays a critical role in the pathogenesis of collagen arthritis but that its pathogenetic role in adjuvant arthritis is insignificant. PMID:6201583

  12. Eupatilin ameliorates collagen induced arthritis.

    PubMed

    Kim, Juryun; Kim, Youngkyun; Yi, Hyoju; Jung, Hyerin; Rim, Yeri Alice; Park, Narae; Jung, Seung Min; Park, Sung-Hwan; Ju, Ji Hyeon

    2015-03-01

    Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-α and then treated with eupatilin, and the levels of IL-6 and IL-1β mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-α treatment of synoviocytes increased the expression of IL-6 and IL-1β mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent.

  13. Exposure to Mimivirus Collagen Promotes Arthritis

    PubMed Central

    Shah, Nikunj; Hülsmeier, Andreas J.; Hochhold, Nina; Neidhart, Michel; Gay, Steffen

    2014-01-01

    Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy-subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens. PMID:24173233

  14. Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

    SciTech Connect

    McCune, W.J.; Buckley, J.A.; Belli, J.A.; Trentham, D.E.

    1982-05-01

    Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type II collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLi and cyclophosphamide are immunosuppressive in an experimentally inducible autoimmune disease.

  15. Effects of cyclosporin on collagen induced arthritis in mice.

    PubMed Central

    Takagishi, K; Kaibara, N; Hotokebuchi, T; Arita, C; Morinaga, M; Arai, K

    1986-01-01

    We have studied the effect of the immunosuppressive agent cyclosporin on collagen induced arthritis in mice. Cyclosporin, when given prophylactically, was capable of suppressing the development of collagen induced arthritis and the immunological response to native type II collagen in a dose dependent manner. Furthermore, treatment with cyclosporin, started on the same day as the booster injection with type II collagen, also resulted in inhibition of development of arthritis and of immunity to collagen. These findings suggest that the time of a booster injection, three weeks after the initial immunisation, might be still within the induction phase of arthritis since reinoculation is required to produce a high incidence of arthritis in mice. In addition, therapeutic treatment with cyclosporin did not affect the clinical course of the disease or the immune response to collagen. PMID:3754714

  16. Perforin deficiency attenuates collagen-induced arthritis

    PubMed Central

    Bauer, Kristin; Knipper, Annika; Tu-Rapp, Hoang; Koczan, Dirk; Kreutzer, Hans-Jürgen; Nizze, Horst; Mix, Eilhard; Thiesen, Hans-Juergen; Holmdahl, Rikard; Ibrahim, Saleh M

    2005-01-01

    Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 ± 3.6; DBA/1J-pfp-/-, 59 ± 4.9 (mean ± SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 ± 1.1; DBA/1J-pfp-/-, 3.4 ± 1.4 (mean ± SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp-/- mice compared with pfp+/+ mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA. PMID:15987490

  17. Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis

    PubMed Central

    Jirholt, Pernilla; Turesson, Olof; Wing, Kajsa; Holmdahl, Rikard; Kihlberg, Jan; Stern, Anna; Mårtensson, Inga-Lill; Henningsson, Louise; Gustafsson, Kenth; Gjertsson, Inger

    2016-01-01

    Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naïve mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases. PMID:27159398

  18. Sirt2 suppresses inflammatory responses in collagen-induced arthritis

    SciTech Connect

    Lin, Jiangtao; Sun, Bing; Jiang, Chuanqiang; Hong, Huanyu; Zheng, Yanping

    2013-11-29

    Highlights: •Sirt2 expression decreases in collagen-induced arthritis (CIA). •Sirt2 knockout aggravates severity of arthritis in mice with CIA. •Sirt2 knockout increases levels of pro-inflammatory factors in the serum. •Sirt2 deacetylates p65 and inhibits pro-inflammatory factors expression. •Sirt2 rescue abates severity of arthritis in mice with CIA. -- Abstract: Arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications and early death. However, the underling mechanisms of arthritis are still unclear. Sirtuins are a NAD{sup +}-dependent class III deacetylase family, and regulate cellular stress, inflammation, genomic stability, carcinogenesis, and energy metabolism. Among the sirtuin family members, Sirt1 and Sirt6 are critically involved in the development of arthritis. It remains unknown whether other sirtuin family members participate in arthritis. Here in this study, we demonstrate that Sirt2 inhibits collagen-induced arthritis (CIA) using in vivo and in vitro evidence. The protein and mRNA levels of Sirt2 significantly decreased in joint tissues of mice with CIA. When immunized with collagen, Sirt2-KO mice showed aggravated severity of arthritis based on clinical scores, hind paw thickness, and radiological and molecular findings. Mechanically, Sirt2 deacetylated p65 subunit of nuclear factor-kappa B (NF-κB) at lysine 310, resulting in reduced expression of NF-κB-dependent genes, including interleukin 1β (IL-1β), IL-6, monocyte chemoattractant protein 1(MCP-1), RANTES, matrix metalloproteinase 9 (MMP-9) and MMP-13. Importantly, our rescue experiment showed that Sirt2 re-expression abated the severity of arthritis in Sirt2-KO mice. Those findings strongly indicate Sirt2 as a considerably inhibitor of the development of arthritis.

  19. Characterization of the T cell receptor repertoire causing collagen arthritis in mice

    PubMed Central

    1993-01-01

    Collagen type II-induced arthritis (CIA) is generated in susceptible rodent strains by intradermal injections of homologous or heterologous native type II collagen in complete Freund's adjuvant. Symptoms of CIA are analogous to those of the human autoimmune disease, rheumatoid arthritis. CIA is a model system for T cell-mediated autoimmune disease. To study the T cell receptor (TCR) repertoire of bovine type II-specific T cells that may be involved in the pathogenesis of CIA in DBA/1Lac.J (H-2q) mice, 13 clonally distinct T cell hybridomas specific for bovine type II collagen have been established and the alpha and beta chains of their TCRs have been analyzed. These T cell hybridomas recognize epitopes that are shared by type II collagens from distinct species and not by type I collagens, and exhibit a highly restricted TCR-alpha/beta repertoire. The alpha chains of the TCRs employ three V alpha gene subfamilies (V alpha 11, V alpha 8, and V alpha 22) and four J alpha gene segments (J alpha 42, J alpha 24, J alpha 37, and J alpha 32). The V alpha 22 is a newly identified subfamily consisting of approximately four to six members, and exhibits a high degree of polymorphism among four mouse strains of distinct V alpha haplotypes. In addition, the beta chains of the TCRs employ three V beta gene subfamilies (V beta 8, V beta 1, and V beta 6), however the V beta 8.2 gene segment is preferentially utilized (58.3%). In contrast, the J beta gene segment usage is more heterogeneous. On the basis of the highly limited TCR-alpha/beta repertoire of the TCRs of the panel of bovine type II-specific T cell hybrid clones, a significant reduction (60%) of the incidence of arthritis in DBA/1Lac.J mice is accomplished by the use of anti-V beta 8.2 antibody therapy. PMID:8381155

  20. Correlation between clotting and collagen metabolism markers in rheumatoid arthritis.

    PubMed

    Gabazza, E C; Osamu, T; Yamakami, T; Ibata, H; Sato, T; Sato, Y; Shima, T

    1994-02-01

    Rheumatoid arthritis is a chronic inflammatory disease caused essentially by an immune-mediated mechanism. However, abnormalities of the clotting system have also been incriminated as having an important role in the pathogenesis of this disease. This study aims at assessing the clotting system and collagen metabolism alterations and the relationship between perturbances of the hemostatic pathway and the destructive and fibroproliferative processes in patients with rheumatoid arthritis. The coagulation system was evaluated by measuring thrombin-antithrombin III complex (TAT), prothrombin time (PT), activated partial thromboplastin time (APTT), and antithrombin III (AT-III). The fibrinolysis system was assessed by measuring fibrin degradation products (FDP), fibrinogen (FBG), alpha 2-antiplasmin (alpha 2-PI), D-dimer (DD) and plasmin-alpha 2-antiplasmin complex (PAP). As markers of collagen metabolism, the type III procollagen peptide (PIIIP) and the 7S domain of type IV collagen (7S-collagen) were determined. Blood concentrations of DD, PAP, TAT, PIIIP, and 7S-collagen were significantly higher in rheumatoid arthritis patients compared to controls. Serum levels of PIIIP were significantly correlated with PT, APTT, AT-III, FDP, and DD. 7S-collagen levels were inversely related to AT-III and FBG values. This study demonstrated the occurrence of a subclinical intravascular coagulation in rheumatoid arthritis and suggested the important role of blood coagulation in the alteration of the extracellular matrix metabolism in this disease.

  1. Therapeutic effect of quercetin in collagen-induced arthritis.

    PubMed

    Haleagrahara, Nagaraja; Miranda-Hernandez, Socorro; Alim, Md Abdul; Hayes, Linda; Bird, Guy; Ketheesan, Natkunam

    2017-03-22

    Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analysed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: negative (untreated) control, positive control (arthritis-induced), arthritis+methotrexate, arthritis+quercetin, and arthritis+methotrexate+quercetin. Assessments of weight, oedema, joint damage, and cytokine production were used to determine the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was associated with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study determined that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.

  2. Paradoxical effects of cyclosporin A on collagen arthritis in rats

    PubMed Central

    1983-01-01

    The effect of the immunosuppressive agent cyclosporin A (CS-A) on collagen arthritis in Sprague-Dawley rats is investigated. A 14-d course of CS-A treatment at doses of 15 mg/kg per day or more, begun on the same day as type II collagen immunization, suppressed the development of arthritis as well as humoral and delayed-type hypersensitivity (DTH) skin test responses to type II collagen, possibly by interfering with helper T cells. Additional studies demonstrated that CS-A treatment only during the induction phase of immunity proved to be successful. When CS-A treatment was started only during the immediately preclinical phase of arthritis or after the disease onset, a significant enhancement of the disease was obtained in a dose-dependent manner. This enhancement was accompanied by an augmentation of DTH skin reactions, while antibody responses were either suppressed or unaffected. These results appear to be attributable at least in part to a suppressive effect of CS-A on a population of suppressor T cells, thus resulting in a T cell-mediated helper effect. It is therefore reasonable to assume that the paradoxical effects of CS-A on collagen arthritis in rats might be caused by an altering of the sensitive balance of the two regulatory subpopulations of T cells. It is also possible that cell-mediated immune responses may play an important role in influencing the course of the disease. PMID:6644238

  3. Lycium barbarum polysaccharide attenuates type II collagen-induced arthritis in mice.

    PubMed

    Liu, Yao; Lv, Jun; Yang, Bo; Liu, Fang; Tian, Zhiqiang; Cai, Yongqing; Yang, Di; Ouyang, Jing; Sun, Fengjun; Shi, Ying; Xia, Peiyuan

    2015-01-01

    No curative treatment is yet available for rheumatoid arthritis (RA), wherein chronic synovitis progresses to cartilage and bone destruction. Considering the recently recognized anti-inflammatory properties of Lycium barbarum polysaccharide (LBP; a derivative of the goji berry), we established the collagen type II-induced arthritis (CIA) mouse model to investigate the potential therapeutic effects and mechanisms of LBP. The CIA-induced changes and LBP-related effects were assessed by micro-computed tomography measurement of bone volume/tissue volume and by ELISA and western blotting detection of inflammatory mediators and matrix metalloproteinases (MMPs). The CIA mice showed substantial bone damage, bone loss, and increased concentrations of TNF-α, IL-6, IL-17, PGE2, MIP-1, anti-type II collagen IgG, MMP-1, and MMP-3. LBP treatments produced significant dose-dependent improvements in CIA-induced bone damage and bone loss, and significantly reduced CIA-stimulated expression of the inflammatory mediators and MMPs. Thus, LBP therapy can preserve bone integrity in CIA mice, possibly through down-regulation of inflammatory mediators.

  4. Inhibition of arthritis by systemic administration of endostatin in passive murine collagen induced arthritis

    PubMed Central

    Kurosaka, D; Yoshida, K; Yasuda, J; Yokoyama, T; Kingetsu, I; Yamaguchi, N; Joh, K; Matsushima, M; Saito, S; Yamada, A

    2003-01-01

    Methods: Four kinds of monoclonal anti-type II collagen antibody followed by lipopolysaccharide (LPS) three days later were given to 6 week old, female Balb/c mice to induce arthritis. Three groups of mice received 0.2 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day of endostatin, respectively, whereas a control group received phosphate buffered saline (PBS). Endostatin or PBS was given for 13 days, starting before the development of arthritis. Arthritis was evaluated by arthritis scores and hind paw thicknesses. Mice were killed for histological examination on the 22nd day after the administration of monoclonal anti-type II collagen antibody. Results: Arthritis developed within three days after LPS administration in both the control and endostatin treatment groups. No difference in the development rate of arthritis was noted between the control and endostatin treatment groups. Arthritis scores remained significantly lower in the endostatin 10 mg/kg/day group than in the control group. Hind paw thicknesses also remained significantly smaller in the endostatin 10 mg/kg/day group than in the control group. Histopathological examination showed that synovial thickening and subchondral bone erosion improved more in the endostatin treatment groups than in the control group. Conclusion: The systemic administration of endostatin had an arthritis inhibiting effect in RA animal models. Endostatin inhibited, in particular, pannus formation and bone destruction. PMID:12810435

  5. Suppression of collagen induced arthritis by idiotype coupled lymphoid cells

    SciTech Connect

    Nagler-Anderson, C.; Gurish, M.F.; Robinson, M.E.; Thorbecke, G.J.

    1986-03-01

    Studies were initiated to evaluate the regulatory influence of idiotype (Id) networks in an experimental auto-immune disease. Collagen induced arthritis is an animal model of polyarthritis induced in susceptible mice by immunization with collagen II (CII). A humoral immune response to CII appears to be critical for the development of diseases. If subpopulations of the anti-CII abs, important for the induction of arthritis, could be identified and manipulated through the presence of a major Id, it should be possible to decrease arthritis incidence by suppressing the production of these Ids. Specifically purified anti-CII abs from arthritic DBA/1 mice were coupled to syngeneic spleen cells and administered IV prior to intradermal immunization with CII. By day 34 after 1/sup 0/ immunization, 100% of control mice and 50% of treated mice had developed arthritis. Suppression of the Id population administered to the treated group was confirmed by RIA. Sera from individual mice were tested as inhibitors of binding of /sup 125/I-labelled polyclonal DBA/1 anti-CII to a rabbit anti-Id directed against polyclonal anti-CII isolated from the sera of arthritic mice. Mean percentage of inhibition of binding of /sup 125/I-Id to rabbit anti-Id by sera from non-arthritic treated mice was found to be significantly lower than that observed in the arthritic control group (p = .045), but did not correlate with total anti-CII ab titers.

  6. Paclitaxel suppresses collagen-induced arthritis: a reevaluation

    PubMed Central

    Zhao, Yi; Chang, Zhi-Fang; Li, Ru; Li, Zhan-Guo; Li, Xiao-Xia; Li, Lin

    2016-01-01

    Objective: To reevaluate the suppressive effect of paclitaxel (PTX) liposome on collagen-induced arthritis (CIA) in rats and explore its mechanisms. Methods: Female Lewis rats were immunized with bovine type II collagen (CII) to induce arthritis. The rats with CIA were randomly divided into three groups: 5% GS control group, 2.5 mg/kg PTX treatment group and 1 mg/kg methotrexate (MTX) positive control group. The drugs were administered by intraperitoneal injection on the second day after arthritis onset. The body weights, arthritis scores and paw volumes were observed consecutively. The ankle joints of rats were collected for X-ray examination and histological evaluation. Serum samples were collected to test the levels of anti-CII antibodies and cytokines. Results: Body weights were not significantly affected after PTX or MTX treatments (p>0.05). Compared with 5% GS control or MTX treatment groups, PTX group showed significant decrease of arthritis scores and paw volumes (p<0.05). Radiographic and histologic evaluation provided evidence that rats with PTX treatment had less synovial proliferation and bone erosion. In addition, the levels of anti-CII antibodies as well as serum tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels were remarkably lower in PTX group than those in 5% GS controls (p<0.05). Conclusions: PTX inhibits the progression of CIA in rats and prevents the destruction of joints. The mechanism might be related to its inhibition on the levels of serum anti-CII antibodies, TNF-α and VEGF. PMID:27904705

  7. Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

    PubMed Central

    Wang, Xian-wei; Zhang, Fen-xi; Yang, Fen; Ding, Zu-feng; Agarwal, Nidhi; Guo, Zhi-kun; Mehta, Jawahar L

    2016-01-01

    Aim: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose- and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms. Methods: Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang II for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-κB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin. Results: Glucose (1–40 mmol/L) and Ang II (10−8–10−5 mol/L) dose-dependently increased the expression of fibronectin, collagens, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. High concentrations of glucose (≥40 mmol/L) and Ang II (≥10−6 mol/L) caused a significant degradation of F-actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 μmol/L) and NF-κB inhibitor JSH-23 (10 μmol/L) both markedly suppressed glucose- and angiotensin II-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10–100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose- and Ang II-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang II-induced F-actin degradation. Conclusion

  8. Adjuvant arthritis pretreatment with type II collagen and Mycobacterium butyricum.

    PubMed

    Franch, A; Cassany, S; Castellote, C; Castell, M

    1992-11-01

    A treatment previous to adjuvant arthritis induction has been performed with type II collagen (CII) or Mycobacterium butyricum (Mb), which is the inducer of the pathology. Pretreatment was administered in two different ways: a) subcutaneously or intradermally 14 days before arthritis induction, and b) intravenously 3 days before induction. In order to relate the change in inflammation to the corresponding antigen immune response, serum antibodies and delayed type hypersensitivity (DTH) against CII or Mb were studied. Pretreatment with s.c. CII 14 days before induction produced slight protection against arthritis and significantly delayed its onset; systemic inflammation showed good positive correlation with anti-CII antibodies. The CII administered i.v. 3 days before arthritic challenge did not significantly modify the inflammatory process. The use of i.d. subarthritogenic doses of Mb 14 days before induction protected a high percentage of the animals from the posterior arthritic challenge; this protection was accompanied by high anti-Mb antibody titers and DTH reaction. When Mb was given i.v. 3 days before induction, a partial protection of inflammation was observed; arthritis was milder and its onset was delayed. These changes were accompanied by reduced humoral and cellular response to Mb.

  9. Water-soluble undenatured type II collagen ameliorates collagen-induced arthritis in mice.

    PubMed

    Yoshinari, Orie; Shiojima, Yoshiaki; Moriyama, Hiroyoshi; Shinozaki, Junichi; Nakane, Takahisa; Masuda, Kazuo; Bagchi, Manashi

    2013-11-01

    Earlier studies have reported the efficacy of type II collagen (C II) in treating rheumatoid arthritis (RA). However, a few studies have investigated the ability of the antigenic collagen to induce oral tolerance, which is defined as active nonresponse to an orally administered antigen. We hypothesized that water-soluble undenatured C II had a similar effect as C II in RA. The present study was designed to examine the oral administration of a novel, water-soluble, undenatured C II (commercially known as NEXT-II) on collagen-induced arthritis (CIA) in mice. In addition, the underlying mechanism of NEXT-II was also identified. After a booster dose (collagen-Freund's complete adjuvant), mice were assigned to control CIA group, or NEXT-II treatment group, to which saline and NEXT-II were administered, respectively. The arthritis index in the NEXT-II group was significantly lower compared with the CIA group. Serum IL-6 levels in the NEXT-II group were significantly lower compared with the CIA group, while serum IL-2 level was higher. Furthermore, oral administration of NEXT-II enhanced the proportion of CD4+CD25+T (Treg) cells, and gene expressions of stimulated dendritic cells induced markers for regulatory T cells such as forkhead box p3 (Foxp3), transforming growth factor (TGF)-β1, and CD25. These results demonstrated that orally administered water-soluble undenatured C II (NEXT-II) is highly efficacious in the suppression of CIA by inducing CD4+CD25+ Treg cells.

  10. Muscle wasting in collagen-induced arthritis and disuse atrophy.

    PubMed

    de Oliveira Nunes Teixeira, Vivian; Filippin, Lidiane Isabel; Viacava, Paula Ramos; de Oliveira, Patrícia Gnieslaw; Xavier, Ricardo Machado

    2013-12-01

    The mechanisms of muscle wasting and decreased mobility have a major functional effect in rheumatoid arthritis, but they have been poorly studied. The objective of our study is to describe muscular involvement and the pathways in an experimental model of arthritis compared to the pathways in disuse atrophy. Female Wistar rats were separated into three groups: control (CO), collagen-induced arthritis (CIA), and immobilized (IM). Spontaneous locomotion and weight were evaluated weekly. The gastrocnemius muscle was evaluated by histology and immunoblotting to measure the expression of myostatin (a negative regulator), LC3 (autophagy), MuRF-1 (proteasome-mediated proteolysis), MyoD, and myogenin (satellite-cell activation). The significance level was set at P < 0.05, and histological analysis of joints confirmed the severity of the arthropathy. There was a significant difference in spontaneous locomotion in the CIA group. Animal body weight, gastrocnemius muscle weight, and relative muscle weight decreased 20%, 30%, and 20%, respectively, in the CIA rats. Inflammatory infiltration and swelling were present in the gastrocnemius muscles of the CIA rats. The mean cross-sectional area was reduced by 30% in the CIA group and by 60% in the IM group. The expressions of myostatin and LC3 between the groups were similar. There was increased expression of MuRF-1 in the IM (1.9-fold) and CIA (3.1-fold) groups and of myogenin in the muscles of the CIA animals (1.7-fold), while MyoD expression was decreased in the IM (20%) rats. This study demonstrated that the development of experimental arthritis is associated with decreased mobility, body weight, and muscle loss. Both IM and CIA animal models presented muscle atrophy, but while proteolysis and the regeneration pathways were activated in the CIA model, there was no activation of regeneration in the IM model. We can assume that muscle atrophy in experimental arthritis is associated with the disease itself and not simply with

  11. Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced arthritis in rats.

    PubMed

    Nielsen, R H; Christiansen, C; Stolina, M; Karsdal, M A

    2008-04-01

    As anti-inflammatory treatments used in rheumatoid arthritis, such as glucocorticoids, often result in secondary detrimental effects on bone health, the objective of this study was to investigate the effects of oestrogen therapy (ET) on the development and activity of collagen-induced arthritis (CIA) in rats, with a focus on assessment of chondroprotective effects using biomarkers of type II collagen degradation. Forty female Lewis rats were allocated into four intervention groups: (i) control + vehicle; (ii) CIA + vehicle; (iii) CIA + ET; and (iv) CIA + prednisolone. During the 28-day intervention period we monitored body weight, time-point of disease onset, incidence of manifest disease and paw volume. Levels of the type II collagen degradation marker (CTX-II) were measured in serum. At euthanasia, hind paws were isolated, extracted for proteins and measured for the concentration of CTX-II. Matrix metalloproteinase (MMP) activity was evaluated using gelatinase zymography. Oestrogen treatment delayed the time-point of disease onset and reduced the incidence and degree of manifest immunoarthritis significantly, assessed by macroscopic evaluation of hind paw inflammation and paw volume. Measures of serum or tissue levels of CTX-II showed significantly reduced type II collagen degradation elicited by oestrogen treatment. In alignment, a decreased activity of MMP-2 and MMP-9 was found in the paw protein extracts. We have demonstrated that the anti-inflammatory effect of ET is linked to chondroprotective effects in an animal model of systemic immunoarthritis. As ET has positive rather than negative effects on bone health in contrast to prednisolone, these observations may be important for potential combination therapy.

  12. Isorhamnetin attenuates collagen-induced arthritis via modulating cytokines and oxidative stress in mice

    PubMed Central

    Wang, Xuewen; Zhong, Wei

    2015-01-01

    Inflammation and oxidative stress were involved in the development and progression of rheumatoid arthritis (RA). Isorhamnetin has anti-inflammatory and anti-oxidative activities, but its effects on RA have not been investigated. In order to observe the possible therapeutic effects of isorhamnetin on RA, we established a collagen-induced arthritis mouse model and treated the animal with isorhamnetin for 3 weeks. Besides, fibroblast-like synoviocytes (FLS) were treated with lipopolysaccharide (LPS) and isorhamnetin. The severity of arthritis was assessed by arthritis score, joint destruction score and inflammation score. Levels of cytokines TNF-α, IL-1β, IL-6, IL-17A, IL-17F, IL-10 and IL-35 in the joint tissue homogenate and cell culture medium as well as anti-type II collagen antibody in serum were measured using ELISA. Contents of H2O2 and malondialdehyde (MDA) in joint tissue homogenate were measured using assay kits. We found collagen immunization induced significant arthritis in mice and isorhamnetin at the dose of 10 and 20 mg/kg/day could significantly attenuate the collagen-induced arthritis. Isorhamnetin also modulated the production of cytokines and suppressed the oxidative stress in the mice with collagen-induced arthritis at the dose of 10 and 20 mg/kg/day. These data suggested that isorhamnetin might be a potential agent for the management of RA. PMID:26629181

  13. Isorhamnetin attenuates collagen-induced arthritis via modulating cytokines and oxidative stress in mice.

    PubMed

    Wang, Xuewen; Zhong, Wei

    2015-01-01

    Inflammation and oxidative stress were involved in the development and progression of rheumatoid arthritis (RA). Isorhamnetin has anti-inflammatory and anti-oxidative activities, but its effects on RA have not been investigated. In order to observe the possible therapeutic effects of isorhamnetin on RA, we established a collagen-induced arthritis mouse model and treated the animal with isorhamnetin for 3 weeks. Besides, fibroblast-like synoviocytes (FLS) were treated with lipopolysaccharide (LPS) and isorhamnetin. The severity of arthritis was assessed by arthritis score, joint destruction score and inflammation score. Levels of cytokines TNF-α, IL-1β, IL-6, IL-17A, IL-17F, IL-10 and IL-35 in the joint tissue homogenate and cell culture medium as well as anti-type II collagen antibody in serum were measured using ELISA. Contents of H2O2 and malondialdehyde (MDA) in joint tissue homogenate were measured using assay kits. We found collagen immunization induced significant arthritis in mice and isorhamnetin at the dose of 10 and 20 mg/kg/day could significantly attenuate the collagen-induced arthritis. Isorhamnetin also modulated the production of cytokines and suppressed the oxidative stress in the mice with collagen-induced arthritis at the dose of 10 and 20 mg/kg/day. These data suggested that isorhamnetin might be a potential agent for the management of RA.

  14. Nimesulide improves the symptomatic and disease modifying effects of leflunomide in collagen induced arthritis.

    PubMed

    Al-Abd, Ahmed M; Al-Abbasi, Fahad A; Nofal, Salwa M; Khalifa, Amani E; Williams, Richard O; El-Eraky, Wafaa I; Nagy, Ayman A; Abdel-Naim, Ashraf B

    2014-01-01

    Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model.

  15. Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-α) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats

    PubMed Central

    ÅKerlund, K; Erlandsson Harris, H; Tracey, K J; Wang, H; Fehniger, T; Klareskog, L; Andersson, J; Andersson, U

    1999-01-01

    A recently developed compound, a multivalent guanylhydrazone (CNI-1493) that inhibits TNF-α production by suppressing TNF-α translational efficiency, was administered in an experimental model of collagen type II-induced arthritis in DA rats. CNI-1493 was injected daily intraperitoneally either before the onset of arthritis or after the establishment of clinical disease. Prophylactic treatment with CNI-1493 significantly prevented or delayed the onset and suppressed the severity of arthritis in a dose-dependent manner. Therapeutic intervention with CNI-1493 in established joint disease also resulted in a significant reduction of clinical signs of arthritis in treated animals. No severe side-effects were noted when animals were treated with daily CNI-1493 doses up to 5 mg/kg. An immunohistochemical study was performed which demonstrated that CNI-1493 led to a reduced expression of TNF-α at the site of disease activity. Thus, CNI-1493 with documented inhibitory effects on TNF-α synthesis, has proven successful in ameliorating the course of arthritis in CIA. We believe that the use of a compound such as CNI-1493 with a defined mode of action provides a useful tool for dissecting and understanding important pathogenic mechanisms operating in the development of chronic arthritis. PMID:9933418

  16. Tolerogenic activity of polymerized type II collagen in preventing collagen-induced arthritis in rats.

    PubMed Central

    Thompson, H S; Henderson, B; Spencer, J M; Hobbs, S M; Peppard, J V; Staines, N A

    1988-01-01

    Rats were exposed parenterally or pergastrically to polymerized type II collagen (POLCII) and became resistant to the subsequent induction of disease with arthritogenic type II collagen (CII) administered intradermally in Freund's incomplete adjuvant (FIA). POLCII was prepared by cross-linking native soluble arthritogenic CII, from bovine nasal septal cartilage, with glutaraldehyde. POLCII injected intradermally in FIA did not induce arthritis. Animals treated in this manner were resistant for a period of at least 100 days to induced disease. The change in the properties of the CII from an arthritogen to a tolerogen was related to the amount of glutaraldehyde (used to polymerize the CII) which was assumed to control the extent of cross-linking of the CII. Highly cross-linked POLCII administered pergastrically, like soluble CII, was not arthritogenic but was tolerogenic, inducing a state of unresponsiveness to a challenge with arthritogenic CII. In general serum anti-CII antibody levels were higher in arthritic than in tolerized non-arthritic rats. It is concluded that the breaking of self-tolerance to CII depends upon its physical state. When polymerized and insoluble, a form analogous to that in which it exists naturally, it is tolerogenic. PMID:3396219

  17. Bacopa monniera (L.) wettst inhibits type II collagen-induced arthritis in rats.

    PubMed

    Viji, V; Kavitha, S K; Helen, A

    2010-09-01

    Bacopa monniera (L.) Wettst is an Ayurvedic herb with antirheumatic potential. This study investigated the therapeutic efficacy of Bacopa monniera in treating rheumatoid arthritis using a type II collagen-induced arthritis rat model. Arthritis was induced in male Wistar rats by immunization with bovine type II collagen in complete Freund's adjuvant. Bacopa monniera extract (BME) was administered after the development of arthritis from day 14 onwards. The total duration of experiment was 60 days. Paw swelling, arthritic index, inflammatory mediators such as cyclooxygenase, lipoxygenase, myeloperoxidase and serum anti-collagen IgG and IgM levels were analysed in control and experimental rats. Arthritic induction significantly increased paw edema and other classical signs of arthritis coupled to upregulation of inflammatory mediators such as cyclooxygenase, lipoxygenase, neutrophil infiltration and increased anti-collagen IgM and IgG levels in serum. BME significantly inhibited the footpad swelling and arthritic symptoms. BME was effective in inhibiting cyclooxygenase and lipoxygenase activities in arthritic rats. Decreased neutrophil infiltration was evident from decreased myeloperoxidase activity and histopathological data where an improvement in joint architecture was also observed. Serum anti-collagen IgM and IgG levels were consistently decreased. Thus the study demonstrates the potential antiarthritic effect of Bacopa monniera for treating arthritis which might confer its antirheumatic activity.

  18. Effects of Oral Administration of Type II Collagen on Rheumatoid Arthritis

    NASA Astrophysics Data System (ADS)

    Trentham, David E.; Dynesius-Trentham, Roselynn A.; Orav, E. John; Combitchi, Daniel; Lorenzo, Carlos; Sewell, Kathryn Lea; Hafler, David A.; Weiner, Howard L.

    1993-09-01

    Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

  19. Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis

    PubMed Central

    Nakahama, Taisuke; Kimura, Akihiro; Nguyen, Nam Trung; Chinen, Ichino; Hanieh, Hamza; Nohara, Keiko; Fujii-Kuriyama, Yoshiaki; Kishimoto, Tadamitsu

    2011-01-01

    The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis have not been elucidated. Here, we show that Ahr deficiency ameliorated collagen-induced arthritis, a mouse model of RA. Collagen-immunized Ahr KO mice showed decreased serum levels of such proinflammatory cytokines as IL-1β and IL-6. The Th17 and Th1 cell populations in lymph nodes from these mice decreased and increased, respectively, whereas the percentage of regulatory T cells was unchanged. Interestingly, a lack of Ahr specifically in T cells significantly suppressed collagen-induced arthritis development, whereas Ahr deficiency in macrophages had no effect. These finding indicate that the development of experimental autoimmune arthritis depends on the presence of Ahr in T cells, and that Th1/Th17 balance may be particularly important for this process. PMID:21825138

  20. Oxidative modification of type II collagen differentially affects its arthritogenic and tolerogenic capacity in experimental arthritis.

    PubMed

    Marcinkiewicz, Janusz; Biedroń, Rafał; Maresz, Katarzyna; Kwaśny-Krochin, Beata; Bobek, Małgorzata; Kontny, Ewa; Maśliński, Wlodzimierz; Chain, Benjamin

    2004-01-01

    Oxidative modification of proteins affects their biological properties. Previously we have shown that hypochlorite (HOCl), the product of activated neutrophils, enhances protein immunogenecity. Collagen type II, a primary component of cartilage, is commonly used in the induction of arthritis in animals (CIA). The aim of this study was to examine whether HOCl may affect immunogenic, tolerogenic, and arthritogenic properties of collagen. DBA/J mice were injected with either native (CNAT) or chlorinated collagen (CHOCl) to induce arthritis. The effect of chlorination on collagen properties was measured by evaluation of incidence and severity of CIA. Moreover, the concentration of serum anti-collagen IgG antibodies and myeloperoxidase (MPO) activity in inflamed joints was determined. Mice immunized with CNAT in adjuvant developed arthritis (CIA) with an incidence of 69%. CNAT also exerted tolerogenic properties when injected intravenously either before or shortly after primary immunization, resulting in decreased incidence and severity of CIA, reduced MPO activity in inflamed joints, and lowered serum levels of anti-CNAT IgG anti-bodies. Chlorination of collagen significantly diminished its ability to induce CIA and to trigger generation of anti-CNAT IgG antibodies. Interestingly, chlorination did not affect tolerogenic properties of collagen administered prior to primary immunization with CNAT. These results suggest that chlorination of collagen may selectively affect functional epitopes of collagen. It is likely that in inflamed joints, neutrophil derived HOCl, in some circumstances, will destroy arthritogenic and immunogenic B cell epitopes, while regulatory T cell epitopes will be preserved.

  1. IL-22 reduces the severity of collagen arthritis in association with increased levels of IL-10

    PubMed Central

    Sarkar, Sujata; Zhou, Xiaoqun; Justa, Shivali; Bommireddy, Swaroopa Rani

    2013-01-01

    Objective The mechanism of action of IL-22 in inflammatory arthritis remains unknown. IL-22 deficient mice have intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen induced arthritis. Further, administration of anti-IL-22 does not reduce severity of clinical arthritis but improves only certain aspects of joint inflammation as assessed by histology. In this report we studied the mechanism of action and the role of systemic IL-22 in modulating target organ inflammation. Methods CIA was induced in DBA mice following immunization with collagen and complete Freund's adjuvant. Expression of IL-22 and its receptor was elucidated in lymphoid organ and target tissues during various phases of arthritis. The effector functions of IL-22 on induction/regulation of various cytokines in in-vitro restimulation cultures were analyzed by ELISA. Recombinant IL-22 with or without anti-IL-10 antibodies was administered to mice following immunization with collagen and prior to the onset of arthritis. Severity of arthritis was evaluated by clinical scoring and histopathology. Anti-collagen antibodies in sera of mice were analyzed by ELISA. Results IL-22 and IL-22 receptor were upregulated in lymphoid organs and joints during the course of arthritis. In vitro IL-22 augmented IL-10, IL-17 and IL-6 in lymphoid tissues. Administration of recombinant IL-22 was associated with increase in IL-10 in-vivo and significant reduction in the progression of severity of arthritis. Anti-IL-10 antibody was associated with the abrogation of this protective effect of IL-22. Conclusion Our data shows, for the first time, that IL-22 plays a protective role in inflammatory arthritis. PMID:23334981

  2. SND-117, a sinomenine bivalent alleviates type II collagen-induced arthritis in mice.

    PubMed

    Zhou, Yu-Ren; Zhao, Yang; Bao, Bei-Hua; Li, Jian-Xin

    2015-06-01

    Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that affects about 1% of the population worldwide. RA is mainly manifested by persistent synovitis and progressive joint destruction. The aim of the present study was to examine the anti-arthritis effects of SND-117, a sinomenine bivalent that is obtained from the structure modification of a clinically available anti-RA drug, sinomenine. The arthritis model (CIA) was established by immunizing DBA/1 mice with type II collagen, and the arthritis scores including inflammation, joint destruction and bone erosion were assessed after booster immunization for 3weeks. The levels of cytokines such as IL-1β, IL-6 and TNF-α were analyzed by quantitative PCR and ELISA. The TNF-α induced NF-κB activation in fibroblast-like synovial cells (FLSCs) was analyzed by Western blot. SND-117 significantly relieved the inflammatory symptoms of collagen-induced arthritis, reduced bone erosion and joint destruction in CIA mice. The serum levels of IL-1β, IL-6 and TNF-α of CIA mice were markedly decreased by SND-117. SND-117 also strongly inhibited the phosphorylation and nuclear translocation of NF-κB p65 in FLSCs upon TNF-α stimulation. These data demonstrated that SND-117 could effectively block the pathogenesis of collagen-induced arthritis in CIA mice via inhibition of NF-κB signaling, and might provide potential clinic benefits in rheumatoid arthritis management.

  3. Anti-Tumor Necrosis Factor Ameliorates Joint Disease in Murine Collagen- Induced Arthritis

    NASA Astrophysics Data System (ADS)

    Williams, Richard O.; Feldmann, Marc; Maini, Ravinder N.

    1992-10-01

    There is considerable evidence implicating tumor necrosis factor α (TNF-α) in the pathogenesis of rheumatoid arthritis. This evidence is based not only on the universal presence of TNF-α in arthritic joints accompanied by the upregulation of TNF-α receptors but also on the effects of neutralizing TNF-α in joint cell cultures. Thus, neutralization of TNF-α in vitro results in inhibition of the production of interleukin 1, which like TNF-α, is believed to contribute to joint inflammation and erosion. To determine the validity of this concept in vivo, the effect of administering TNF-neutralizing antibodies to mice with collagen-induced arthritis has been studied. This disease model was chosen because of its many immunological and pathological similarities to human rheumatoid arthritis. TN3-19.12, a hamster IgG1 monoclonal antibody to murine TNF-α/β, was injected i.p. into mice either before the onset of arthritis or after the establishment of clinical disease. Anti-TNF administered prior to disease onset significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of circulating anti-type II collagen IgG. More relevant to human disease was the capacity of the antibody to reduce the clinical score, paw swelling, and the histological severity of disease even when injected after the onset of clinical arthritis. These results have implications for possible modes of therapy of human arthritis.

  4. Peripheral elimination of the sympathetic nervous system stimulates immunocyte retention in lymph nodes and ameliorates collagen type II arthritis.

    PubMed

    Klatt, Susanne; Stangl, Hubert; Kunath, Julia; Lowin, Torsten; Pongratz, Georg; Straub, Rainer H

    2016-05-01

    In collagen type II-induced arthritis (CIA), early activation of the sympathetic nervous system (SNS) is proinflammatory. Here, we wanted to find new target organs contributing to proinflammatory SNS effects. In addition, we wanted to clarify the importance of SNS-modulated immunocyte migration. A new technique termed spatial energy expenditure configuration (SEEC) was developed to demonstrate bodily areas of high energy demand (to find new targets). We studied homing of labeled cells in vivo, lymphocyte expression of CCR7, supernatant concentration of CCL21, and serum levels of sphingosine-1-phosphate (S1P) in sympathectomized control/arthritic animals. During the course of arthritis, SEEC identified an early marked increase of energy expenditure in draining lymph nodes and spleen (nowhere else!). Although early sympathectomy ameliorated later disease, early sympathectomy increased energy consumption, organ weight, and cell numbers in arthritic secondary lymphoid organs, possibly a sign of lymphocyte retention (also in controls). Elimination of the SNS retained lymph node cells, elevated expression of CCR7 on lymph node cells, and increased CCL21. Serum levels of S1P, an important factor for lymphocyte egress, were higher in arthritic than control animals. Sympathectomy decreased S1P levels in arthritic animals to control levels. Transfer of retained immune cells from draining lymph nodes of sympathectomized donors to sympathectomized recipients markedly increased arthritis severity over weeks. By using the SEEC technique, we identified draining lymph nodes and spleen as major target organs of the SNS. The data show that the SNS increases egress of lymphocytes from draining lymph nodes to stimulate arthritic inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Experimental colitis delays and reduces the severity of collagen-induced arthritis in mice.

    PubMed

    Hablot, Julie; Peyrin-Biroulet, Laurent; Kokten, Tunay; El Omar, Reine; Netter, Patrick; Bastien, Claire; Jouzeau, Jean-Yves; Sokol, Harry; Moulin, David

    2017-01-01

    Amongst extraintestinal manifestations (EIM) occurring in IBD patients, rheumatologic manifestations are the most frequent. Understanding the relationships between arthritis and colitis is a prerequisite to improving the management of these patients. Microbiota of patients with IBD or rheumatologic diseases, like spondyloarthritis (SpA) is modified compared to healthy individual. Thus, we have evaluated the impact of colitis in the development of arthritis in mice and we have analyzed microbiota changes. Collagen-induced arthritis (CIA) was induced at day 0 in DBA1 mice exposed or not to Dextran Sodium Sulfate (DSS) to induce colitis between day 14 and day 21. Animals were monitored regularly for arthritis and colitis severity (clinical score, hindpaw edema). Fecal microbiota was studied by 16S rRNA deep sequencing at critical time points (D14, D14, D21 & D41). At day 41, histological scoring of the intestines and ankles were performed at the end of experiment. Induction of colitis slightly delayed arthritis onset (2 ± 1 days of delay) and reduced its severity (5.75 ± 1.62 in arthritis only group vs 4.00 ± 1.48 in arthritis + colitis group (p = 0.02 at day 28) macroscopically and histologically. In contrast, colitis severity was not influenced by arthritis development. Induction of colitis promoted a modification of microbiota composition and a decrease of α-diversity. Fecal microbiota composition was different between "colitis" and "arthritis+colitis" groups during colitis development. Interestingly a milder decrease of bacterial diversity in the "arthritis+colitis" group was observed. Concomitant experimental colitis protects mice against collagen-induced arthritis and this is associated with changes in gut microbiome composition.

  6. Arthritis instantaneously causes collagen type I and type II degradation in patients with early rheumatoid arthritis: a longitudinal analysis

    PubMed Central

    Landewé, R B M; Geusens, P; van der Heijde, D M F M; Boers, M; van der Linden, S J; Garnero, P

    2006-01-01

    Background Markers of collagen type I (CTX‐1) and type II (CTX‐II) degradation, reflecting bone and cartilage breakdown, appear to predict long term radiographic progression in chronic persistent arthritis. Objective To analyse longitudinally whether changes in arthritis severity are linked to immediate changes in the level of CTX‐I and CTX‐II degradation. Methods CTX‐I and CTX‐II were measured in urine samples from 105 patients with early rheumatoid arthritis who had participated in the COBRA trial at baseline and at 3, 6, 9, and 12 months after the start of treatment. The course of the biomarkers over time was compared with the course of ESR, swollen and tender joint counts, and 28 joint disease activity score (DAS28), measured at the same time points, with adjustment for rheumatoid factor, treatment, and baseline radiographic damage, by generalised estimating equations (GEE) with first order autoregression. Results GEE showed that CTX‐I was longitudinally associated with DAS28, but not with ESR, swollen joint count, or tender joint count. CTX‐II, however, was longitudinally associated with ESR, swollen joint count and DAS28, but not with tender joint count. The longitudinal association implies that an increase in the extent of arthritis is immediately followed by an increase in collagen type II degradation, and to a lesser extent collagen type I degradation. Conclusions Cartilage degradation as measured by CTX‐II and to a lesser extent bone degradation as measured by CTX‐I closely follows indices of arthritis. Clinically perceptible arthritis is responsible for immediate damage, which will become visible on plain x rays only much later. PMID:16126801

  7. Comparison of collagenase-cleaved articular cartilage collagen in mice in the naturally occurring STR/ort model of osteoarthritis and in collagen-induced arthritis.

    PubMed

    Price, J S; Chambers, M G; Poole, A R; Fradin, A; Mason, R M

    2002-03-01

    The STR/ort mouse develops a naturally occurring osteoarthritis of the femorotibial joint that provides a model with which to establish the time course of biochemical changes taking place in articular cartilage in the disease. Our objective was to define the onset, location and progression of type II collagen cleavage by collagenase in the tibial cartilage of the STR/ort mouse. For comparison, cartilage collagen cleavage was also studied in collagen-induced arthritis in DBA mice. STR and control CBA mice aged 6-45 weeks were examined. DBA/1 mice were studied 2 and 3 weeks after initiating collagen-induced arthritis. Collagen cleavage was detected by immunolocalization using the antibody COL2-3/4Cshort which recognizes a carboxy terminal neoepitope created by collagenase cleavage of type I and II collagens. No COL 2-3/4Cshort immunostaining was observed in the intact cartilage of healthy young or old mice. The earliest detectable collagen degradation occurred at the cartilage surface coincident with the appearance of surface roughening. As fibrillations developed, further collagen degradation was evident around the edge of the lesion and in adjacent extracellular matrix. In contrast, staining was observed throughout the cartilage matrix in type II collagen-induced arthritis prior to the development of histopathological lesions. No evidence was found for collagen cleavage in intact/pre-lesional cartilage from STR/ort mice. Local collagen cleavage was, however, clearly associated with very early histopathological lesions and immunostaining with COL 2-3/4Cshort increased with progression of the latter. In contrast, type II collagen cleavage occurs throughout the articular cartilage at an early stage in collagen-induced arthritis. Copyright 2002 OsteoArthritis Research Society International.

  8. Anti-arthritic effect of eugenol on collagen-induced arthritis experimental model.

    PubMed

    Grespan, Renata; Paludo, Marcia; Lemos, Henrique de Paula; Barbosa, Carmem Patrícia; Bersani-Amado, Ciomar Aparecida; Dalalio, Marcia Machado de Oliveira; Cuman, Roberto Kenji Nakamura

    2012-01-01

    This study was designed to test the efficacy of eugenol, a compound obtained from the essential oil of cloves (Syzygium aromaticum) in collagen-induced arthritis (CIA), a well characterized murine model of rheumatoid arthritis. Macroscopic clinical evidence of CIA manifests first as periarticular erythema and edema in the hind paws. Treatment with eugenol starting at the onset of arthritis (day 25) ameliorated these clinical signs of CIA. Furthermore, eugenol inhibited mononuclear cell infiltration into the knee joints of arthritic mice and also lowered the levels of cytokines (tumor necrosis factor (TNF)-α, interferon (IFN)-γ and tumor growth factor (TGF)-β) within the ankle joints. Eugenol treatment did not affect the in vitro cell viability as assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Therefore, eugenol ameliorates experimental arthritis and could be useful as a beneficial supplement in treating human arthritis.

  9. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production.

    PubMed

    Boilard, Eric; Nigrovic, Peter A; Larabee, Katherine; Watts, Gerald F M; Coblyn, Jonathan S; Weinblatt, Michael E; Massarotti, Elena M; Remold-O'Donnell, Eileen; Farndale, Richard W; Ware, Jerry; Lee, David M

    2010-01-29

    In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

  10. Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production

    PubMed Central

    Boilard, Eric; Nigrovic, Peter A.; Larabee, Katherine; Watts, Gerald F. M.; Coblyn, Jonathan S.; Weinblatt, Michael E.; Massarotti, Elena M.; Remold-O'Donnell, Eileen; Farndale, Richard W.; Ware, Jerry; Lee, David M.

    2010-01-01

    In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles—submicrometer vesicles elaborated by activated platelets—in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases. PMID:20110505

  11. Aortic VCAM-1: an early marker of vascular inflammation in collagen-induced arthritis.

    PubMed

    Denys, Anne; Clavel, Gaëlle; Lemeiter, Delphine; Schischmanoff, Olivier; Boissier, Marie-Christophe; Semerano, Luca

    2016-05-01

    Cardiovascular disease (CVD) is a major cause of morbidity and mortality in rheumatoid arthritis (RA). There are limited experimental data on vascular involvement in arthritis models. To study the link between CVD and inflammation in RA, we developed a model of vascular dysfunction and articular inflammation by collagen-induced arthritis (CIA) in C57Bl/6 (B6) mice. We studied the expression of vascular inflammatory markers in CIA with and without concomitant hyperlipidic diet (HD). Collagen-induced arthritis was induced with intradermal injection of chicken type-II collagen followed by a boost 21 days later. Mice with and without CIA were fed a standard diet or an HD for 12 weeks starting from the day of the boost. Arthritis severity was evaluated with a validated clinical score. Aortic mRNA levels of vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS) and interleukin-17 were analysed by quantitative RT-PCR. Vascular cell adhesion molecule-1 localization in the aortic sinus was determined by immunohistochemistry. Atherosclerotic plaque presence was assessed in aortas. Collagen-induced arthritis was associated with increased expression of VCAM-1, independent of diet. VCAM-1 overexpression was detectable as early as 4 weeks after collagen immunization and persisted after 15 weeks. The HD induced atheroma plaque formation and aortic iNOS expression regardless of CIA. Concomitant CIA and HD had no additive effect on atheroma or VCAM-1 or iNOS expression. CIA and an HD diet induced a distinct and independent expression of large-vessel inflammation markers in B6 mice. This model may be relevant for the study of CVD in RA.

  12. Effects of agkistrodon in different dosage forms on collagen-induced arthritis in rats.

    PubMed

    Bao, Jie; Xie, Zhi-Jun; Chen, Lei-Ming; Sun, Jing; Fan, Yong-Sheng

    2016-12-01

    To determine the effective dosage and formulation of agkistrodon in collagen-induced arthritis (CIA) rats. CIA was induced by injection of collagen in complete/incomplete Freund's adjuvant. Agkistrodon decoction, agkistrodon powder, and agkistrodon wine were administered daily starting from the onset of arthritis. Paw swelling degree was measured by using a volume-measuring instrument every 7 days after primary immunization. Arthritis index was measured and calculated using the "five scoring method" every 7 days. The levels of serum interleukin-1ß (IL-1ß) and type II collagen IgG antibodies were detected by enzyme-linked immunosorbent assay. Finally, all ankles were removed, and X-ray radiography was performed with In-vivo Imaging System FX. Samples were counterstained with hematoxylin and eosin for analysis. Among the various dosage formulations of agkistrodon, high-dose powder, which was equivalent to an amount of 6 g/day in adults, showed better effects on the inhibition of joint swelling and reduction of arthritis index score. The relatively low levels of serum IL-1 and anti-type II collagen IgG antibodies, as well as the X-ray radiography and pathology results, further proved the superiority of the high-dose powder over the other formulations. The effect of decoction on inhibiting joint swelling was inversely proportional to the dosage. Other effects, such as reduction of arthritis index score and the levels of serum IL-1 and anti-type II collagen IgG antibodies, were directly proportional to the dosage. While the use of large dose agkistrodon wine led to negative effects. These data highlight the potential function of high-dose agkistrodon powder, which was equivalent to an amount of 6 g/day in adults. The powder can quickly relieve the symptoms of rheumatoid arthritis and prevent aggravation of disease, especially during the early period.

  13. Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis.

    PubMed

    Willis, V C; Banda, N K; Cordova, K N; Chandra, P E; Robinson, W H; Cooper, D C; Lugo, D; Mehta, G; Taylor, S; Tak, P P; Prinjha, R K; Lewis, H D; Holers, V M

    2017-01-27

    Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4-selective inhibitor, GSK199, in the murine collagen-induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end-points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non-citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan-PAD inhibitor Cl-amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end-points.

  14. Mesenchymal stromal cells versus betamethasone can dampen disease activity in the collagen arthritis mouse model.

    PubMed

    El-Denshary, E S M; Rashed, L A; Elhussiny, M

    2014-08-01

    The objective of this study was to compare between the effects of mesenchymal stem cell (MSC) and betamethasone in the treatment of rheumatoid arthritis. Sixty male albino mice were divided equally into 2 models. They are MSC model, group 1: saline control group, group 2: collagen-induced arthritis (CIA), group 3: induced arthritis mice that received intravenous injection of MSCs. Betamethasone model, group 1: phosphate buffer saline, group 2: CIA, group 3: induced arthritis mice that received intraperitoneal injection of betamethasone. Mice arthritis models were assessed by clinical paw edema and X-rays, at the proper time of sacrefaction, tissues were collected and examined using real-time PCR, and synovial tissue was examined for interleukin-10, tumor necrosis factor α, cartilage oligomeric matrix protein and matrix metalloproteinase 3. While serum levels of rheumatoid factor and C-reactive protein were detected by enzyme-linked immunosorbent assay kits. Also blood erythrocyte sedimentation rate was detected. Histopathological, paw edema and PCR results showed improvement in the groups that received MSC compared with the diseased group and the groups which received betamethasone. MSC significantly enhanced the effect of collagen-induced arthritis treatment, which is superior to betamethasone treatment, likely through the modulation of the expression of various cytokines.

  15. Clinical and histopathological characterization of a large animal (ovine) model of collagen-induced arthritis.

    PubMed

    Abdalmula, A; Washington, E A; House, J V; Dooley, L M; Blacklaws, B A; Ghosh, P; Bailey, S R; Kimpton, W G

    2014-05-15

    Collagen induced arthritis (CIA) is the most studied and used rheumatoid arthritis (RA) model in animals, as it shares many pathological and immunological features of the human disease. The aim of this study was to characterize clinical and immunological aspects of the ovine CIA model, and develop lameness and histopathological scoring systems, in order to validate this model for use in therapeutic trials. Sheep were sensitized to bovine type II collagen (BCII), arthritis was induced by injection of bovine collagen type II into the hock joint and the response was followed for two weeks. Clinical signs of lameness and swelling were evident in all sheep and gross thickening of the synovium surrounding the tibiotarsal joint and erosion on the cartilage surface in the arthritic joints. Leucocyte cell counts were increased in synovial fluid and there was synovial hyperplasia, thickening of the intimal layer, inflammation and marked angiogenesis in the synovial tissue. There was a large influx of monocytes and lymphocytes into the synovial tissue, and increased expression of TNF-α and IL-1β in arthritic intima, angiogenesis and upregulation of VCAM-1. CIA in sheep appears to be an excellent large animal model of RA and has the potential for testing biological therapeutics for the treatment of rheumatoid arthritis.

  16. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function.

    PubMed

    Xuzhu, Gao; Komai-Koma, Mousa; Leung, Bernard P; Howe, Hwee Siew; McSharry, Charles; McInnes, Iain B; Xu, Damo

    2012-01-01

    Alcohol intake is inversely related to rheumatoid arthritis (RA) disease incidence and severity. Resveratrol, a safe, well-described plant-derived compound, possesses anti-inflammation and immune-regulatory properties and is present in red wine. As such, it could mediate anti-inflammatory properties of the latter and offer novel therapeutic utility in is own right. To evaluate the therapeutic effect of resveratrol on collagen-induced arthritis (CIA) and its putative immune modulation in mice. CIA was induced in DBA1 mice by immunisation with collagen II. Different doses of resveratrol were administered before or after the development of CIA. The levels of antibody and cytokines in serum or in draining lymph node (DLN) lymphocyte culture supernatants were measured by ELISA and Th17 cell development in DLN was monitored by flow cytometry. Either prophylactic or therapeutic administration of resveratrol attenuated clinical parameters and bone erosion in CIA mice. The arthritis-protective effects were associated with markedly reduced serum levels of pro-inflammatory cytokines and collagen-specific, but not total, IgG, and with reduced numbers of Th17 cells and the production of IL-17 in DLN. Resveratrol modulates inflammatory arthritis in rodents by selectively suppressing key cellular and humoral responses necessary for disease development. This may partly explain the protective effects of red wine but importantly may offer a novel, effective and safe pathway whereby novel agents could be developed to treat RA.

  17. Isoegomaketone Alleviates the Development of Collagen Antibody-Induced Arthritis in Male Balb/c Mice.

    PubMed

    Jin, Chang Hyun; So, Yangkang; Nam, Bomi; Han, Sung Nim; Kim, Jin-Baek

    2017-07-19

    In this study, we attempted to identify and assess effects of isoegomaketone (IK) isolated from Perilla frutescens var. crispa on the development of rheumatoid arthritis (RA). RA was induced in male Balb/c mice by collagen antibody injection. Experimental animals were randomly divided into five groups: normal, collagen antibody-induced arthritis (CAIA), CAIA + IK (5 mg/kg/day), CAIA + IK (10 mg/kg/day), and CAIA + apigenin (16 mg/kg/day) and respective treatments were administered via oral gavage once per day for four days. Mice treated with IK (10 mg/kg/day) developed less severe arthritis than the control CAIA mice. Arthritic score, paw volume, and paw thickness were less significant compared to the control CAIA mice at day seven (73%, 15%, and 14% lower, respectively). Furthermore, histopathological examination of ankle for inflammation showed that infiltration of inflammatory cells and edema formation were reduced by IK treatment. Similarly, neutrophil to lymphocyte ratio (NLR) in whole blood was lower in mice treated with IK (10 mg/kg/day) by 85% when compared to CAIA mice. Taken together, treatment with IK delays the onset of the arthritis and alleviates the manifestations of arthritis in CAIA mice.

  18. Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice.

    PubMed

    Chukkapalli, Sasanka; Rivera-Kweh, Mercedes; Gehlot, Prashasnika; Velsko, Irina; Bhattacharyya, Indraneel; Calise, S John; Satoh, Minoru; Chan, Edward K L; Holoshitz, Joseph; Kesavalu, Lakshmyya

    2016-07-12

    It has been previously hypothesized that oral microbes may be an etiological link between rheumatoid arthritis (RA) and periodontal disease. However, the mechanistic basis of this association is incompletely understood. Here, we investigated the role of periodontal bacteria in induction of joint inflammation in collagen-induced arthritis (CIA) in B10.RIII mice. CIA-prone B10.RIII mice were infected orally with a polybacterial mixture of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia for 24 weeks before induction of CIA. The ability of polybacterial mixture to colonize the periodontium and induce systemic response, horizontal alveolar bone resorption in infected B10.RIII mice was investigated. Arthritis incidence, severity of joint inflammation, pannus formation, skeletal damage, hematogenous dissemination of the infection, matrix metalloproteinase 3 (MMP3) levels, and interleukin-17 expression levels were evaluated. B10.RIII mice had gingival colonization with all three bacteria, higher levels of anti-bacterial immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, significant alveolar bone resorption, and hematogenous dissemination of P. gingivalis to synovial joints. Infected B10.RIII mice had more severe arthritis, and higher serum matrix metalloproteinase 3 levels and activity. Histopathological analysis showed increased inflammatory cell infiltration, destruction of articular cartilage, erosions, and pannus formation. Additionally, involved joints showed had expression levels of interleukin-17. These findings demonstrate that physical presence of periodontal bacteria in synovial joints of B10.RIII mice with collagen-induced arthritis is associated with arthritis exacerbation, and support the hypothesis that oral bacteria, specifically P. gingivalis, play a significant role in augmenting autoimmune arthritis due to their intravascular dissemination to the joints.

  19. Smoking and nicotine exposure delay development of collagen-induced arthritis in mice.

    PubMed

    Lindblad, Sofia S; Mydel, Piotr; Jonsson, Ing-Marie; Senior, Robert M; Tarkowski, Andrej; Bokarewa, Maria

    2009-01-01

    Recent epidemiologic studies have implicated smoking as an environmental risk factor for the development of rheumatoid arthritis (RA). The aim of the present study is the evaluation of the role of cigarette smoke (CS) in the pathogenesis of collagen-induced arthritis in mice. DBA/1 mice exposed to CS for 16 weeks (n = 25) and mice exposed to nicotine in drinking water (n = 10) were immunized with collagen type II (CII). Severity of arthritis was evaluated clinically and morphologically and compared with control mice (n = 35). Intensity of inflammation was evaluated by serum IL-6 and TNF-alpha levels. Additionally, antibody response to CII (anti-CII) and citrullinated peptides (aCCP) was measured. Clinical evaluation of arthritis showed a delayed onset of arthritis in CS-exposed mice compared with non-smoking controls (P < 0.05). Histologic index and weight changes were comparable between the groups; however, smoking mice presented less weight loss during the acute phase of the disease and gained weight significantly faster in the recovery phase (P < 0.05). Similar results were obtained in the mice exposed to nicotine. Nicotine also showed a direct anti-inflammatory effect diminishing IL-6 production by stimulated splenocytes in vitro (P < 0.001). Additionally, smoking mice had lower levels of aCCP and anti-CII antibodies compared with non-smoking (P < 0.05). Neither smoking nor nicotine exposure aggravates development of CII-induced arthritis in mouse model. Moreover, CS exposure was associated with a lower level of anti-CII antibodies, providing a possible explanation for a delay of arthritis onset in this group.

  20. The Extract of Chrysanthemum zawadskii var. latilobum Ameliorates Collagen-Induced Arthritis in Mice

    PubMed Central

    Kim, Hyuk Soon; Kim, Do Kyun; Lee, Jun Ho; Yoo, Young Hyo; Park, Sun Kyu; Nam, Seung Taek; Kim, Hyun Woo; Park, Young Hwan; Lee, Dajeong; Lee, Min Beom

    2016-01-01

    Chrysanthemum zawadskii var. latilobum (CZ) has been used for beverage or tea and also as folk medicine for the remedy of diverse inflammatory diseases. Nevertheless, the therapeutic effect of CZ on arthritis remains to be unknown. In this paper we aim to investigate the CZ's antiarthritic effect and mechanism of action both in vitro and in vivo. To assess CZ's antiarthritic effect, mouse models of type II collagen-induced arthritis (CIA) were used. Mice were used to gauge clinical arthritis index and histopathological changes. Reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting, electrophoretic mobility shift assay (EMSA), and other biological methods were adopted to measure CZ's effect on arthritis and to understand the veiled mechanism of action. CZ greatly suppressed CIA, histopathological score, bone erosion, and osteoclast differentiation. Mechanistically, CZ inhibited the production of various inflammatory and arthritic mediators like inflammatory cytokines, matrix metalloproteinases (MMPs), and chemokines. Of note, CZ significantly suppressed the activation of the NF-κB pathway in vivo. CZ exerted an antiarthritic effect in CIA mice by curbing the production of crucial inflammatory and arthritis mediators. This study warrants further investigation of CZ for the use in human rheumatoid arthritis (RA). PMID:27840652

  1. Gallium nitrate ameliorates type II collagen-induced arthritis in mice.

    PubMed

    Choi, Jae-Hyeog; Lee, Jong-Hwan; Roh, Kug-Hwan; Seo, Su-Kil; Choi, Il-Whan; Park, Sae-Gwang; Lim, Jun-Goo; Lee, Won-Jin; Kim, Myoung-Hun; Cho, Kwang-rae; Kim, Young-Jae

    2014-05-01

    Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Gallium nitrate has been reported to reserve immunosuppressive activities. Therefore, we assessed the therapeutic effects of gallium nitrate in the mouse model of developed type II collagen-induced arthritis (CIA). CIA was induced by bovine type II collagen with Complete Freund's adjuvant. CIA mice were intraperitoneally treated from day 36 to day 49 after immunization with 3.5mg/kg/day, 7mg/kg/day gallium nitrate or vehicle. Gallium nitrate ameliorated the progression of mice with CIA. The clinical symptoms of collagen-induced arthritis did not progress after treatment with gallium nitrate. Gallium nitrate inhibited the increase of CD4(+) T cell populations (p<0.05) and also inhibited the type II collagen-specific IgG2a-isotype autoantibodies (p<0.05). Gallium nitrate reduced the serum levels of TNF-α, IL-6 and IFN-γ (p<0.05) and the mRNA expression levels of these cytokine and MMPs (MMP2 and MMP9) in joint tissues. Western blotting of members of the NF-κB signaling pathway revealed that gallium nitrate inhibits the activation of NF-κB by blocking IκB degradation. These data suggest that gallium nitrate is a potential therapeutic agent for autoimmune inflammatory arthritis through its inhibition of the NF-κB pathway, and these results may help to elucidate gallium nitrate-mediated mechanisms of immunosuppression in patients with RA. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice.

    PubMed

    Hammaker, Deepa; Topolewski, Katharyn; Edgar, Meghan; Yoshizawa, Toshio; Fukushima, Akihisa; Boyle, David L; Burak, Esther Cory; Sah, Robert L; Firestein, Gary S

    2012-03-01

    The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model. Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-) mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction. MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-) mice and intermediate in MKK-3(-/-) mice compared with WT mice. MKK-6(-/-) mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-) mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-) mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice. Reduced disease severity in MKK-6(-/-) mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA. Copyright © 2012 by the American College of Rheumatology.

  3. Metabolomics analysis of collagen-induced arthritis in rats and interventional effects of oral tolerance.

    PubMed

    Ding, Xinghong; Hu, Jinbo; Li, Jinfeng; Zhang, Yan; Shui, Bingjie; Ding, Zhishan; Yao, Li; Fan, Yongsheng

    2014-08-01

    A serum metabolomics method based on rapid resolution liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (RRLC-Q-TOF-MS) was performed for a holistic evaluation of the metabolic changes of collagen-induced arthritis (CIA) in rats and to assess the interventional effects of type II collagen (CII) in this model. Partial least-squares-discriminant analysis (PLS-DA) was employed to study the metabolic profiling of CIA rats and control rats. Ten metabolites, namely, 12(S)-HHTrE, 12(S)-HEPE, PGE2, TXB2, 12(S)-HETE, LysoPE(16:0), PE(O-18:0/0:0), Lyso-PE(18:2), Lyso-PE(20:4), and Lyso-PC(22:5) were identified as differential metabolites associated with the pathogenesis of CIA. These results suggested that dysregulation of the arachidonic acid (AA) and phospholipid metabolic networks is involved in the pathomechanism of CIA. Differential metabolomics and histopathological analyses demonstrated that CII inhibits the progress of arthritis. Furthermore, the therapeutic effects of CII on CIA may involve regulation of the disordered AA and phospholipid metabolic networks. This metabolomics study provides new insights into the pathogenesis of arthritis and, furthermore, indicates the potential mechanism underlying the significantly increased prevalence of metabolic syndrome, defined as a clustering of cardiovascular disease (CVD) risk factors, in arthritis patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis.

    PubMed

    Damsker, Jesse M; Okwumabua, Ifeanyi; Pushkarsky, Tatiana; Arora, Kamalpreet; Bukrinsky, Michael I; Constant, Stephanie L

    2009-01-01

    CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147-cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147-cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4(+) T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by >75%. Such findings suggest that CD147-cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues.

  5. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis

    PubMed Central

    Damsker, Jesse M; Okwumabua, Ifeanyi; Pushkarsky, Tatiana; Arora, Kamalpreet; Bukrinsky, Michael I; Constant, Stephanie L

    2009-01-01

    CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147–cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147–cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4+ T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by > 75%. Such findings suggest that CD147–cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues. PMID:18557953

  6. Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.

    PubMed Central

    Zhang, H; Yang, Y; Horton, J L; Samoilova, E B; Judge, T A; Turka, L A; Wilson, J M; Chen, Y

    1997-01-01

    Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease. PMID:9329958

  7. Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis.

    PubMed

    Umar, Sadiq; Umar, Khalid; Sarwar, Abu Hasnath Md Golam; Khan, Altaf; Ahmad, Niyaz; Ahmad, Sayeed; Katiyar, Chandra Kant; Husain, Syed Akhtar; Khan, Haider A

    2014-05-15

    Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system.

  8. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis

    PubMed Central

    2013-01-01

    Introduction Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model. Methods DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund’s adjuvant (CFA) or incomplete Freund’s adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression. Results Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA

  9. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis.

    PubMed

    Marchesan, Julie Teresa; Gerow, Elizabeth Ann; Schaff, Riley; Taut, Andrei Dan; Shin, Seung-Yun; Sugai, James; Brand, David; Burberry, Aaron; Jorns, Julie; Lundy, Steven Karl; Nuñez, Gabriel; Fox, David A; Giannobile, William V

    2013-11-12

    Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model. DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression. Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA/CII group and IL-1β, tumor necrosis

  10. Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice

    PubMed Central

    Svetlicky, N; Kivity, S; Odeh, Q; Shovman, O; Gertel, S; Amital, H; Gendelman, O; Volkov, A; Barshack, I; Bar-Meir, E; Blank, M; Shoenfeld, Y

    2015-01-01

    Administration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anti-citrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, low-dose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzyme-linked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (Treg) population by fluorescence activated cell sorter (FACS). ACPA-sIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the Treg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing

  11. Prophylactic and Therapeutic Effects of Acanthopanax senticosus Harms Extract on Murine Collagen-induced Arthritis

    PubMed Central

    Takahashi, Yusuke; Tanaka, Maki; Murai, Ryosei; Kuribayashi, Kageaki; Kobayashi, Daisuke; Yanagihara, Nozomi; Watanabe, Naoki

    2014-01-01

    Evidences are accumulating that extract of Acanthopanax senticosus Harms (ASH; syn Eleutherococcus senticosus [Rupr. & Maxim.] Maxim), a shrub native to Northeastern Asia, has antiinflammatory effects. In this study, we examined prophylactic and therapeutic effects of ASH extract (ASHE) on rheumatoid arthritis using collagen-induced arthritis (CIA) mouse model. Acanthopanax senticosus Harms extract was administered before the onset of arthritis in the prophylaxis model. In the therapeutic model, ASHE was administered after the onset of arthritis with or without anti-TNF-α antibody. The ASHE treatment showed efficacy before onset of CIA but there was no effect after CIA was established. The ASHE treatment delayed the onset and decreased severity of CIA. In vitro examinations showed that ASHE is an antioxidant and that ASHE suppresses TNF-α and interleukin-6 production in human peripheral blood mononuclear cells. The combination therapy with ASHE and anti-TNF-α antibody reduced the severity of arthritis compared with anti-TNF-α antibody alone. The present study shows that ASHE has prophylactic effect against CIA and support therapeutic effect of anti-TNF-α antibody. © 2014 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd. PMID:24797499

  12. Prophylactic and therapeutic effects of Acanthopanax senticosus Harms extract on murine collagen-induced arthritis.

    PubMed

    Takahashi, Yusuke; Tanaka, Maki; Murai, Ryosei; Kuribayashi, Kageaki; Kobayashi, Daisuke; Yanagihara, Nozomi; Watanabe, Naoki

    2014-10-01

    Evidences are accumulating that extract of Acanthopanax senticosus Harms (ASH; syn Eleutherococcus senticosus [Rupr. & Maxim.] Maxim), a shrub native to Northeastern Asia, has antiinflammatory effects. In this study, we examined prophylactic and therapeutic effects of ASH extract (ASHE) on rheumatoid arthritis using collagen-induced arthritis (CIA) mouse model. Acanthopanax senticosus Harms extract was administered before the onset of arthritis in the prophylaxis model. In the therapeutic model, ASHE was administered after the onset of arthritis with or without anti-TNF-α antibody. The ASHE treatment showed efficacy before onset of CIA but there was no effect after CIA was established. The ASHE treatment delayed the onset and decreased severity of CIA. In vitro examinations showed that ASHE is an antioxidant and that ASHE suppresses TNF-α and interleukin-6 production in human peripheral blood mononuclear cells. The combination therapy with ASHE and anti-TNF-α antibody reduced the severity of arthritis compared with anti-TNF-α antibody alone. The present study shows that ASHE has prophylactic effect against CIA and support therapeutic effect of anti-TNF-α antibody.

  13. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats.

    PubMed

    Radhakrishnan, Ammu; Tudawe, Dulanthi; Chakravarthi, Srikumar; Chiew, Gan Seng; Haleagrahara, Nagaraja

    2014-05-01

    Tocotrienols exhibit a significant anti-inflammatory and antioxidant effect in numerous human diseases. However, the anti-inflammatory and antioxidant effects of tocotrienols in arthritic conditions are not well documented. Therefore, the effect of γ-tocotrienol supplementation against oxidative stress and joint pathology in collagen-induced arthritis in rats was investigated in the present study. Adult female Dark Agouti rats were randomly divided into groups: Control, γ-tocotrienol alone, arthritis alone and arthritis with γ-tocotrienol. Arthritis was induced using 4 mg/kg body weight collagen in complete Freund's adjuvant. The rats were treated orally with 5 mg/kg body weight of γ-tocotrienol between day 21 and day 45. After 45 days, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) and total glutathione (GSH) assays were conducted. γ-tocotrienol significantly reduced the arthritis-induced changes in body weight, CRP, TNF-α, SOD and the total GSH levels. There was a significant reduction in the arthritis-induced histopathological changes in the γ-tocotrienol treatment group. The data indicated that administration of γ-tocotrienol resulted in a significant antioxidant and anti-inflammatory effect on collagen-induced arthritis; therefore, γ-tocotrienol may have therapeutic potential as a long-term anti-arthritic agent in rheumatoid arthritis therapy.

  14. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats

    PubMed Central

    RADHAKRISHNAN, AMMU; TUDAWE, DULANTHI; CHAKRAVARTHI, SRIKUMAR; CHIEW, GAN SENG; HALEAGRAHARA, NAGARAJA

    2014-01-01

    Tocotrienols exhibit a significant anti-inflammatory and antioxidant effect in numerous human diseases. However, the anti-inflammatory and antioxidant effects of tocotrienols in arthritic conditions are not well documented. Therefore, the effect of γ-tocotrienol supplementation against oxidative stress and joint pathology in collagen-induced arthritis in rats was investigated in the present study. Adult female Dark Agouti rats were randomly divided into groups: Control, γ-tocotrienol alone, arthritis alone and arthritis with γ-tocotrienol. Arthritis was induced using 4 mg/kg body weight collagen in complete Freund’s adjuvant. The rats were treated orally with 5 mg/kg body weight of γ-tocotrienol between day 21 and day 45. After 45 days, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) and total glutathione (GSH) assays were conducted. γ-tocotrienol significantly reduced the arthritis-induced changes in body weight, CRP, TNF-α, SOD and the total GSH levels. There was a significant reduction in the arthritis-induced histopathological changes in the γ-tocotrienol treatment group. The data indicated that administration of γ-tocotrienol resulted in a significant antioxidant and anti-inflammatory effect on collagen-induced arthritis; therefore, γ-tocotrienol may have therapeutic potential as a long-term anti-arthritic agent in rheumatoid arthritis therapy. PMID:24940448

  15. Locomotion and muscle mass measures in a murine model of collagen-induced arthritis.

    PubMed

    Hartog, Anita; Hulsman, Judith; Garssen, Johan

    2009-06-03

    Rheumatoid arthritis (RA) is characterized by chronic poly-arthritis, synovial hyperplasia, erosive synovitis, progressive cartilage and bone destruction accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in the skeletal muscle and can in part be explained by a decreased physical activity. The murine collagen induced arthritis (CIA) model has been proven to be a useful model in RA research since it shares many immunological and pathological features with human RA. The present study explored the interactions between arthritis development, locomotion and muscle mass in the CIA model. CIA was induced in male DBA/1 mice. Locomotion was registered at different time points by a camera and evaluated by a computerized tracing system. Arthritis severity was detected by the traditionally used semi-quantitative clinical scores. The muscle mass of the hind-legs was detected at the end of the study by weighing. A methotrexate (MTX) intervention group was included to study the applicability of the locomotion and muscle mass for testing effectiveness of interventions in more detail. There is a strong correlation between clinical arthritis and locomotion. The correlations between muscle mass and locomotion or clinical arthritis were less pronounced. MTX intervention resulted in an improvement of disease severity accompanied by an increase in locomotion and muscle mass. The present data demonstrate that registration of locomotion followed by a computerized evaluation of the movements is a simple non invasive quantitative method to define disease severity and evaluate effectiveness of therapeutic agents in the CIA model.

  16. The role of lipopolysaccharide injected systemically in the reactivation of collagen-induced arthritis in mice

    PubMed Central

    Yoshino, Shin; Ohsawa, Motoyasu

    2000-01-01

    We investigated the role of bacterial lipopolysaccharide (LPS) in the reactivation of autoimmune disease by using collagen-induced arthritis (CIA) in mice in which autoimmunity to the joint cartilage component type II collagen (CII) was involved.CIA was induced by immunization with CII emulsified with complete Freund's adjuvant at the base of the tail (day 0) followed by a booster injection on day 21. Varying doses of LPS from E. coli were i.p. injected on day 50.Arthritis began to develop on day 25 after immunization with CII and reached a peak on day 35. Thereafter, arthritis subsided gradually but moderate joint inflammation was still observed on day 50. An i.p. injection of LPS on day 50 markedly reactivated arthritis on a dose-related fashion. Histologically, on day 55, there were marked oedema of synovium which had proliferated by the day of LPS injection, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. The reactivation of CIA by LPS was associated with increases in anti-CII IgG and IgG2a antibodies as well as various cytokines including IL-12, IFN-γ, IL-1β, and TNF-α. LPS from S. enteritidis, S. typhimurium, and K. neumoniae and its component, lipid A from E. coli also reactivated the disease. Polymyxin B sulphate suppressed LPS- or lipid A-induced reactivation of CIA.These results suggest that LPS may play an important role in the reactivation of autoimmune joint inflammatory diseases such as rheumatoid arthritis in humans. PMID:10742285

  17. Phenotypic characterization of type II collagen-induced arthritis in Wistar rats.

    PubMed

    Song, Hou-Pan; Li, Xin; Yu, Rong; Zeng, Guang; Yuan, Zhen-Yi; Wang, Wei; Huang, Hui-Yong; Cai, Xiong

    2015-10-01

    The aim of the present study was to determine a more specific, efficient and simple method for the induction of collagen-induced arthritis (CIA) in rats. Different strains of rats were injected at the base of the tail with bovine type II collagen (CII) emulsified in incomplete Freund's adjuvant (IFA). The onset and severity of arthritis were evaluated by clinical assessment. The established CIA model was analyzed using a comprehensive examination of clinical, hematological, histological and radiological parameters. The results demonstrated that Wistar rats were the most susceptible strain to CIA followed by Wistar Furth rats, with Sprague Dawley rats being the least susceptible. Following primary and booster immunization, female Wistar rats developed severe arthritis, with an incidence of >83% and low variability in clinical signs. The development of arthritis was accompanied by a significantly elevated erythrocyte sedimentation rate compared with that in the control rats. The radiographic examination revealed bone matrix resorption, considerable soft tissue swelling, periosteal new bone formation and bone erosion in the arthritic joints of the CIA rats. Histopathologically, the synovial joints of CIA rats were characterized by synovial hyperplasia, pannus formation, marked cellular infiltration, bone and cartilage erosion and narrowing of the joint space. The administration of an intradermal injection of only 200 µg bovine CII emulsified in IFA at the base of the tail therefore leads to the successful development of a CIA rat model. This well-characterized CIA rat model could be specifically used to study the pathophysiology of human rheumatoid arthritis as well as to test and develop anti-arthritic agents for humans.

  18. Partial depletion of natural gut flora by antibiotic aggravates collagen induced arthritis (CIA) in mice.

    PubMed

    Dorożyńska, Iwona; Majewska-Szczepanik, Monika; Marcińska, Katarzyna; Szczepanik, Marian

    2014-04-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects about 1% of the adult population and occurs twice as frequently among women than men. At present it is accepted that pathogenesis of RA is based on inflammatory response mediated by CD4(+) Th1 and Th17 lymphocytes. The most commonly applied model imitating RA is the collagen induced arthritis (CIA). A growing evidence shows that there is a correlation between microbial dysbiosis and human pathology which includes autoimmunity, allergic diseases, obesity, inflammatory bowel disease (IBD), metabolic syndrome. Collagen induced arthritis was used to study influence of natural gut flora on course of rheumatoid arthritis. Current work employing CIA model showed that partial depletion of natural gut flora with orally administered antibiotic Baytril (enrofloxacin) aggravates disease severity when compared to control mice. Observed partial depletion of both aerobic and anaerobic bacteria did not affect animal body weight. Additionally, in vitro study showed increased production of IFN-? and IL-17A and decreased release of IL-4 by axillary lymph node cells (ALNC) isolated from mice treated with antibiotic and induced CIA when compared to positive control. Furthermore, treatment with antibiotic prior to CIA induction results in augmented production of IFN-?, IL-17A and IL-6 by mesenteric lymph node cells (MLNC). Presented data suggest that alteration of gut microbiota via use of enrofloxacin may play a role in modulating arthritis symptom severity in this mouse model. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Age-Related Differences in Collagen-Induced Arthritis: Clinical and Imaging Correlations

    PubMed Central

    Wilson-Gerwing, Tracy D; Pratt, Isaac V; Cooper, David M L; Silver, Tawni I; Rosenberg, Alan M

    2013-01-01

    Arthritis is among the most common chronic diseases in both children and adults. Although intraarticular inflammation is the feature common among all patients with chronic arthritis there are, in addition to age at onset, clinical characteristics that further distinguish the disease in pediatric and adult populations. In this study, we aimed to demonstrate the utility of microCT (µCT) and ultrasonography in characterizing pathologic age-related differences in a collagen-induced arthritis (CIA) rat model. Juvenile (35 d old) and young adult (91 d old) male Wistar rats were immunized with bovine type II collagen and incomplete Freund adjuvant to induce polyarthritis. Naïve male Wistar rats served as controls. All paws were scored on a scale of 0 (normal paw) to 4 (disuse of paw). Rats were euthanized at 14 d after the onset of arthritis and the hindpaws imaged by µCT and ultrasonography. Young adult rats had more severe signs of arthritis than did their juvenile counterparts. Imaging demonstrated that young adult CIA rats exhibited more widespread and severe skeletal lesions of the phalanges, metatarsals, and tarsal bones, whereas juvenile CIA rats had more localized and less proliferative and osteolytic damage that was confined predominantly to the phalanges and metatarsals. This report demonstrates the utility of imaging modalities to compare juvenile and young adult rats with CIA and provides evidence that disease characteristics and progression differ between the 2 age groups. Our observations indicate that the CIA model could help discern age-related pathologic processes in inflammatory joint diseases. PMID:24326225

  20. The adaptor protein CIKS/Act1 is necessary to induce collagen-induced arthritis pathology and it contributes to collagen-specific antibody production

    PubMed Central

    Pisitkun, Prapaporn; Claudio, Estefania; Ren, Nina; Wang, Hongshan; Siebenlist, Ulrich

    2010-01-01

    Objective CIKS/Act1 is an adaptor molecule necessary for signaling by members of the IL-17 cytokine family. Here we aim to determine whether this adaptor is required for collagen-induced arthritis (CIA). If required, CIKS-mediated signaling could be a potential target for therapeutic intervention in rheumatoid arthritis. Methods CIA model studies were performed with CIKS deficient and sufficient mice on an otherwise wild-type C57BL/6 background or on a background lacking FcγRIIb. In addition, wild-type and CIKS deficient mice were subjected to collagen-antibody induced arthritis (CAIA) studies. Arthritis pathology was determined by visual inspection of the paws, by histochemical analysis of tissue sections and by measurements of collagen-specific antibodies. Results Arthritis pathology could be readily induced with the CIA model in wild-type mice and pathology was exacerbated in FcγRIIb-deficient mice. In contrast, CIKS deficient mice were protected from all aspects of CIA pathology, even in FcγRIIb deficient mice. The absence of CIKS completely prevented neutrophil infiltration into joints, bone erosion and cartilage damage; furthermore, production of collagen type 2-specific antibodies (CII-Abs) was reduced. In contrast to the CIA model, CIKS deficient mice remained susceptible to arthritis induced with the CAIA model. Conclusion CIKS-mediated signaling is necessary for the pathogenesis in the CIA model, but not in the CAIA model. These findings suggest critical functions of CIKS during the development of arthritis in the CIA model, including in the formation of CII-Abs, and they mark the CIKS adaptor as a potential therapeutic target in RA. PMID:20662069

  1. Dynamics of Early Synovial Cytokine Expression in Rodent Collagen-Induced Arthritis

    PubMed Central

    Palmblad, Karin; Erlandsson-Harris, Helena; Tracey, Kevin J.; Andersson, Ulf

    2001-01-01

    This study was performed to elucidate pathophysiological events before and during the course of collagen-induced arthritis in Dark Agouti rats, a model for rheumatoid arthritis. Kinetic studies of local cytokine responses were determined using immunohistochemical techniques, quantified by computer-assisted image analysis. We recently reported that the macrophage-pacifying agent CNI-1493 successfully ameliorated collagen-induced arthritis. In the present trial, we investigated the potential of CNI-1493 to down-regulate pro-inflammatory cytokines. Synovial cryosections were analyzed at various time points for the presence of interleukin (IL)-1β, tumor necrosis factor (TNF), and transforming growth factor (TGF)-β. Unexpectedly, an early simultaneous TNF and IL-1β expression was detected in resident cells in the lining layer, preceding disease onset and inflammatory cell infiltration by >1 week. The predominant cytokine synthesis by synovial (ED1+) macrophages coincided with clinical disease. TNF production greatly exceeded that of IL-1β. CNI-1493 treatment did not affect the early disease-preceding TNF and IL-1β synthesis in the lining layer. However, after disease onset, CNI-1493 intervention resulted in a pronounced reduced IL-1β and in particular TNF expression. Furthermore, CNI-1493 significantly up-regulated synthesis of the anti-inflammatory cytokine TGF-β and thereby shifted the balance of pro-inflammatory and anti-inflammatory cytokines in the arthritic joint in a beneficial way. PMID:11159186

  2. Preventive Effect of Lactobacillus helveticus SBT2171 on Collagen-Induced Arthritis in Mice

    PubMed Central

    Yamashita, Maya; Matsumoto, Kurumi; Endo, Tsutomu; Ukibe, Ken; Hosoya, Tomohiro; Matsubara, Yumi; Nakagawa, Hisako; Sakai, Fumihiko; Miyazaki, Tadaaki

    2017-01-01

    We recently reported that the intraperitoneal inoculation of Lactobacillus helveticus SBT2171 inhibited the development of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis (RA). In the present study, we evaluated the effect of the oral administration of L. helveticus SBT2171 on CIA development and on the regulation of antigen-specific antibody production and inflammatory immune cells, which have been implicated in the development of RA. Both oral administration and intraperitoneal inoculation of L. helveticus SBT2171 reduced joint swelling, body weight loss, and the serum level of bovine type II collagen (CII)-specific antibodies in the CIA mouse model. The intraperitoneal inoculation also decreased the arthritis incidence, joint damage, and serum level of interleukin (IL)-6. In addition, the numbers of total immune cells, total B cells, germinal center B cells, and CD4+ T cells in the draining lymph nodes were decreased following intraperitoneal inoculation of L. helveticus SBT2171. These findings demonstrate the ability of L. helveticus SBT2171 to downregulate the abundance of immune cells and the subsequent production of CII-specific antibodies and IL-6, thereby suppressing the CIA symptoms, indicating its potential for use in the prevention of RA. PMID:28680422

  3. Attenuation of collagen-induced arthritis in mice by salmon proteoglycan.

    PubMed

    Yoshimura, Sayuri; Asano, Krisana; Nakane, Akio

    2014-01-01

    Rheumatoid arthritis (RA) is a serious autoimmune disease caused by chronic inflammation of connective tissues. The basic principle of RA treatment is aimed to reduce joint inflammation. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in different mouse inflammatory diseases. In this study, we investigated the prophylactic effect of PG on the progression of RA using an experimental mouse model, collagen-induced arthritis (CIA). Clinical and histological severity of CIA was attenuated by daily oral administration of PG. In the joints of PG-administered mice, infiltration of macrophages and neutrophils and also osteoclast accumulation were limited. In comparison to nonadministered mice, anti-collagen antibodies in the sera of PG-administered mice did not alter. On the other hand, local expression of interleukin-17A (IL-17A), IL-6, IL-1 β, interferon- γ (IFN- γ), C-C chemokine ligand 2 (CCL2), C-X-C chemokine ligand 1 (CXCL1), and CXCL2 in the joints of PG-administered mice decreased. Moreover, in the response of type II collagen- (CII-) restimulation ex vivo, IL-17A and IFN- γ production by splenocytes from PG-administered mice was less than that of control mice. These data suggested that daily ingested PG attenuated CIA pathogenesis by modulating immune response of splenocytes to CII stimulation and local production inflammatory cytokines and chemokines in the joints.

  4. Interleukin-22 reduces the severity of collagen-induced arthritis in association with increased levels of interleukin-10.

    PubMed

    Sarkar, Sujata; Zhou, Xiaoqun; Justa, Shivali; Bommireddy, Swaroopa Rani

    2013-04-01

    The mechanism of action of interleukin- 22 (IL-22) in inflammatory arthritis remains unknown. IL-22-deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen-induced arthritis (CIA). Further, administration of anti-IL-22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL-22 in modulating target organ inflammation. CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL-22 and its receptor (IL-22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL-22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme-linked immunosorbent assay (ELISA). Recombinant IL-22 with or without anti-IL-10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA. IL-22 and IL-22R were up-regulated in lymphoid organs and joints during the course of arthritis. IL-22 augmented IL-10, IL-17, and IL-6 in lymphoid tissues in vitro. Administration of recombinant IL-22 was associated with an increase in IL-10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti-IL-10 antibody treatment was associated with the abrogation of this protective effect of IL-22. Our data demonstrate, for the first time, that IL-22 has a protective role in inflammatory arthritis. Copyright © 2013 by the American College of Rheumatology.

  5. A proinflammatory role for Fas in joints of mice with collagen-induced arthritis

    PubMed Central

    Tu-Rapp, Hoang; Hammermüller, André; Mix, Eilhard; Kreutzer, Hans-Jürgen; Goerlich, Roland; Köhler, Hansjürgen; Nizze, Horst; Thiesen, Hans-Jürgen; Ibrahim, Saleh M

    2004-01-01

    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. PMID:15380040

  6. The Role of Leukocyte-Associated Ig-like Receptor-1 in Suppressing Collagen-Induced Arthritis.

    PubMed

    Kim, Seunghyun; Easterling, Ellis R; Price, Lauren C; Smith, Savannah L; Coligan, John E; Park, Jeoung-Eun; Brand, David D; Rosloniec, Edward F; Stuart, John M; Kang, Andrew H; Myers, Linda K

    2017-09-08

    Several observations implicate a critical role for T cell dysregulation as a central problem in rheumatoid arthritis. We investigated a mechanism for suppressing T cell activation by stimulating a natural inhibitory receptor called leukocyte-associated Ig-like receptor-1 (LAIR-1). The collagen-induced arthritis (CIA) model and DR-1 transgenic mice were used to study the importance of LAIR-1 in autoimmune arthritis. Splenocytes from wild-type or LAIR-1(-/-) mice were stimulated with soluble anti-CD3 Ab in the presence or absence of α1(II) and supernatants were collected for cytokine analysis. B6.DR1 mice were immunized with type II collagen/CFA to induce arthritis and were treated with either the stimulatory mAb to LAIR-1 or a hamster IgG control. Finally, B6.DR1/LAIR-1(-/-) and B6.DR1/LAIR-1(+/+) mice were challenged for CIA and mean severity scores were recorded thrice weekly. Using splenocytes or purified CD4(+) cells that were sufficient in LAIR-1, CD3-induced cytokine secretion was significantly suppressed in the presence of collagen, whereas LAIR-1-deficient splenocytes had no attenuation. Treatment with a stimulatory mAb to LAIR-1 also significantly attenuated CIA in the LAIR(+/+) mice. When B6.DR1/LAIR-1(-/-) mice were immunized with type II collagen they developed more severe arthritis and had a greater percentage of affected limbs than the wild-type mice. These data demonstrate that collagen can suppress the T cell cytokine response through the action of LAIR-1. Treatment with stimulating LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1(-/-) mice develop more severe arthritis than wild-type controls. These data suggest that LAIR-1 may be a potential therapeutic target for suppressing rheumatoid arthritis. Copyright © 2017 by The American Association of Immunologists, Inc.

  7. Decreased collagen-induced arthritis severity and adaptive immunity in mitogen activated protein kinase kinase 6 -deficient mice

    PubMed Central

    Hammaker, Deepa; Topolewski, Katharyn; Edgar, Meghan; Yoshizawa, Toshio; Fukushima, Akihisa; Boyle, David L.; Firestein, Gary S.

    2011-01-01

    Objective MAPK kinases MKK3 and MKK6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis. Previous studies demonstrated that MKK3- or MKK6-deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK3- and MKK6-deficiency in the collagen induced arthritis model. Methods Wildtype, MKK3−/−, and MKK6−/− mice were immunized with bovine type II collagen (CII). Disease activity was evaluated by semiquantitative scoring, histology, and microcomputed tomography. Serum anti-collagen antibody levels were quantified by ELISA. In-vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinase was determined by qPCR. Results MKK6-deficiency markedly reduced arthritis severity compared with WT mice, while absence of MKK3 had an intermediate effect. Joint damage was minimal in arthritic MKK6−/− mice and intermediate in MKK3−/− mice compared with wild type mice. MKK6−/− mice had modestly lower levels of pathogenic anti-collagen antibodies than WT or MKK3−/− mice. In vitro T cell assays showed reduced proliferation and IL-17 production by MKK6−/− cells in response to type II collagen. Gene expression of synovial IL-6, matrix metalloproteinases MMP3, and MMP13 was significantly inhibited in MKK6-deficient mice. Conclusion Reduced disease severity in MKK6−/− mice correlated with decreased anti-collagen responses indicating that MKK6 is a crucial regulator of inflammation joint destruction in CIA. MKK6 is a potential therapeutic target in complex diseases involving adaptive immune responses like rheumatoid arthritis. PMID:21953132

  8. Supplement of 5-hydroxytryptophan before induction suppresses inflammation and collagen-induced arthritis.

    PubMed

    Yang, Tao-Hsiang; Hsu, Peng-Yang; Meng, Menghsiao; Su, Che-Chun

    2015-12-15

    Evidence is accumulating that a preclinical phase is present before the onset of clinical signs and symptoms of rheumatoid arthritis (RA). This phase represents an important therapeutic window within which interventions can dramatically modulate outcomes. An agent able to prevent RA for high risk individuals in this phase is therefore desired. In this study, we investigated whether tryptophan metabolite, 5-hydroxytryptophan (5-HTP) or 5-methoxytryptophan (5-MTP), can act as such an agent for primary prevention of collagen-induced arthritis (CIA). Mouse splenocytes were pretreated with 5-HTP or 5-MTP and activated by anti-CD3 plus anti-CD28 antibodies in vitro. The percentages of interferon-γ (IFNγ)(+)CD4(+) T cells and interleukin-17 (IL-17)(+)CD4(+) T cells were measured by flow cytometry. The production of pro-inflammatory cytokines, serotonin and kynurenine was measured by enzyme-linked immunosorbent assay. A CIA model was used to investigate the in vivo effects of 5-HTP on the prevention of arthritis. 5-HTP decreased the percentages of IFNγ(+)CD4(+) T cells and IL-17(+)CD4(+) T cells and suppressed the production of IL-2, IL-4, IL-6, IL-17, tumor necrosis factor-α (TNFα) and IFNγ in activated splenocytes. 5-HTP administered before induction decreased the disease activities in CIA mice and suppressed the production of TNFα, IL-6 and cyclooxygenase-2 in arthritic joints. 5-HTP also increased serotonin, but decreased kynurenine in the CIA mice. 5-HTP suppresses inflammation and arthritis through decreasing the production of pro-inflammatory mediators. 5-HTP supplement before induction ameliorates arthritis in a CIA model.

  9. Recombinant Galectin-1 and Its Genetic Delivery Suppress Collagen-Induced Arthritis via T Cell Apoptosis

    PubMed Central

    Rabinovich, Gabriel A.; Daly, Gordon; Dreja, Hanna; Tailor, Hitakshi; Riera, Clelia M.; Hirabayashi, Jun; Chernajovsky, Yuti

    1999-01-01

    Galectin-1 (GAL-1), a member of a family of conserved β-galactoside–binding proteins, has been shown to induce in vitro apoptosis of activated T cells and immature thymocytes. We assessed the therapeutic effects and mechanisms of action of delivery of GAL-1 in a collagen-induced arthritis model. A single injection of syngeneic DBA/1 fibroblasts engineered to secrete GAL-1 at the day of disease onset was able to abrogate clinical and histopathological manifestations of arthritis. This effect was reproduced by daily administration of recombinant GAL-1. GAL-1 treatment resulted in reduction in anticollagen immunoglobulin (Ig)G levels. The cytokine profile in draining lymph node cells and the anticollagen IgG isotypes in mice sera at the end of the treatment clearly showed inhibition of the proinflammatory response and skewing towards a type 2–polarized immune reaction. Lymph node cells from mice engaged in the gene therapy protocol increased their susceptibility to antigen-induced apoptosis. Moreover, GAL-1–expressing fibroblasts and recombinant GAL-1 revealed a specific dose-dependent inhibitory effect in vitro in antigen-dependent interleukin 2 production to an Aq-restricted, collagen type 2–specific T cell hybridoma clone. Thus, a correlation between the apoptotic properties of GAL-1 in vitro and its immunomodulatory properties in vivo supports its therapeutic potential in the treatment of T helper cell type 1–mediated autoimmune disorders. PMID:10430627

  10. Potent Antiarthritic Properties of Phloretin in Murine Collagen-Induced Arthritis

    PubMed Central

    Wang, Shun-Ping; Li, Shiming; Chao, Ya-Hsuan

    2016-01-01

    In the exploration of potential therapeutic agents for rheumatoid arthritis (RA), DBA/1J mice are used as the RA model of collagen-induced arthritis (CIA). Phloretin, a flavonoid compound extracted from Prunus mandshurica, has been found to exhibit anti-inflammatory activity, making it a potential candidate for treatment of RA. The objective of this study was to evaluate the therapeutic effects of phloretin on CIA mice. CIA mice were dosed daily with phloretin at either 50 or 100 mg/kg among two treatment groups. CIA treated mice showed mitigation of clinical symptoms of RA in addition to reduced inflammation of hind-limbs compared to mice who did not receive phloretin. Histological analysis showed that phloretin suppressed the severity of RA and effectively mitigated joint inflammation and cartilage- and bone-destruction via reducing proinflammatory cytokine productions (TNF-α, IL-6, IL-1β, and IL-17). This was at least partially mediated by causing inadequate splenocyte activation and proliferation. Moreover, phloretin-treated CIA mice showed decreased oxidative stress and diminished levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in paw tissues as well as reduced productivity of anti-collagen antibodies in serum. We have concluded that phloretin could be a potent and effective antiarthritis agent, demonstrating anti-inflammatory, antioxidative, and immunomodulatory effects in CIA mice. PMID:28044086

  11. Suppression of collagen-induced arthritis with a serine proteinase inhibitor (serpin) derived from myxoma virus.

    PubMed

    Brahn, Ernest; Lee, Sarah; Lucas, Alexandra; McFadden, Grant; Macaulay, Colin

    2014-08-01

    Many viruses encode virulence factors to facilitate their own survival by modulating a host's inflammatory response. One of these factors, secreted from cells infected with myxoma virus, is the serine proteinase inhibitor (serpin) Serp-1. Because Serp-1 had demonstrated anti-inflammatory properties in arterial injury models and viral infections, it was cloned and evaluated for therapeutic efficacy in collagen-induced arthritis (CIA). Clinical severity was significantly lower in the Serp-1 protocols (p<0.0001) and blinded radiographs indicated that the Serp-1 group had significantly less erosions than the controls (p<0.01). Delayed-type hypersensitivity was lower in the Serp-1 group but antibody titers to type II collagen were not significantly altered. Recipients had minimal histopathologic synovial changes and did not develop neutralizing antibodies to Serp-1. These results indicate that Serp-1 impedes the pathogenesis of CIA and suggests that the therapeutic potential of serine proteinase inhibitors in inflammatory joint diseases, such as rheumatoid arthritis, should be investigated further.

  12. The destruction evaluation in different foot joints: new ideas in collagen-induced arthritis rat model.

    PubMed

    Zhang, Peng; Han, Dong; Tang, Tingting; Zhang, Xiaoling; Dai, Kerong

    2009-04-01

    Collagen-induced arthritis (CIA) has been widely used as the animal model of rheumatoid arthritis since 1977, while till now, no paper has depicted the destruction characteristics in different foot joints. In this study, we observed the differences among the foot joint destruction process of CIA to elucidate further the pathological process of this model. CIA was induced in male Wistar rat immunized with bovine type II collagen and Freund's incomplete adjuvant. Radiological studies were performed 1, 2, 4, 6, and 8 months after the second immunization to follow the development of disease. At last, all the animals were killed and histological research was performed. In the histological observation, three main types of joint destructions such as subchondral side erosion, external joint erosion and the cartilaginous fusion of articular cartilage were identified. All these destruction forms exist in one joint or several different joints. Furthermore, we found that tartrate-resistant acid phosphatase (TRAP) stain-positive cells participated in the destruction of articular cartilage. These new findings showed that in the disease process of the CIA model, different foot joints show different destruction characteristics and cartilaginous fusion of foot joints is another typical pathological characteristic.

  13. Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis.

    PubMed

    Bashi, T; Shovman, O; Fridkin, M; Volkov, A; Barshack, I; Blank, M; Shoenfeld, Y

    2016-04-01

    Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin-PC (TPC), a novel helminth-based compound in collagen-induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 µg/0.1 ml) or orally (250 µg/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme-linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (Treg ) and regulatory B (Breg ) cell phenotypes by fluorescence-activated cell sorter (FACS). TPC-treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC-treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL-10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)-α, interleukin (IL)-17 and IL-1β (P < 0.0001). TPC significantly expanded the CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) Treg cells and CD19(+) IL-10(+) CD5(high) CD1d(high) T cell immunoglobulin mucin-1 (TIM-1(+) ) Breg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti-inflammatory cytokine expression, as well as expansion of Treg and Breg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset.

  14. Iridoid glycosides from the flowers of Gentiana macrophylla Pall. ameliorate collagen-induced arthritis in rats.

    PubMed

    Jia, Na; Chu, Wei; Li, Yuwen; Ding, Likun; Duan, Jialin; Cui, Jia; Cao, Shanshan; Zhao, Chao; Wu, Yin; Wen, Aidong

    2016-08-02

    The flowers of Gentiana macrophylla have been usually applied to cure the joint inflammation and rheumatoid arthritis in Traditional Chinese Medicine. This work aimed to investigate the anti-rheumatoid arthritic effect and possible mechanism of iridoid glycosides from G. macrophylla (GMI) using an animal model of collagen-induced rheumatoid arthritis (CIA) in rats. All rats were randomly divided into five groups: normal control, CIA, dexamethasone, 15mg/kg and 30mg/kg GMI. CIA was induced (day 0) in male Sprague-Dawley rats by intradermal injection of complete Bovine CII at the base of the tail. Dexamethasone was chosen as the positive drug. The administration of different drugs started from day 1 and continued for 28 days. Paw swelling, arthritis score and histopathological changes were examined to assess the severity of arthritis. In addition, the serum levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions in joint synovial tissues were detected. GMI reduced paw edema, arthritis scores and the index of spleen and thymus from day 7 to 21 after CIA compared with those in the CIA group. Our data also demonstrated that GMI inhibited pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, regulated the expression of iNOS and COX-2 compared with those in the CIA group. We also obtained four major components from GMI, identified as loganic acid, swertamarin, gentiopicroside and sweroside, and the contents of them were also calculated respectively. Taken together, our results shed light on the therapeutic efficacy of GMI in rats rheumatoid arthritis model by reducing the levels of IL-1β, IL-6 and TNF-α in serum as well as down-regulating the levels of iNOS and COX-2. Therefore, GMI may be an effective therapy for the treatment of rheumatoid arthritis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Ascidian tunicate extracts attenuate rheumatoid arthritis in a collagen-induced murine model.

    PubMed

    Hong, Seong-Ho; Kwone, Jung-Taek; Lee, Jae-Ho; Lee, Somin; Lee, Ah Young; Cho, Won-Young; Bat-Erdene, Munkhjargal; Choi, Byeong-Dae; Cho, Myung-Haing

    2014-06-01

    Murine rheumatoid arthritis models are often used to investigate the potential therapeutic effects of candidate drugs. The present study has been conducted in order to investigate the therapeutic efficacy of ascidian tunicate extracts in a collagen-induced arthritis DBA1/J mice model. Four types of formulas, ascidian tunicate extracts (ATE), crude ascidian tunicate glycans (ATEC), ascidian tunicate extracts with licorice extracts (ATEL), and crude ascidian tunicate glycans with licorice extracts (ATECL) were orally administered into DBA/1J mice for 3 weeks and paw edema and thickness were evaluated. Changes in inflammatory proteins and cytokines levels were monitored in hind leg tissues by Western blot and quantitative PCR analysis. The oral administration of ascidian tunicate extracts alleviated paw edema and improved the histological hind leg cartilage status. The extracts also reduced the matrix metalloproteinase-9 (MMP-9) protein and prostaglandin E synthase (PGES) levels. In addition, the extracts-treated groups showed increased interleukin-10 (IL-10) levels compared with the non-treated group. These findings suggest that orally administered ascidian tunicate extracts might have potential therapeutic effects for the treatment of rheumatoid arthritis.

  16. Etanercept-Synthesising Mesenchymal Stem Cells Efficiently Ameliorate Collagen-Induced Arthritis

    PubMed Central

    Park, Narae; Rim, Yeri Alice; Jung, Hyerin; Kim, Juryun; Yi, Hyoju; Kim, Youngkyun; Jang, Yeonsue; Jung, Seung Min; Lee, Jennifer; Kwok, Seung-Ki; Park, Sung-Hwan; Ju, Ji Hyeon

    2017-01-01

    Mesenchymal stem cells (MSCs) have multiple properties including anti-inflammatory and immunomodulatory effects in various disease models and clinical treatments. These beneficial effects, however, are sometimes inconsistent and unpredictable. For wider and proper application, scientists sought to improve MSC functions by engineering. We aimed to invent a novel method to produce synthetic biological drugs from engineered MSCs. We investigated the anti-arthritic effect of engineered MSCs in a collagen-induced arthritis (CIA) model. Biologics such as etanercept are the most successful drugs used in anti-cytokine therapy. Biologics are made of protein components, and thus can be theoretically produced from cells including MSCs. MSCs were transfected with recombinant minicircles encoding etanercept (trade name, Enbrel), which is a tumour necrosis factor α blocker currently used to treat rheumatoid arthritis. We confirmed minicircle expression in MSCs in vitro based on GFP. Etanercept production was verified from the conditioned media. We confirmed that self-reproduced etanercept was biologically active in vitro. Arthritis subsided more efficiently in CIA mice injected with mcTNFR2MSCs than in those injected with conventional MSCs or etanercept only. Although this novel strategy is in a very early conceptual stage, it seems to represent a potential alternative method for the delivery of biologics and engineering MSCs. PMID:28084468

  17. Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis

    PubMed Central

    Mancheño-Corvo, Pablo; Lopez-Santalla, Mercedes; Menta, Ramon; DelaRosa, Olga; Mulero, Francisca; del Rio, Borja; Ramirez, Cristina; Büscher, Dirk; Bueren, Juan A.; Lopez-Belmonte, Juan; Dalemans, Wilfried; Garin, Marina I.; Lombardo, Eleuterio

    2017-01-01

    Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulatory properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Previous studies have demonstrated that MSCs, administered systemically, migrate to lymphoid tissues associated with the inflammatory site where functional MSC-induced immune cells with a regulatory phenotype were increased mediating the immunomodulatory effects of MSCs. These results suggest that homing of MSCs to the lymphatic system plays an important role in the mechanism of action of MSCs in vivo. Thus, we hypothesized that direct intralymphatic (IL) (also referred as intranodal) administration of MSCs could be an alternative and effective route of administration for MSC-based therapy. Here, we report the feasibility and efficacy of the IL administration of human expanded adipose mesenchymal stem cells (eASCs) in a mouse model of collagen-induced arthritis (CIA). IL administration of eASCs attenuated the severity and progression of arthritis, reduced bone destruction and increased the levels of regulatory T cells (CD25+Foxp3+CD4+ cells) and Tr1 cells (IL10+CD4+), in spleen and draining lymph nodes. Taken together, these results indicate that IL administration of eASCs is very effective in modulating established CIA and may represent an alternative treatment modality for cell therapy with eASCs. PMID:28484460

  18. Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys

    PubMed Central

    Murakami, Ikuo; Ishikawa, Yuichi; Suzuki, Tomoki; Sumida, Shun-ichiro; Ibaragi, Shigeru; Kasai, Hayato; Horai, Naoto; Drolet, Daniel W.; Gupta, Shashi; Janjic, Nebojsa

    2016-01-01

    Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis. PMID:26579954

  19. Effect of Brand's glucosamine with essence of chicken on collagen-induced arthritis in rats.

    PubMed

    Tsi, Daniel; Khow, Agatha; Iino, Taeko; Kiso, Yoshinobu; Ono, Hiroyuki

    2003-10-24

    The anti-arthritic effects of glucosamine incorporated in a chicken-meat extract known as Brand's Glucosamine with Essence of Chicken versus glucosamine or Essence of Chicken (EOC) alone were investigated on collagen induced arthritis (CIA) in dark agouti (DA) rats. Four groups of rats received basic food (control), 1.2% glucosamine (GLU), 0.8% EOC and 1.2% GLU + 0.8% EOC (GLU + EOC) admixed with basic food for 25 days following CIA. Foot pads were isolated on day 25 for histopathological evaluation. Clinical assessment of hind paw swelling as measured by foot pad volumes and histopathological scoring based on the degree of edema, periosteal new bone formation, periostitis and inflammatory cell infiltration of the isolated foot pad were performed. Arthritic rats given GLU + EOC showed significant reduction in left hind paw swelling following onset of arthritis. Correspondingly, a lesser degree of edema, periosteal new bone formation, periostitis and inflammatory cell infiltration was seen in histological sections of the left hind foot pads of these rats. A similar trend of reduced hind paw swelling was observed in the right hind paws of the same rats and those fed with EOC. Rats fed with GLU alone did not demonstrate these beneficial effects. The present findings demonstrate that a combination of glucosamine and EOC is effective in reducing the histopathological severity of arthritis, probably due to its ability to reduce the inflammatory conditions in CIA.

  20. Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.

    PubMed

    Tang, Kuo-Tung; Chao, Ya-Hsuan; Chen, Der-Yuan; Lim, Yun-Ping; Chen, Yi-Ming; Li, Yi-Rong; Yang, Deng-Ho; Lin, Chi-Chen

    2016-10-01

    The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.

  1. Unmasking of a Protective TNFR1 Mediated Signal in the Collagen Arthritis Model

    PubMed Central

    Williams-Skipp, Cheryll; Raman, Thiagarajan; Valuck, Robert J.; Watkins, Herschel; Palmer, Brent E.; Scheinman, Robert I.

    2009-01-01

    OBJECTIVE: TNFR1 plays a major role in rheumatoid arthritis (RA). Here we explore the relative importance of TNFR1 signaling in the hematopoietic tissue compartment for disease progression. METHODS: DBA/1 mice were lethally irradiated and rescued with bone marrow derived from either DBA/1 or TNFR1−/− animals. The mice were then input into the collagen induced arthritis (CIA) model and disease progression characterized. RESULTS: Surprisingly, TNFR1−/− transplant mice input into the CIA model develop increased disease as compared to controls. This could not be attributed to either an increased primary response to collagen or to the contribution of a non-DBA genetic background. Histological markers of advanced disease were evident in TNFR1−/− transplant mice shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNFα was undetectable while serum IL-12p40 levels were increased in TNFR1−/− transplant mice at the end point of the study. CONCLUSION: These data raise the intriguing possibility of the existence of an anti-inflammatory TNFR1 mediated circuit in the hematopoietic compartment. This circuit bears a resemblance to emerging data delineating a switch in TNFα function observed in the resolution of bacterial infections. These data suggest that TNFR1 mediated signals in the radio-resistant tissues contributes to disease progression while TNFR1 mediated signals in the radio-sensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of responce to TNFα blockade in RA is dependent, in part, on the relative genetic strengths of these two pathways. PMID:19180511

  2. Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis.

    PubMed

    Gui, Huan; Liu, Xia; Liu, Li-Rong; Su, Ding-Feng; Dai, Sheng-Ming

    2015-06-01

    Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which is devoid of psychoactivity. We have demonstrated the expression of CB2R in synovial tissue from patients with rheumatoid arthritis (RA), and its specific activation shows inhibitory effects on fibroblast-like synoviocytes. However, it is still unclear whether selective activation of CB2R inhibits joint inflammation or protects joint damage in RA. A murine model of collagen-induced arthritis (CIA) was used to evaluate the therapeutic efficacy of HU-308, a selective CB2R agonist. The disease severity was evaluated by semi-quantitative scoring of joint swelling, histological assessment of joint inflammation and structure, and radiographic assessment of joint destruction by using digital plain radiographs and micro-CT scans. The concentrations of various isotypes of anti-collagen II antibodies in sera and the levels of cytokines in culture supernatants were determined by ELISA. Compared with vehicle treatment, protective treatment with intraperitoneal injection of HU-308 (0.3-1.0 mg/kg) failed to decrease the incidence of the development of CIA, but it effectively suppressed the severity of the disease. In CIA mice, treatment with HU-308 significantly decreased joint swelling, synovial inflammation, and joint destruction, as well as serum levels of anti-collagen II antibodies. In vitro, HU-308 (1-10 μM) significantly suppressed the production of proinflammatory cytokines IL-6 and TNF-α from lipopolysaccharide-stimulated murine peritoneal macrophages with intact CB2R in dose-dependent manners. HU-308 failed to elicit any inhibitory effect of on lipopolysaccharide-stimulated macrophages from CB2R-knockout mice. Activation of CB2R by HU-308 has therapeutic potential for RA to suppress synovitis and alleviate joint destruction by inhibiting the production of autoantibodies and proinflammatory cytokines. Copyright © 2014 Elsevier GmbH. All

  3. Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA).

    PubMed

    Ando, Wataru; Hashimoto, Jun; Nampei, Akihide; Tsuboi, Hideki; Tateishi, Kosuke; Ono, Takeshi; Nakamura, Norimasa; Ochi, Takahiro; Yoshikawa, Hideki

    2006-01-01

    Macrophage colony-stimulating factor (M-CSF) is a key factor for osteoclastogenesis at the bone-pannus interface in patients with rheumatoid arthritis as well as a receptor activator of NF-kappaB ligand (RANKL). Imatinib mesylate inhibits the phosphorylation of c-fms, a receptor for M-CSF. The present study investigates the effect of imatinib mesylate on joint destruction in rats with collagen-induced arthritis (CIA) and on osteoclastogenesis in vitro. Imatinib mesylate (50 or 150 mg/kg), dexamethasone, or vehicle was administered daily to CIA rats for 4 weeks from the onset of arthritis. Hind-paw swelling and body weight were measured weekly. At weeks 2 and 4, the metatarsophalangeal (MTP) joints and the ankle and subtalar joints were radiographically and histologically assessed. The effect of imatinib mesylate on osteoclast formation from rat bone marrow cells with M-CSF and soluble RANKL (sRANKL) in vitro was also examined. Radiographic assessment showed that 150 mg/kg imatinib mesylate suppressed the destruction of the MTP and the ankle and subtalar joints at week 2, and MTP joint destruction at week 4 in CIA rats, although hind-paw swelling was not suppressed. The number of TRAP-positive cells at the bone-pannus interface was significantly reduced in the group administered with 150 mg/kg imatinib mesylate compared with that given vehicle at week 4. Imatinib mesylate dose-dependently inhibited the proliferation of M-CSF-dependent osteoclast precursor cells in vitro as well as osteoclast formation induced by M-CSF and sRANKL. These findings suggest that imatinib mesylate could prevent joint destruction in patients with rheumatoid arthritis.

  4. Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.

    PubMed

    van den Brand, B T; Abdollahi-Roodsaz, S; Vermeij, E A; Bennink, M B; Arntz, O J; Rothlin, C V; van den Berg, W B; van de Loo, F A J

    2013-03-01

    Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA). Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression. Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis. This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis

  5. Protective effects of a blueberry extract in acute inflammation and collagen-induced arthritis in the rat.

    PubMed

    Figueira, Maria-Eduardo; Oliveira, Mónica; Direito, Rosa; Rocha, João; Alves, Paula; Serra, Ana-Teresa; Duarte, Catarina; Bronze, Rosário; Fernandes, Adelaide; Brites, Dora; Freitas, Marisa; Fernandes, Eduarda; Sepodes, Bruno

    2016-10-01

    Here we investigated the anti-inflammatory effect of a blueberry extract in the carrageenan-induced paw edema model and collagen-induced arthritis model, both in rats. Along with the chemical characterization of the phenolic content of the fruits and extract, the antioxidant potential of the extract, the cellular antioxidant activity and the effects over neutrophils' oxidative burst, were studied in order to provide a mechanistic insight for the anti-inflammatory effects observed. The extract significantly inhibited paw edema formation in an acute model the rat. Our results also demonstrate that the standardized extract had pharmacological activity when administered orally in the collagen-induced arthritis model in the rat and was able to significantly reduce the development of clinical signs of arthritis and the degree of bone resorption, soft tissue swelling and osteophyte formation, consequently improving articular function in treated animals.

  6. Nimesulide improves the disease modifying anti-rheumatic profile of methotrexate in mice with collagen-induced arthritis.

    PubMed

    Al-Abd, Ahmed M; Inglis, Julia J; Nofal, Salwa M; Khalifa, Amani E; Williams, Richard O; El-Eraky, Wafaa I; Abdel-Naim, Ashraf B

    2010-10-10

    Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis.

  7. An essential role for mast cells as modulators of neutrophils influx in collagen-induced arthritis in the mouse

    PubMed Central

    Pimentel, Tatiana Aparecida; Sampaio, Andrxsé Luiz Franco; D’Acquisto, Fulvio; Perretti, Mauro; Oliani, Sonia Maria

    2012-01-01

    Mast cells are involved in immune disorders so that many of the proinflammatory and tissue destructive mediators produced by these cells have been implicated in the pathogenesis of rheumatoid arthritis. This scenario prompted us to investigate the correlation between mast cell degranulation and neutrophil influx within the digits and knees joints of arthritic mice assessing what could be the functional role(s) of joint mast cells in the response to collagen immunization. DBA/1J mice were submitted to collagen-induced arthritis and disease was assessed on day 21, 32 and 42 post-immunization. Pharmacological treatment with the glucocorticoid prednisolone, commonly used in the clinic, and nedocromil, a mast cell stabilizer, was performed from day 21 to 30. Arthritis developing after immunization gradually increased up to day 42. Neutrophil infiltration peaked on day 32 and 21, in the digits and knees, respectively, showing an unequal pattern of recruitment between these tissues. This difference emerged for mast cell they peaked in the digits on day 21, but a higher degree of degranulation could be measured in the knee joints. Uneven modulation of arthritis occurred after treatment of mice with prednisolone or nedocromil. Neutrophils migration to the tissue was reduced after both therapies, but only prednisolone augmented mast cell migration to the joints. Nedocromil exerted inhibitory properties both on mast cell proliferation and migration, more effectively on the digit joints. Thus, collagen induced an inflammatory process characterized by tissue mast cells activation and degranulation, suggesting a potential driving force in propagating inflammatory circuits yielding recruitment of neutrophils. However, the different degree of affected joint involvement suggests a time-related implication of digits and knees during collagen-induced arthritis development. These results provide evidence for local alterations whereby mast cells contribute to the initiation of

  8. Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice

    PubMed Central

    2013-01-01

    Introduction N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, antiinflammatory, and neuroprotective mediator. The aim of this study was to investigate the effect of co-ultramicronized PEA + luteolin formulation on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). Methods CIA was induced by an intradermally injection of 100 μl of the emulsion (containing 100 μg of bovine type II collagen (CII)) and complete Freund adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice subjected to CIA were administered PEA (10 mg/kg 10% ethanol, intraperitoneally (i.p.)) or co-ultramicronized PEA + luteolin (1 mg/kg, i.p.) every 24 hours, starting from day 25 to 35. Results Mice developed erosive hind-paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hindpaws. The incidence of CIA was 100% by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with a resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with PEA or PEA + luteolin ameliorated the clinical signs at days 26 to 35 and improved histologic status in the joint and paw. The degree of oxidative and nitrosative damage was significantly reduced in PEA + luteolin-treated mice, as indicated by nitrotyrosine and malondialdehyde (MDA) levels. Plasma levels of the proinflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment. Conclusions We demonstrated that PEA co-ultramicronized with luteolin exerts an antiinflammatory effect during chronic inflammation and ameliorates CIA. PMID:24246048

  9. Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis

    SciTech Connect

    Gonzalez-Gay, M.A.; Zanelli, E.; Krco, C.J.

    1995-05-01

    Collagen-induced arthritis (CIA) is an animal model of auto immune polyarthritis, sharing similarities with rheumatoid arthritis (RA). Paradoxally, susceptibility to mouse CIA is controlled by the H2A loci (DQ homologous) while RA is linked to HLA.DR genes (H2E homologous). We recently showed that the E{beta}{sup d} molecule prevents CIA development in susceptible H2{sup q} mice. We addressed the question of whether H2Eb polymorphism will influence CIA incidence as HLA.DRB1 polymorphism does in RA. In F{sub 1} mice, only H2Eb{sup d} and H2Eb{sup s} molecules showed protection. Using recombinant B10.RDD (Eb{sup d/b}) mice, we found that CIA protection was mediated by the first domain of the E{beta}{sup d} molecule. Using peptides covering the third hypervariable region of the E{beta} chain, we found a perfect correlation between presentation of E{beta} peptides by the H2A{sup q} molecule and protection on CIA. Therefore, the mechanism by which H2Eb protects against CIA seems to rely on the affinity of E{beta} peptides for the H2A{sup q} molecule. 35 refs., 2 figs., 3 tabs.

  10. Resistance to collagen-induced arthritis in SHPS-1 mutant mice

    SciTech Connect

    Okuzawa, Chie; Kaneko, Yoriaki; Murata, Yoji; Miyake, Astuko; Saito, Yasuyuki; Okajo, Jun; Tomizawa, Takeshi; Kaneko, Yuka; Okazawa, Hideki; Ohnishi, Hiroshi; Matozaki, Takashi Nojima, Yoshihisa

    2008-07-04

    SHPS-1 is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Here we show that mice expressing a mutant form of SHPS-1 fail to develop type-II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans. Histological examinations of the arthritic paws from immunized wild-type mice revealed that cartilage was destroyed in association with marked mononuclear cell infiltration, while only mild cell infiltration was observed in immunized SHPS-1 mutant mice. Consistently, the serum levels of both IgG and IgG2a specific to CII and of IL-1{beta} in immunized SHPS-1 mutant mice were markedly reduced compared with those apparent for wild-type mice. The CII-induced proliferation of, and production of cytokines by, T cells from immunized SHPS-1 mutant mice were reduced compared to wild-type cells. These results suggest that SHPS-1 is essential for development of CIA.

  11. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis

    PubMed Central

    Muschter, Dominique; Schäfer, Nicole; Stangl, Hubert; Straub, Rainer H.; Grässel, Susanne

    2015-01-01

    Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10-6M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors. PMID:26431344

  12. Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis

    PubMed Central

    Wang, Qingtong; Wang, Longsheng; Wu, Li; Zhang, Mei; Hu, Shanshan; Wang, Rui; Han, Yongsheng; Wu, Yujing; Zhang, Lingling; Wang, Xinming; Sun, Wuyi; Wei, Wei

    2017-01-01

    T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4+ helper T (Th) cell and CD8+ cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1β, TNF-α and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway. PMID:28349925

  13. Treatment with recombinant Hsp72 suppresses collagen-induced arthritis in mice.

    PubMed

    Luo, Xinjing; Zuo, Xiaoxia; Mo, Xuanrong; Zhou, Yaou; Xiao, Xianzhong

    2011-10-01

    Although the level of heat shock protein (Hsp72) has been shown to be enhanced in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid, it remains unclear what role extracellular Hsp72 plays in the pathogenesis of RA. This study was conducted to investigate the effects of recombinant human Hsp72 on collagen-induced arthritis (CIA) when administered therapeutically and elucidate its underlying mechanism. We demonstrated that recombinant Hsp72 significantly reduced disease severity. Hsp72-treated animals displayed significantly less cartilage and bone destruction than that in the controls. Hsp72 treatment also reduced the expression of tumor necrosis factor alpha and interleukin 6 in the sera. Furthermore, Hsp72 treatment significantly inhibited activation of nuclear factor kappa B (NF-κB) in synovial tissues of CIA mice. These findings suggest that recombinant Hsp72 effectively suppressed synovial inflammation and the development and progress of CIA, which is mediated through the reduction of production of proinflammatory cytokines and the suppression of activation of NF-κB pathway.

  14. Loss of IL-22 inhibits autoantibody formation in collagen-induced arthritis in mice.

    PubMed

    Corneth, Odilia B J; Reijmers, Rogier M; Mus, Adriana M C; Asmawidjaja, Patrick S; van Hamburg, Jan Piet; Papazian, Natalie; Siegers, Jurre Y; Mourcin, Frédéric; Amin, Rada; Tarte, Karin; Hendriks, Rudi W; Cupedo, Tom; Lubberts, Erik

    2016-06-01

    Interleukin 22 (IL-22) expression is associated with increased joint destruction and disease progression in rheumatoid arthritis (RA). Although IL-22 is considered a pro-inflammatory cytokine, its mechanism of action in RA remains incompletely understood. Here, we used the collagen-induced arthritis model in IL-22 deficient (IL-22(-/-) ) mice to study the role of IL-22 in RA. In spite of normal disease incidence, disease severity is significantly diminished in IL-22(-/-) mice. Moreover, pathogenicity of Th17 cells and development and function of B cells are unaffected. In contrast, splenic plasma cells, as well as serum autoantibody titers, are reduced in the absence of IL-22. At the peak of disease, germinal centers (GCs) are severely reduced in the spleens of IL-22(-/-) mice, correlating with a decline in GC B-cell numbers. Within the GC, we identified IL-22R1 expressing follicular dendritic cell-like stromal cells. Human lymphoid stromal cells respond to IL-22 ex vivo by inducing transcription of CXCL12 and CXCL13. We therefore postulate IL-22 as an important enhancer of the GC reaction, maintaining chemokine levels for the persistence of GC reactions, essential for the production of autoantibody-secreting plasma cells. Blocking IL-22 might therefore prevent immune-complex deposition and destruction of joints in RA patients. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis

    PubMed Central

    Sevastou, Ioanna; Sirioti, Ivi; Samiotaki, Martina; Madan, Damian; Prestwich, Glenn D.; Aidinis, Vassilis

    2013-01-01

    Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA. PMID:23923032

  16. Eye-mediated immune tolerance to Type II collagen in arthritis-prone strains of mice.

    PubMed

    Farooq, Shukkur M; Kumar, Ashok; Ashour, Hossam M

    2014-12-01

    Type II collagen (CII) is a cartilage structural protein that plays important roles in joint function, arthritis and ageing. In studying the ability of CII to induce eye-mediated specific immune tolerance, we have recently proven that CII is capable of inducing anterior chamber-associated immune deviation (ACAID) in Balb/c mice. Here, we study the ability of CII to induce eye-mediated immune tolerance in strains of mice that are prone to the induction of rheumatoid arthritis. Thus, we hypothesized that CII induces ACAID in DBA/1 mice and in C57BL/6 mice through the AC route (direct injection) or the intravenous route (adoptive transfer of in vitro-generated CII-specific ACAID macrophages or of CII-specific in vitro-generated T regulatory cells). Specific immune tolerance induction was assessed using both delayed-type hypersensitivity (DTH) and local adoptive transfer (LAT) assays. Results indicated the ability of CII to generate CII-specific ACAID-mediated immune tolerance in vivo and in vitro in both DBA/1 mice and C57BL/6 mice. These findings could be beneficial in studies of immune tolerance induction using CII.

  17. Anti-arthritogenic and cardioprotective action of hesperidin and daidzein in collagen-induced rheumatoid arthritis.

    PubMed

    Ahmad, Shafeeque; Alam, Khursheed; Hossain, M Mobarak; Fatima, Mahino; Firdaus, Fakiha; Zafeer, Mohammad Faraz; Arif, Zarina; Ahmed, Murad; Nafees, K A

    2016-12-01

    Atherosclerosis has been linked to chronic inflammatory processes. Changes in the levels of lipoproteins, especially low-density lipoprotein or its variants, as well as inflammatory markers are risk factors for the atherosclerosis. In the present study, an experimental model of rheumatoid arthritis was developed by administrating collagen suspension intradermally in the tail region of Wistar albino rats. At the same time, a suspension of hesperidin (50 mg/kg body weight) and daidzein (20 mg/kg body weight) was orally administrated. The compounds were given in the morning and evening for 21 days. Levels of inflammatory markers in the homogenate of knee joints of experimental rats as well as plasma lipoproteins were investigated. The administration of hesperidin and daidzein caused significant (p < 0.001) decrease in articular elastase activity, TNF-α, and malondialdehyde levels. Further, arthritis scoring and histological findings supported the anti-inflammatory actions of the test compounds. Interestingly, the test compounds also lowered the plasma low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglyceride but increased the level of high-density lipoprotein cholesterol. The test compounds thus ameliorated the risk factors of atherosclerosis. Furthermore, antioxidant roles of hesperidin as well as daidzein were evident from decrease in free radical load demonstrated as increase in total antioxidant level in plasma of arthritic animals treated with hesperidin and daidzein. In a separate in vitro experiment, enhanced free radical scavenging activity of hesperidin was demonstrated against 2,2-diphenyl-1-picrylhydrazyl and 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid. The anti-inflammatory, hypolipidemic, and antioxidant actions of the naturally occurring test compounds, particularly hesperidin, seem to be quite effective against rheumatoid arthritis and atherosclerosis. Thus, their consumption may be helpful in

  18. Cyclophilin A Aggravates Collagen-Induced Arthritis via Promoting Classically Activated Macrophages.

    PubMed

    Dongsheng, Zhai; Zhiguang, Fu; Junfeng, Jia; Zifan, Lu; Li, Wang

    2017-07-29

    Activated macrophages exhibiting diverse phenotypes and various functions contribute to the pathogenesis or amelioration of different diseases like cancer, inflammation, and infectious and autoimmune diseases. However, the mechanisms of macrophage polarization in inflamed joint and its effects on rheumatoid arthritis (RA) are still not clarified. This study is designed to explore the effects of cyclophilin A (CypA) on macrophage polarization and describe the underlying mechanisms. Collagen-induced arthritis (CIA) was employed to address the pro-arthritic effects of CypA. Flow cytometry was performed to investigate the populations of M1 and M2 macrophages in synovial tissues of the mice. Knockdown or overexpression of CypA macrophage cells was used to study the functions of CypA on macrophage polarization. Western blot was carried out to examine the potential signaling pathways. We found that CypA aggravated the severity of CIA in mice, as assessed by the increase of clinical score of inflammation, cartilage damage, and bone erosion. Moreover, the level of cytokines, such as IL-6, IL-1β, and IL-17, and the number of pro-inflammatory macrophages in synovial fluid were significantly elevated. In accordance with our observation, CypA dysregulation could actually influence the M1 macrophages polarization and pro-inflammatory cytokines production. Further mechanism study disclosed that CypA could regulate the transcriptional activity of NF-κB, the pivotal transcriptional factor regulating M1 polarization, dependent of its PPIase activity. Our findings provide evidence that PPIase CypA promoted macrophages polarization toward pro-inflammatory M1 phenotype via transcriptional activating NF-κB, thus leading to aggravated arthritis.

  19. Polymerized-Type I Collagen Induces Upregulation of Foxp3-Expressing CD4 Regulatory T Cells and Downregulation of IL-17-Producing CD4+ T Cells (Th17) Cells in Collagen-Induced Arthritis

    PubMed Central

    Furuzawa-Carballeda, Janette; Macip-Rodríguez, Perla; Galindo-Feria, Angeles S.; Cruz-Robles, David; Soto-Abraham, Virgina; Escobar-Hernández, Sergio; Aguilar, Diana; Alpizar-Rodríguez, Deshiré; Férez-Blando, Karen; Llorente, Luis

    2012-01-01

    Previous studies showed that polymerized-type I collagen (polymerized collagen) exhibits potent immunoregulatory properties. This work evaluated the effect of intramuscular administration of polymerized collagen in early and established collagen-induced arthritis (CIA) in mice and analyzed changes in Th subsets following therapy. Incidence of CIA was of 100% in mice challenged with type II collagen. Clinimorphometric analysis showed a downregulation of inflammation after administration of all treatments (P < 0.05). Histological analysis showed that the CIA-mice group had extensive bone erosion, pannus and severe focal inflammatory infiltrates. In contrast, there was a remarkable reduction in the severity of arthritis in mice under polymerized collagen, methotrexate or methotrexate/polymerized collagen treatment. Polymerized Collagen but not methotrexate induced tissue joint regeneration. Polymerized Collagen and methotrexate/polymerized collagen but not methotrexate alone induces downregulation of CD4+/IL17A+ T cells and upregulation of Tregs and CD4+/IFN-γ+ T cells. Thus, Polymerized Collagen could be an effective therapeutic agent in early and established rheumatoid arthritis by exerting downregulation of autoimmune inflammation. PMID:22028728

  20. Attenuation of collagen induced arthritis by Centella asiatica methanol fraction via modulation of cytokines and oxidative stress.

    PubMed

    Sharma, Shikha; Gupta, Ritu; Thakur, Sonu Chand

    2014-12-01

    To investigate the anti-inflammatory, antioxidant and anti-arthritic effects of Centella asiatica methanolfraction (CaME) on collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Arthritis was induced in female wistar rats by immunization with porcine type II collagen. The CIA rats were treated orally with CaME (50, 150, and 250 mg/kg/day) for 15 d (beginning on day 21 of the experimental period). The clinical, histological, biochemical, and immunological parameters were assessed. CaME treatment (150 and 250 mg/kg) significantly attenuated the severity of CIA and reduced the synovial inflammation, cartilage erosion, and bone erosion as evident from both histological and radiographic data. The escalated plasma levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12 alongwith nitric oxide in CIA rats decreased significantly on CaME treatment. The serum levels of type-II collagen antibody were significantly lower in rats of CaME (150 and 250 mg/kg) treated group than those in the arthritic group. Furthermore, by inhibiting the above mediators, CaME also contributed towards the reversal of the disturbed antioxidant levels and peroxidative damage. Our results clearly indicate that oral administration of CaME suppresses joint inflammation, cytokine expression as well as antioxidant imbalance, thereby contributing to an amelioration of arthritis severity in CIA rats. Copyright © 2014 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  1. Soluble complement receptor one (sCR1) inhibits the development and progression of rat collagen-induced arthritis.

    PubMed

    Goodfellow, R M; Williams, A S; Levin, J L; Williams, B D; Morgan, B P

    2000-01-01

    We set out to determine whether inhibition of complement using sCR1 could influence the development and progression of collagen arthritis in the Lewis rat. Collagen arthritis was successfully established in the Lewis rat, using a novel immunization schedule. In separate experiments, cobra venom factor (CVF) and sCR1 were used to achieve systemic complement inhibition. Their respective effects on disease onset and on the progression of established disease compared with saline-treated control animals was explored. Arthritis was assessed by measurement of clinical score, paw diameter and paw volume. Complement inhibition using either CVF or sCR1, prior to the onset of clinical signs of inflammation, delayed the development of disease. CVF was ineffective in the treatment of established disease, whereas sCR1 delayed the progression of disease in affected joints and prevented the recruitment of further joints while the animals were complement-depleted. In the control saline-treated groups the disease continued to progress relentlessly. We conclude that complement activation is important in the initiation and maintenance of inflammation in collagen arthritis. The potent disease-modulating effect of sCR1 provides persuasive evidence that specific complement inhibiting agents may be an effective approach to the treatment of inflammatory joint diseases

  2. Effects of Calcium Gluconate, a Water Soluble Calcium Salt on the Collagen-Induced DBA/1J Mice Rheumatoid Arthritis

    PubMed Central

    Sohn, Ki Cheul; Kang, Su Jin; Kim, Joo Wan; Kim, Ki Young; Ku, Sae Kwang; Lee, Young Joon

    2013-01-01

    This study examined the effects of calcium (Ca) gluconate on collagen-induced DBA mouse rheumatoid arthritis (CIA). A single daily dose of 200, 100 or 50 mg/kg Ca gluconate was administered orally to male DBA/1J mice for 40 days after initial collagen immunization. To ascertain the effects administering the collagen booster, CIA-related features (including body weight, poly-arthritis, knee and paw thickness, and paw weight increase) were measured from histopathological changes in the spleen, left popliteal lymph node, third digit and the knee joint regions. CIA-related bone and cartilage damage improved significantly in the Ca gluconate- administered CIA mice. Additionally, myeloperoxidase (MPO) levels in the paw were reduced in Ca gluconate-treated CIA mice compared to CIA control groups. The level of malondialdehyde (MDA), an indicator of oxidative stress, decreased in a dosedependent manner in the Ca gluconate group. Finally, the production of IL-6 and TNF-α, involved in rheumatoid arthritis pathogenesis, were suppressed by treatment with Ca gluconate. Taken together, these results suggest that Ca gluconate is a promising candidate anti-rheumatoid arthritis agent, exerting anti-inflammatory, anti-oxidative and immunomodulatory effects in CIA mice. PMID:24244814

  3. Effects of low molecular weight chondroitin sulfate on type II collagen-induced arthritis in DBA/1J mice.

    PubMed

    Cho, So Yean; Sim, Joon-Soo; Jeong, Choon Sik; Chang, Seung Yeup; Choi, Don Woong; Toida, Toshihiko; Kim, Yeong Shik

    2004-01-01

    In order to evaluate the improvement in the treatment of chronic arthritis, we investigated chondroitin sulfate depolymerization product (low molecular weight chondroitin sulfate, LMWCS) and intact chondroitin sulfate (CS) in vitro and in vivo. LMWCS was prepared by a chemical depolymerization process induced by hydrogen peroxide in the presence of copper salts. LMWCS (300 mg/kg) and CS (1200 mg/kg) were orally administered to DBA/1J mice once daily for 14 d prior to initial immunization with type II collagen. Their elastase activities and the production of cytokines in sera were examined on type II collagen-induced arthritis in DBA/1J mice. We also compared the paracellular transport of LMWCS and CS across Caco-2 cell monolayers and examined the inhibitory effects on elastase activities. LMWCS inhibited elastase activity slightly, but CS did not show inhibition. Hind paw edema was significantly decreased by LMWCS treatment. Levels of anti-type II collagen antibody and tumor necrosis factor-alpha (TNF-alpha) in sera were also reduced by LMWCS treatment but not in case of CS, although no significant difference was observed between LMWCS and CS on interleukin-6 (IL-6) induction. The LMWCS preparation showed preventive effects on the type II collagen-induced arthritis in DBA/1J mice and better permeability through Caco-2 cells.

  4. Acarbose Decreases the Rheumatoid Arthritis Risk of Diabetic Patients and Attenuates the Incidence and Severity of Collagen-induced Arthritis in Mice

    PubMed Central

    Chen, Hsin-Hua; Chen, Der-Yuan; Chao, Ya-Hsuan; Chen, Yi-Ming; Wu, Chao-Liang; Lai, Kuo-Lung; Lin, Ching-Heng; Lin, Chi-Chen

    2015-01-01

    Acarbose has been found to decrease some inflammatory parameters in diabetic patients. This study aimed to examine the influence of acarbose on rheumatoid arthritis (RA) risk in diabetes mellitus (DM) patients and on the incidence and severity of collagen-induced arthritis (CIA) in mice. In a nationwide, matched case–control study, we identified 723 incident RA cases and selected 7,230 age-, sex- and RA diagnosis date–matched controls from all newly treated DM patients. We found that use of acarbose at > 16,950 mg per year was associated with a lower RA risk (odds ratio 0.60; 95% CI, 0.41–0.89). In the CIA mouse study, acarbose was orally administered from days -7 to 38 relative to type II collagen (CII) immunization. The results revealed that acarbose at the dose of 500 mg/kg/day attenuated the incidence and severity of arthritis and the expression of proinflammatory cytokines, including TNF-α, IL-6 and IL-17 in the paw tissues. Acarbose further decreased the productions of anti-CII-IgG, IL-17 and IFN-γ by collagen-reactive lymph node cells. This work suggests that the use of acarbose decreased RA risk in DM patients and the incidence of CIA in mice. Acarbose also attenuated the severity of CIA via anti-inflammatory and immunomodulatory effects. PMID:26678745

  5. Parasite-mediated down-regulation of collagen-induced arthritis (CIA) in DA rats.

    PubMed

    Mattsson, L; Larsson, P; Erlandsson-Harris, H; Klareskog, L; Harris, R A

    2000-12-01

    Microbial infection can impact on the course of autoimmune disease, both in disease-inducing and disease-protecting capacities. Here we investigated if infection with Trypanosoma brucei brucei (Tbb), the protozoan causative agent of African Sleeping Sickness, could ameliorate the course of CIA in the Dark Agouti rat, an experimental model which shares many features with human rheumatoid arthritis. Infection of animals with living, but not inoculation with dead Tbb resulted in complete or significant reduction of clinical arthritic symptoms. Infection prior to collagen immunization was more effective than a later treatment, and this effect was related to the level of parasitaemia. Using reverse transcriptase-polymerase chain reaction we detected an increase in interferon-gamma mRNA in the draining lymph nodes of Tbb-treated animals relative to controls at day 28 after disease induction. Transforming growth factor-beta could be detected in the lymph nodes in four out of six animals that had received Tbb. In the joints, immunohistochemistry revealed reduced production of tumour necrosis factor-alpha in Tbb-treated animals relative to controls. The most striking difference between Tbb-infected and control groups, as measured by ELISA, was the down-regulation of anti-collagen II IgG antibody responses in parasite-infected animals. We conclude that live parasites can exert an immunomodulatory and protective effect in CIA in which several mechanisms may work in parallel, although the almost complete down-regulation of the anti-collagen antibody response may alone explain the protective effect in CIA. The described model may be useful in further attempts to use the mechanisms involved in parasite immune defence to prevent and treat certain autoimmune conditions.

  6. Suppression of collagen-induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of type II collagen.

    PubMed

    Iizuka, Mana; Wakasa, Yuhya; Tsuboi, Hiroto; Asashima, Hiromitsu; Hirota, Tomoya; Kondo, Yuya; Matsumoto, Isao; Takaiwa, Fumio; Sumida, Takayuki

    2014-10-01

    Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We previously reported that altered peptide ligands (APLs) of type II collagen (CII256-271) suppress the development of collagen-induced arthritis (CIA). In this study, we generated transgenic rice expressing CII256-271 and APL6 contained in fusion proteins with the rice storage protein glutelin in the seed endosperm. These transgene products successfully and stably accumulated at high levels (7-24 mg/g seeds) in protein storage vacuoles (PB-II) of mature seeds. We examined the efficacy of these transgenic rice seeds by performing oral administration of the seeds to CIA model mice that had been immunized with CII. Treatment with APL6 transgenic rice for 14 days significantly inhibited the development of arthritis (based on clinical score) and delayed disease onset during the early phase of arthritis. These effects were mediated by the induction of IL-10 from CD4(+ ) CD25(-) T cells against CII antigen in splenocytes and inguinal lymph nodes (iLNs), and treatment of APL had no effect on the production of IFN-γ, IL-17, IL-2 or Foxp3(+) Treg cells. These findings suggest that abnormal immune suppressive mechanisms are involved in the therapeutic effect of rice-based oral vaccine expressing high levels of APLs of type II collagen on the autoimmune disease CIA, suggesting that the seed-based mucosal vaccine against CIA functions via a unique mechanism.

  7. Interleukin-35 upregulates OPG and inhibits RANKL in mice with collagen-induced arthritis and fibroblast-like synoviocytes.

    PubMed

    Li, Y; Li, D; Li, Y; Wu, S; Jiang, S; Lin, T; Xia, L; Shen, H; Lu, J

    2016-04-01

    IL-35 is a novel anti-inflammatory cytokine, but the exact role of IL-35 in the progression of RA remains unclear, especially associated with osteoporosis and bone erosion. The present research has not been reported. Our purpose is to study how IL-35 affects RA bone destruction. This study investigated the effect of interleukin-35 (IL-35) on OPG and RANKL expression in collagen-induced arthritis (CIA) in rats and in cultured fibroblast-like synoviocytes (FLS). Thirty DBA/1J mice were randomly assigned to three groups (n = 10 per group): the control group, the CIA group, and the CIA + IL-35 group. Collagen-induced arthritis was induced by immunization with collagen. IL-35 was intraperitoneally injected daily for 10 days, starting from the 24(th) day after immunization. FLS cells were isolated and cultured from CIA. The expression of IL-17, RANKL, and OPG was determined by RT-PCR and Western blot. Each experiment was repeated three times. CIA mice exhibited arthritis symptoms on day 24, followed by a rapid progression of arthritis. The expression of IL-17 and RANKL was increased and the expression of OPG was decreased in CIA mice compared with control mice. IL-35 treatment inhibited the development of arthritis in CIA mice, accompanied by a decrease in the expression of IL-17 and RANKL and an increase in the expression of OPG. Furthermore, IL-35 dose-dependently inhibited the expression of RANKL and increased the expression of OPG in cultured FLS cells. IL-35 inhibits RANKL expression and increases OPG expression in CIA mice. IL-35 may be used for treating rheumatoid arthritis.

  8. Anti-type II collagen antibodies detection and avidity in patients with oligoarticular and polyarticular forms of juvenile idiopathic arthritis.

    PubMed

    Araujo, Galber R; Fonseca, João E; Fujimura, Patricia T; Cunha-Junior, Jair P; Silva, Carlos H M; Mourão, Ana F; Canhão, Helena; Goulart, Luiz R; Gonçalves, João; Ueira-Vieira, Carlos

    2015-05-01

    Juvenile idiopathic arthritis (JIA) refers to a heterogeneous group of illnesses that have in common the occurrence of chronic joint inflammation in children younger than 16 years of age. The diagnosis is made only on clinical assessment. The identification of antibody markers could improve the early diagnosis, optimizing the clinical management of patients. Type II collagen is one potential autoantigen that has been implicated in the process of arthritis development. The aims of our study were to investigate the occurrence of anti-type II collagen antibodies and also to determine the avidity of the antibody-antigen binding. Ninety-six patients with oligoarticular or polyarticular JIA, 13 patients with ankylosing spondylitis (AS) and 61 healthy controls (HC) were tested for anti-type II collagen antibodies by ELISA and avidity ELISA. Sensitivity and specificity were determined by the receiver operating characteristic (ROC) curve analysis. Forty-two JIA patients (44%) were positive for antibodies against type II collagen. Its detection was significantly higher in JIA patients than in AS patients (p=0.006) and HCs (p<0.0001). Furthermore, anti-type II collagen antibody detection was significantly more frequent in patients with JIA of ≤6 months duration (p=0.0007). Antibodies displaying high avidity to type II collagen were associated with disease activity (p=0.004). This study demonstrates that antibodies against type II collagen are present in the serum of patients with oligoarticular and polyarticular JIA, being its presence more prevalent in patients with early disease. It also demonstrates that JIA patients with active disease present antibodies with high avidity against type II collagen.

  9. Prophylactic Injection of Recombinant Alpha-Enolase Reduces Arthritis Severity in the Collagen-Induced Arthritis Mice Model

    PubMed Central

    Guillou, Clément; Derambure, Céline; Fréret, Manuel; Verdet, Mathieu; Avenel, Gilles; Golinski, Marie-Laure; Sabourin, Jean-Christophe; Loarer, François Le; Adriouch, Sahil; Boyer, Olivier; Lequerré, Thierry; Vittecoq, Olivier

    2015-01-01

    Objective To evaluate the ability of the glycolytic enzyme alpha-enolase (ENO1) or its immunodominant peptide (pEP1) to reduce the severity of CIA in DBA/1 mice when injected in a prophylactic way. Methods Mice were treated with mouse ENO1 or pEP1 one day prior to collagen II immunization. Clinical assessment was evaluated using 4 parameters (global and articular scores, ankle thickness and weight). Titers of serum anti-ENO1, anti-cyclic citrullinated peptides (anti-CCP) and anti-CII (total IgG and IgG1/IgG2a isotypes) antibodies were measured by ELISA at different time-points. Disease activity was assessed by histological analysis of both anterior and hind paws at the end of experimentation. Results Prophylactic injection of 100 μg of ENO1 reduced severity of CIA. Serum levels of anti-CII antibodies were reduced in ENO1-treated mice. Concordantly, ENO1-treated mice joints presented less severe histological signs of arthritis. ENO1 did not induce a shift toward a Th2 response since IgG1/IgG2a ratio of anti-CII antibodies remained unchanged and IL-4 serum levels were similar to those measured in the control group. Conclusions Pre-immunization with ENO1 or its immunodominant peptide pEP1 reduces CIA severity at the clinical, immunological and histological levels. Effects of pEP1 were less pronounced. This immunomodulatory effect is associated with a reduction in anti-CII antibodies production but is not due to a Th1/Th2 shift. PMID:26302382

  10. Puerarin attenuates inflammation and oxidation in mice with collagen antibody-induced arthritis via TLR4/NF-κB signaling.

    PubMed

    Wang, Changxing; Wang, Weidong; Jin, Xiaping; Shen, Jianguo; Hu, Weifeng; Jiang, Tao

    2016-08-01

    Puerarin is an important active ingredient in the root of kudzu vine due to its pharmacological properties. The aim of the present study is to contribute to the existing knowledge of the effect of puerarin in the attenuation of inflammation and oxidation in mice with collagen antibody-induced arthritis via toll‑like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling. Arthritis was induced using injection of anti‑type II collagen antibodies. Treatment with puerarin was observed to significantly decrease clinical scoring of the collagen antibody‑induced arthritis and suppress oxidative stress and the inflammatory response in mice. Furthermore, puerarin was demonstrated to inhibit mRNA expression of matrix metalloproteinase‑9 and protein expression of TLR4 following collagen antibody-induced arthritis in mice. The effect of puerarin may be associated with the suppression of NF‑κB activity in collagen antibody‑induced arthritis mice. Furthermore, upregulation of phosphorylated (p)‑Janus kinase 2 and p‑signal transducer and activator of transcription 3 protein expression was suppressed by puerarin. The results of the present study indicate, for the first time, the effect of puerarin to attenuate inflammation and oxidation in mice with collagen antibody‑induced arthritis via TLR4/NF-κB signaling.

  11. Telmisartan inhibited angiotensin II-induced collagen metabolic imbalance without directly targeting TGF-β 1/Smad signaling pathway in cardiac fibroblasts.

    PubMed

    Zhang, Y; Zhao, N A; Wang, J K; Zhu, S M; Zhu, H L; Liu, B; Cui, Q W; Guan, G C; Tian, G

    2015-12-01

    Cardiac fibrosis is an important pathological process of cardiac remodeling. A large number of studies have shown that telmisartan can attenuate cardiac fibrosis through acting on angiotensin II 1 receptor (AT1R), and TGF-β 1/Smad signaling molecule is an important pathway to achieve this effect. The aim of the study was to clarify whether, with excessive activation of RAAS system, telmisartan could also directly target TGF-β 1/Smad signaling pathway to have the function of anti-cardiac fibrosis. In this study, neonatal rat cardiac fibroblasts were cultured and AngII or TGF-β 1 was administered for treatment or pre-incubation, and then telmisartan was used for 24 hours' incubation. Western blot and enzyme-linked immunosorbent assay (ELISA) tests were performed to detect protein expressions. The results showed that telmisartan could inhibit collagen synthesis and collagen metabolic imbalance under the effect of Ang II, but telmisartan could not have such function in TGF-β 1-induced cardiac fibroblasts. It was further confirmed by western blot method that telmisartan could inhibit TGF-β 1/Smad signaling molecule expression under the effect of Ang II, but telmisartan had no effect on TGF-β 1-induced Smad signaling molecule expression. According to the present study telmisartan played a role of anticardiac fibrosis without directly targeting TGF-β 1/Smad signaling pathway molecule.

  12. Mast cell depletion in the preclinical phase of collagen-induced arthritis reduces clinical outcome by lowering the inflammatory cytokine profile.

    PubMed

    van der Velden, Daniël; Lagraauw, H Maxime; Wezel, Anouk; Launay, Pierre; Kuiper, Johan; Huizinga, Tom W J; Toes, René E M; Bot, Ilze; Stoop, Jeroen N

    2016-06-13

    Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis. We induced collagen-induced arthritis (CIA), the most frequently used animal model of arthritis, in an inducible mast cell knock-out mouse and determined the effect of mast cell depletion on the development and severity of arthritis. Depletion of mast cells in established arthritis did not affect clinical outcome. However, depletion of mast cells during the preclinical phase resulted in a significant reduction in arthritis. This reduction coincided with a decrease in circulating CD4(+) T cells and inflammatory monocytes but not in the collagen-specific antibody levels. Mast cell depletion resulted in reduced levels of IL-6 and IL-17 in serum. Furthermore, stimulation of splenocytes from mast cell-depleted mice with collagen type II resulted in reduced levels of IL-17 and enhanced production of IL-10. Here we show that mast cells contribute to the preclinical phase of CIA. Depletion of mast cells before disease onset resulted in an altered collagen-specific T cell and cytokine response. These data may suggest that mast cells play a role in the regulation of the adaptive immune response during the development of arthritis.

  13. Evaluation of anti-inflammatory effect of Withania somnifera root on collagen-induced arthritis in rats.

    PubMed

    Gupta, Apurva; Singh, Surendra

    2014-03-01

    Withania somnifera (Linn.) Dunal (Solanaceae) has long been used as an herb in Ayurvedic and indigenous medicine and has received intense attention in recent years for its chemopreventive properties. The present study focuses on the effect of W. somnifera root powder on the behavioral and radiological changes in collagen-induced arthritic rats. The rats were randomly divided into five groups: normal control, arthritic control, arthritic rats treated with W. somnifera root powder (at dose levels 600 and 800 mg kg⁻¹) and arthritic rats treated with methotrexate (at dose level 0.3 mg kg⁻¹). The treatment with W. somnifera (daily) and methotrexate (weekly) was initiated from the 20th day post collagen immunization and continued up until the 45th day. Arthritis was assessed macroscopically by measuring paw thickness, ankle size and body weight. Arthritic pain was assessed by toe-spread and total print length of the affected paw. Functional recovery due to the oral treatment of W. somnifera and methotrexate was assessed by sciatic functional index and rota rod activity. Administration of W. somnifera root powder (600 mg kg⁻¹) to the arthritic rats significantly decreased the severity of arthritis by effectively suppressing the symptoms of arthritis and improving the functional recovery of motor activity and radiological score. W. somnifera root has a protective effect against collagen-induced arthritis (CIA) in rats. The results suggest that W. somnifera root powder acts as an anti-inflammatory and antioxidant agent in decreasing the arthritic effects in collagen-induced arthritic rats.

  14. Anti-inflammatory effect of Curcuma longa (turmeric) on collagen-induced arthritis: an anatomico-radiological study.

    PubMed

    Taty Anna, K; Elvy Suhana, M R; Das, S; Faizah, O; Hamzaini, A H

    2011-01-01

    Curcuma longa (CL) or turmeric is an Ayurvedic herb that has been traditionally used to treat inflammatory conditions like rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is a well established experimental auto-immune mediated polyarthritis in susceptible strains of rodents. The main aim of the study was to observe the inflammatory, macroscopic and radiological changes in the arthritic ankle joints of experimentally collagen-induced arthritis animals treated with or without CL extract. Thirty six male Sprague-Dawley (6-8 weeks-old, 150 ± 50) rats were equally divided into six groups. The first group served as a control while the rest five groups were immunized subdermally with 150 µg collagen type-II on day-0. All rats with established CIA with arthritis score (AS) exceeding 1 were treated orally with betamethasone (0.5 mg/ml/kg body weight) and varying doses of CL extract (30, 60 and 110 mg/ml/kg body weight) using olive oil as vehicle, daily for four weeks. Arthritic scoring (AS) of the paws, measurement of erythrocyte sedimentation rate (ESR) and paw thickness and radiological scoring were performed. Treatment with 110 mg/ml/kg CL showed significant mean difference in the ESR (p<0.01), AS (p<0.05) and radiological scores (p<0.01) on day-28 compared to the vehicle treated group. The mean difference for the ESR, AS and radiological scores of this highest CL dose group were found to be insignificant compared to the betamethasone treated group. The administration of CL extract arrested the degenerative changes in the bone and joints of collagen-induced arthritic rats.

  15. Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

    PubMed Central

    2010-01-01

    Background Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis. Methods Female B10.Q-ncf1*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines. Results Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6. Conclusions This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA. PMID:21159208

  16. Treatment of Collagen-Induced Arthritis Using Immune Modulatory Properties of Human Mesenchymal Stem Cells.

    PubMed

    Park, Kyu-Hyung; Mun, Chin Hee; Kang, Mi-Il; Lee, Sang-Won; Lee, Soo-Kon; Park, Yong-Beom

    2016-01-01

    Mesenchymal stem cells (MSCs) have immune modulatory properties. We investigated the potential therapeutic effects of human bone marrow (BM)-, adipose tissue (AD)-, and cord blood (CB)-derived MSCs in an experimental animal model of rheumatoid arthritis (RA) and explored the mechanism underlying immune modulation by MSCs. We evaluated the therapeutic effect of clinically available human BM-, AD-, and CB-derived MSCs in DBA/1 mice with collagen-induced arthritis (CIA). CIA mice were injected intraperitoneally with three types of MSCs. Treatment control animals were injected with 35 mg/kg methotrexate (MTX) twice weekly. Clinical activity in CIA mice, degree of inflammation, cytokine expression in the joint, serum cytokine levels, and regulatory T cells (Tregs) were evaluated. Mice treated with human BM-, AD-, and CB-MSCs showed significant improvement in clinical joint score, comparable to MTX-treated mice. Histologic examination showed greatly reduced joint inflammation and damage in MSC-treated mice compared with untreated mice. Microcomputed tomography also showed little joint damage in the MSC-treated group. MSCs significantly decreased serum interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon-γ and increased IL-10 and transforming growth factor-β levels. Tregs were increased in mice treated with MSCs compared to untreated or MTX-treated mice. Human BM-, AD-, and CB-MSCs significantly suppressed joint inflammation in CIA mice. The cells decreased proinflammatory cytokines and upregulated anti-inflammatory cytokines and induced Tregs. Therefore, our study suggests that the use of human BM-, AD-, and CB-MSCs could be an effective therapeutic approach for RA.

  17. Effects of cichoric acid extract from Echinacea purpurea on collagen-induced arthritis in rats.

    PubMed

    Jiang, Ling; Li, Weizu; Wang, Yuchan; Zhang, Xiaosu; Yu, Deqiang; Yin, Yanyan; Xie, Zhongwen; Yuan, Yi

    2014-01-01

    Cichoric acid extract (CAE) from Echinacea purpurea L. was used to investigate the anti-arthritic effect by using collagen-induced arthritis (CIA) rat model. The hind paw swelling volume and the body weight were measured and recorded. All the drug solutions were administered orally to rats for a total of 28 days. On day 28, the rats were anaesthetized and decapitated. The thymus and spleen were weighed for the determination of the organ index. The concentration of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β) and prostaglandin E2 (PGE-2) in the serum was measured using commercially available ELISA kits. Total and phosphor-NF-κB and Cox-2 protein expression in synovial tissues were determined by histological slides quantification and western blot analysis. Our data showed that administration of all doses of CAE (8, 16, and 32 mg/kg) significantly decreased the paw swelling, restored body weight gain and decreased the organ index of the thymus and spleen compared with that of the CIA group. CAE (8, 16, and 32 mg/kg) treatment significantly reduced the levels of TNFα, IL-1β and PGE-2 in serum compared with the CIA group. Histopathological analysis demonstrated that CAE has obvious anti-arthritic activity. In addition, CAE (32 mg/kg) significantly decreased the levels of nuclear factor-κB (NF-κB), TNFα and cyclooxygenase 2 (Cox-2) in synovium tissues of the ankle joint compared with the CIA group. Furthermore, CAE administration significantly decreased the protein expression of phosphor-NF-κB and Cox-2 in synovium tissues of the knee joint compared with the CIA group. The results suggest that the anti-inflammatory activity of CAE may account for its anti-arthritic effect, and CAE could be a potential therapeutic drug for the treatment of rheumatoid arthritis (RA).

  18. Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

    PubMed Central

    Garimella, Manasa G.; Kour, Supinder; Piprode, Vikrant; Mittal, Monika; Kumar, Anil; Rani, Lekha; Pote, Satish T.; Mishra, Gyan C.; Chattopadhyay, Naibedya

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis leading to joint destruction and systemic bone loss. The inflammation-induced bone loss is mediated by increased osteoclast formation and function. Current antirheumatic therapies primarily target suppression of inflammatory cascade with limited or no success in controlling progression of bone destruction. Mesenchymal stem cells (MSCs) by virtue of their tissue repair and immunomodulatory properties have shown promising results in various autoimmune and degenerative diseases. However, the role of MSCs in prevention of bone destruction in RA is not yet understood. In this study, we investigated the effect of adipose-derived MSCs (ASCs) on in vitro formation of bone-resorbing osteoclasts and pathological bone loss in the mouse collagen-induced arthritis (CIA) model of RA. We observed that ASCs significantly inhibited receptor activator of NF-κB ligand (RANKL)–induced osteoclastogenesis in both a contact-dependent and -independent manner. Additionally, ASCs inhibited RANKL-induced osteoclastogenesis in the presence of proinflammatory cytokines such as TNF-α, IL-17, and IL-1β. Furthermore, treatment with ASCs at the onset of CIA significantly reduced clinical symptoms and joint pathology. Interestingly, ASCs protected periarticular and systemic bone loss in CIA mice by maintaining trabecular bone structure. We further observed that treatment with ASCs reduced osteoclast precursors in bone marrow, resulting in decreased osteoclastogenesis. Moreover, ASCs suppressed autoimmune T cell responses and increased the percentages of peripheral regulatory T and B cells. Thus, we provide strong evidence that ASCs ameliorate inflammation-induced systemic bone loss in CIA mice by reducing osteoclast precursors and promoting immune tolerance. PMID:26538398

  19. ASC plays a role in the priming phase of the immune response to type II collagen in collagen-induced arthritis.

    PubMed

    Yamazaki, Hideshi; Takeoka, Michiko; Kitazawa, Masato; Ehara, Takashi; Itano, Naoki; Kato, Hiroyuki; Taniguchi, Shun'ichiro

    2012-06-01

    Although rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, the role of IL-1β and IL-18 in the pathophysiology of RA has been well established. IL-1β and IL-18 are generated via cleavage of their pro-forms in the presence of the apoptosis-associated speck-like protein containing a caspase recruit domain (ASC), a known adaptor protein that activates procaspase-1. As such, we investigated the involvement of ASC in the progression of murine collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) using ASC-deficient (ASC(-/-)) and wild-type (ASC(+/+)) mice. Analyses were performed by immunohistochemistry for tissues and ELISA for sera. We observed an increase in the expression of ASC, as well as IL-1β and IL-18, in the joints of CIA DBA mice, which indicated that ASC is involved in disease development. Next, we demonstrated that the infiltration of inflammatory cells and cartilage/bone destruction in CIA knee joints were significantly increased in ASC(+/+) mice compared with ASC(-/-) mice. No such differences were noted in ASC(+/+) and ASC(-/-) CAIA mice. In terms of cytokine expression in knee joints, IL-1β and IL-18 were depressed in ASC-deficient CIA mice compared with wild-type mice, but were similarly expressed in CAIA joints in both mice groups. Taken together, we can conclude that ASC is involved in the development of CIA and plays a role in the priming phase of the immune response to type II collagen.

  20. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion.

    PubMed

    Lubberts, E; Joosten, L A; Chabaud, M; van Den Bersselaar, L; Oppers, B; Coenen-De Roo, C J; Richards, C D; Miossec, P; van Den Berg, W B

    2000-06-01

    Bone destruction is the most difficult target in the treatment of rheumatoid arthritis (RA). Here, we report that local overexpression of IL-4, introduced by a recombinant human type 5 adenovirus vector (Ad5E1mIL-4) prevents joint damage and bone erosion in the knees of mice with collagen arthritis (CIA). No difference was noted in the course of CIA in the injected knee joints between Ad5E1mIL-4 and the control vector, but radiographic analysis revealed impressive reduction of joint erosion and more compact bone structure in the Ad5E1mIL-4 group. Although severe inflammation persisted in treated mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistant acid phosphatase (TRAP) activity, indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production. Osteoprotegerin ligand (OPGL) expression was markedly suppressed by local IL-4, but no loss of OPG expression was noted with Ad5E1mIL-4 treatment. Finally, in in vitro studies, bone samples of patients with arthritis revealed consistent suppression by IL-4 of type I collagen breakdown. IL-4 also enhanced synthesis of type I procollagen, suggesting that it promoted tissue repair. These findings may have significant implications for the prevention of bone erosion in arthritis.

  1. Therapeutic effect of erythroid differentiation regulator 1 (Erdr1) on collagen-induced arthritis in DBA/1J mouse

    PubMed Central

    Kim, Kyung Eun; Kim, Sungryung; Park, Sunyoung; Houh, Younkyung; Yang, Yoolhee; Park, Seung Beom; Kim, Sangyoon; Kim, Daejin; Hur, Dae Young; Kim, Seonghan

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and multiple inflammatory cytokines are involved in RA pathogenesis. Interleukin (IL)-18, in particular, has a significant positive correlation with RA. In this study, we investigated the effect of erythroid differentiation regulator 1 (Erdr1), which is negatively regulated by IL-18, in an animal model of inflammatory arthritis, collagen-induced arthritis (CIA) in DBA/1J mice. Treatment of mice with recombinant (r)Erdr1 significantly suppressed the severity of arthritis, histologic features of arthritic tissue, and serum levels of anti-collagen autoantibodies (IgG, IgG1, IgG2a and IgM) in CIA. In addition, IL-18 expression was reduced in the affected synovium of rErdr1-treated mice. Interestingly, Erdr1 treatment suppressed migration in contrast to the pro-migratory effect of IL-18, indicating the therapeutic effects of Erdr1 on CIA through inhibiting synovial fibroblast migration. In addition, Erdr1 inhibited activation of ERK1/2, a key signaling pathway in migration of various cell types. Taken together, these data show that rErdr1 exerts therapeutic effects on RA by inhibiting synovial fibroblast migration, suggesting that rErdr1 treatment might be an effective therapeutic approach for RA. PMID:27823968

  2. Effects of Wutou Decoction on DNA Methylation and Histone Modifications in Rats with Collagen-Induced Arthritis

    PubMed Central

    Wen, Cai-Yu-Zhu; Chen, Zhe; Wang, Yu; Huang, Ying; Hu, Yong-Hong; Tu, Sheng-Hao

    2016-01-01

    Background. Wutou decoction (WTD) has been wildly applied in the treatment of rheumatoid arthritis and experimental arthritis in rats for many years. Epigenetic deregulation is associated with the aetiology of rheumatoid arthritis; however, the effects of WTD on epigenetic changes are unclear. This study is set to explore the effects of WTD on DNA methylation and histone modifications in rats with collagen-induced arthritis (CIA). Methods. The CIA model was established by the stimulation of collagen and adjuvant. The knee synovium was stained with hematoxylin and eosin. The DNA methyltransferase 1 (DNMT1) and methylated CpG binding domain 2 (MBD2) expression of peripheral blood mononuclear cells (PBMCs) were determined by Real-Time PCR. The global DNA histone H3-K4/H3-K27 methylation and total histones H3 and H4 acetylation of PBMCs were detected. Results. Our data demonstrated that the DNMT1 mRNA expression was significantly lowered in group WTD compared to that in group CIA (P < 0.05). The DNA methylation level was significantly reduced in group WTD compared to that in group CIA (P < 0.05). Moreover, H3 acetylation of PBMCs was overexpressed in WTD compared with CIA (P < 0.05). Conclusions. WTD may modulate DNA methylation and histone modifications, functioning as anti-inflammatory potential. PMID:27042192

  3. Osteoprotegerin Reduces Osteoclast Numbers and Prevents Bone Erosion in Collagen-Induced Arthritis

    PubMed Central

    Romas, Evan; Sims, Natalie A.; Hards, Daphne K.; Lindsay, Mandy; Quinn, Julian W.M.; Ryan, Peter F.J.; Dunstan, Colin R.; Martin, T. John; Gillespie, Matthew T.

    2002-01-01

    Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though

  4. Oral type II collagen treatment in early rheumatoid arthritis. A double-blind, placebo-controlled, randomized trial.

    PubMed

    Sieper, J; Kary, S; Sörensen, H; Alten, R; Eggens, U; Hüge, W; Hiepe, F; Kühne, A; Listing, J; Ulbrich, N; Braun, J; Zink, A; Mitchison, N A

    1996-01-01

    To investigate the efficacy of oral type II collagen in the treatment of early rheumatoid arthritis (RA). Ninety patients with RA (disease duration < or = 3 years) were treated for 12 weeks with oral bovine type II collagen at 1 mg/day (n = 30) or 10 mg/day (n = 30) or with placebo (n = 30), in a double-blind randomized study. There were no significant difference between the 3 groups in terms of response to treatment. However, we observed a higher prevalence of responders in the type II collagen-treated groups: 7 responders in the 10-mg type II collagen group and 6 in the 1-mg group, versus 4 in the placebo group. Furthermore, 3 patients in the 10-mg type II collagen group and 1 patient in the 1-mg type II group, but no patients in the placebo group, had very good response. A total of 14 patients had to be withdrawn from the study: 2 because of side effects (nausea) and 12 because of lack of efficacy. Only a minority of patients responded to treatment with oral type II collagen. These results justify further efforts to identify which patients will have good response to such therapy.

  5. Protective effects of Fructus sophorae extract on collagen-induced arthritis in BALB/c mice

    PubMed Central

    Han, Hyoung-Min; Hong, Su-Hyun; Park, Heung-Sik; Jung, Jae-Chul; Kim, Jong-Sik; Lee, Yong-Tae; Lee, Eun-Woo; Choi, Yung-Hyun; Kim, Byung-Woo; Kim, Cheol-Min; Kang, Kyung-Hwa

    2017-01-01

    Styphnolobium japonicum (L.) is utilized in Korean medicine for the treatment of various inflammatory diseases. The aim of the present study was to explore the effects of Fructus sophorae extract (FSE) isolated from the dried ripe fruit of S. japonicum (L.) on the development of type II collagen-induced arthritis (CIA) in BALB/c mice. The CIA mice were orally administered FSE or saline daily for 2 weeks. The incidence and severity of disease and the inflammatory response in the serum and the joint tissues were assessed. Macroscopic and histological investigation indicated that FSE protected against CIA development. FSE was associated with a significant reduction in the levels of total immunoglobulin G2a and proinflammatory cytokines and mediators in the serum. In addition, FSE suppressed the gene expression levels of proinflammatory cytokines and mediators, the mediator of osteoclastic bone remodeling, the receptor activator of nuclear factor κ-B ligand and matrix metalloproteinases in the joint tissues. The present results suggest that FSE may protect against inflammation and bone damage, and would be a valuable candidate for further investigation as a novel anti-arthritic agent. PMID:28123483

  6. Activity of physalin F in a collagen-induced arthritis model.

    PubMed

    Brustolim, Daniele; Vasconcelos, Juliana F; Freitas, Luiz Antônio R; Teixeira, Mauro M; Farias, Marcel T; Ribeiro, Yvone M; Tomassini, Therezinha C B; Oliveira, Geraldo G S; Pontes-de-Carvalho, Lain C; Ribeiro-dos-Santos, Ricardo; Soares, Milena B P

    2010-08-27

    The effects of physalin F (1), a steroid derivative purified from Physalis angulata, were investigated in models of collagen-induced arthritis in DBA/1 mice and allergic airway inflammation in BALB/c mice. Oral treatment with 1 or dexamethasone caused a marked decrease in paw edema and joint inflammation when compared to vehicle-treated arthritic mice. In contrast, treatment with 1 had no effect in mice with allergic airway inflammation caused by ovalbumin immunization, whereas dexamethasone significantly reduced the number of inflammatory cells and eosinophils in the broncoalveolar lavage fluid and in lung sections of challenged mice. To further demonstrate that 1 acts through a mechanism different from that of glucocorticoids, a nuclear translocation assay was performed of the glucocorticoid receptor (GR) using COS-7 cells transfected with a plasmid encoding for a yellow fluorescent protein (YFP)-GR fusion protein. Untreated or treated cells with 1 had YFP staining mainly in the cytoplasm, whereas in dexamethasone-treated cells the YFP staining was concentrated in the nuclei. It is concluded that the mechanism of the immunosuppressive activity of physalin F is distinct from that of the glucocorticoids.

  7. Novel role of Pin1 induction in type II collagen-mediated rheumatoid arthritis.

    PubMed

    Jeong, Hye Gwang; Pokharel, Yuba Raj; Lim, Sung Chul; Hwang, Yong Pil; Han, Eun Hee; Yoon, Jung-Hoon; Ahn, Sang-Gun; Lee, Kwang Yeol; Kang, Keon Wook

    2009-11-15

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints and subsequent destruction of cartilage and bone. Inflammatory mediators such as PGs and proinflammatory cytokines contribute to RA progress. Pin1, a peptidyl prolyl isomerase, plays important pathophysiological roles in several diseases, including cancer and neurodegeneration. We found that both Pin1 and cyclooxygenase-2 (COX-2) were highly expressed in ankle tissues of type II collagen-induced RA mice. HTB-94 cells overexpressing Pin1 and primary cultured human chondrocytes showed increased basal expression of proinflammatory proteins (COX-2, inducible NO synthase, TNF-alpha, and IL-1beta). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-kappaB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-kappaB, CREB, and C/EBP were consistently activated in chondrocytes overexpressing Pin1. Treatment of RA mice with juglone, a chemical inhibitor of Pin1, significantly reduced RA progress and COX-2 expression in the ankle tissues. Moreover, juglone dose dependently decreased the basal COX-2 expression in primary cultured chondrocytes from RA patients. These results demonstrate that Pin1 induction during RA progress stimulates proinflammatory protein expression by activating NF-kappaB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.

  8. The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells.

    PubMed

    Huang, Shichao; Mao, Jianxin; Wei, Bin; Pei, Gang

    2015-07-01

    Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17-producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function.

  9. Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis.

    PubMed

    Fujii, Wataru; Ashihara, Eishi; Hirai, Hideyo; Nagahara, Hidetake; Kajitani, Naoko; Fujioka, Kazuki; Murakami, Ken; Seno, Takahiro; Yamamoto, Aihiro; Ishino, Hidetaka; Kohno, Masataka; Maekawa, Taira; Kawahito, Yutaka

    2013-08-01

    Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4(+) T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-γ, IL-2, TNF-α, and IL-6 by CD4(+) T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4(+) T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4(+) T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis.

  10. Triptolide Prevents Bone Destruction in the Collagen-Induced Arthritis Model of Rheumatoid Arthritis by Targeting RANKL/RANK/OPG Signal Pathway

    PubMed Central

    Zhang, Yanqiong; Kong, Xiangying; Xu, Ying; Chen, Weiheng; Lu, Aiping; Lin, Na

    2013-01-01

    Focal bone destruction within inflamed joints is the most specific hallmark of rheumatoid arthritis (RA). Our previous study indicated that the therapeutic efficiency of triptolide in RA may be due partially to its chondroprotective and anti-inflammatory effects. However, its roles in bone destruction are still unclear. In this study, our data firstly showed the therapeutic effects of triptolide on severity of arthritis and arthritis progression in collagen-induced arthritis (CIA) mice. Then, by micro-CT quantification, triptolide treatment significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints. Interestingly, triptolide treatment could prevent the bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of NF-κB (RANK) ligand (RANKL) and RANK, increasing the expression of osteoprotegerin (OPG), at both mRNA and protein levels, and decreasing the ratio of RANKL to OPG in sera and inflamed joints of CIA mice, which were further confirmed in the coculture system of human fibroblast-like synovial and peripheral blood mononuclear cells. These findings offer the convincing evidence for the first time that triptolide may attenuate RA partially by preventing the bone destruction and inhibit osteoclast formation by regulating RANKL/RANK/OPG signal pathway. PMID:23573139

  11. Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis?

    PubMed Central

    Koivula, M; Aman, S; Karjalainen, A; Hakala, M; Risteli, J

    2005-01-01

    Objectives: To assess the possible presence in patients with rheumatoid arthritis (RA) of autoantibodies recognising citrullinated peptides derived from type I and II collagens. Methods: Firstly, the binding of four pairs of synthetic peptides (arginine-containing and artificially citrullinated forms) related to different regions of human type II collagen were tested with sera from 120 patients with RA and 81 controls. Secondly, two similar pairs of peptides related to the carboxy terminal telopeptides of the α1 and α2 chains of human type I collagen were tested. Results: 42–53% of the RA sera showed increased binding of arginine peptides related to type II collagen. However, 12 RA sera bound the citrullinated form of the α1(II) telopeptide more strongly than the corresponding arginine peptide. 20 RA sera bound the citrullinated carboxytelopeptide from the α1 chain of type I collagen (α1(I) telopeptide) more strongly than the respective arginine peptide. The correlation between the autoantibodies to type I and II collagen telopeptides was rs = 0.576, p<0.001. Anti-cyclic citrullinated peptide (anti-CCP) assay was positive in 71/120 (59%) patients with RA. An anti-CCP assay detects a different subgroup of antibodies than anti-telopeptide assays. However, both anti-telopeptide and anti-CCP antibodies were increased in patients with RA. Conclusion: Some patients with RA were identified whose sera contained antibodies that specifically bound citrullinated peptides related to the carboxy terminal telopeptides of the α1 and α2 chains of type I collagen and the α1 chains of type II collagen (sequences YYXA, FYXA, and YMXA, where X stands for citrulline). PMID:16162901

  12. Artemisinin analogue SM934 attenuate collagen-induced arthritis by suppressing T follicular helper cells and T helper 17 cells

    PubMed Central

    Lin, Ze-Min; Yang, Xiao-Qian; Zhu, Feng-Hua; He, Shi-Jun; Tang, Wei; Zuo, Jian-Ping

    2016-01-01

    SM934 is an artemisinin analogue with immunosuppressive properties and potent therapeutic activity against lupus-like diseases in autoimmune mice. In this report, the therapeutic efficacy and underlying mechanisms of SM934 on rheumatoid arthritis (RA) was investigated using collagen-induced arthritis (CIA) in DBA/1J mice. We demonstrated that SM934 treatment alleviate the severity of arthritis in CIA mice with established manifestations. The therapeutic benefits were associated with ameliorated joint swelling and reduced extent of bone erosion and destruction. Further, administration of SM934 diminished the development of T follicular helper (Tfh) cells and Th17 cells and suppressed the production of pathogenic antibodies, without altering the proportion of germinal center B cells. Ex vivo, SM934 treatment inhibited the bovine type II collagen (CII) induced proliferation and inflammatory cytokines secretion of CII -reactive T cells. In vitro, SM934 impeded the polarization of naïve CD4+ T cells into Tfh cells and the expression of its transcript factor Bcl-6. Moreover, SM934 decreased the IL-21-producing CD4+ T cells and dampened the IL-21 downstream signaling through STAT3. These finding offered the convincing evidence that artemisinin derivative might attenuate RA by simultaneously interfering with the generation of Tfh cells and Th17 cells as well as the subsequent antibody-mediated immune responses. PMID:27897259

  13. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis.

    PubMed

    Malfait, A M; Gallily, R; Sumariwalla, P F; Malik, A S; Andreakos, E; Mechoulam, R; Feldmann, M

    2000-08-15

    The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-gamma production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.

  14. Deficiency of β-arrestin1 ameliorates collagen-induced arthritis with impaired TH17 cell differentiation

    PubMed Central

    Li, Juan; Wei, Bin; Guo, Ao; Liu, Chang; Huang, Shichao; Du, Fang; Fan, Wei; Bao, Chunde; Pei, Gang

    2013-01-01

    Rheumatoid arthritis (RA) is an inflammatory disease in which interleukin 17 (IL-17)-producing T helper 17 (TH17) cells have been critically involved. We show that in patients with RA, the expression of a multifunctional regulator β-arrestin1 was significantly up-regulated in peripheral and synovial CD4+ T cells, which correlated well with active phases of RA. In collagen-induced arthritis, deficiency of β-arrestin1 ameliorated disease with decreased TH17 cell differentiation, proinflammatory cytokine production, synovitis, and cartilage and bone destruction. Further mechanistic study reveals that β-arrestin1 promoted signal transducer and activator of transcription 3 (STAT3) activation required for TH17 cell differentiation through scaffolding the interaction of Janus kinase 1 and STAT3. These findings indicate a critical role for β-arrestin1 in the pathogenesis of collagen-induced arthritis and TH17 cell differentiation and suggest β-arrestin1 as a potential diagnostic biomarker and therapeutic target for RA. PMID:23589893

  15. Protection of chronic intermittent hypobaric hypoxia against collagen-induced arthritis in rat through increasing apoptosis.

    PubMed

    Shi, Min; Cui, Fang; Liu, Ai-Jing; Li, Jiao; Ma, Hui-Juan; Cheng, Ming; Yang, Jing; Zhang, Yi

    2011-04-25

    The aim of present study was to investigate the effect of chronic intermittent hypobaric hypoxia (CIHH) on collagen-induced arthritis (CIA) in rat. Fifty male adult Sprague-Dawley rats were randomly divided into 5 groups: CIHH pre-treatment group (Pre-T), pre-control group (Pre-C), CIHH post-treatment group (Post-T), post-control group (Post-C) and blank control group (Con). The rats in Pre-T and Post-T groups were exposed to 28 d of hypobaric hypoxia (simulated 3 000 m altitude, 5 h per day, pO2 = 108.8 mmHg, 14% O2) in a hypobaric chamber before and 12 days after CIA induction, respectively. The rats in Pre-C and Post-C groups were only experienced CIA induction, being control groups for Pre-T and Post-T groups, respectively. The rats in Con group were not given any treatment. The thickness of two-hind paw of rat was measured with spiral micrometer and the degree of arthritis was evaluated by arthritis index (AI). Morphological changes of ankle joint were observed through HE staining. The apoptotic rate in synovial tissue was measured by terminal dUTP nick end labeling (TUNEL) and the apoptotic rate of CD3(+) T lymphocyte in spleen was measured by flow cytometry technique. The protein expressions of Bcl-2 and Bax were measured using immunohistochemistry SP method. The results showed that incidence rate of CIA in Pre-T rats was lower than that in Pre-C rats (P < 0.05). AI in Pre-T and Post-T rats were smaller than those in Pre-C and Post-C, respectively (P < 0.05). In Pre-C and Post-C rats, there were hyperplasia of synovial cell, pannus forming, infiltration with inflammatory cell, and destroyed cartilage and bone in ankle joint. On the contrary, pathological changes of ankle joint were alleviated significantly in Pre-T and Post-T rats. Compared with Pre-C and Post-C rats, apoptotic rates of synovial cell and T lymphocyte in Pre-T and Post-T rats were increased (P < 0.05). As to the possible anti-apoptosis mechanism, CIHH, no matter before and after CIA induction

  16. Evaluation of anti-IL-6 monoclonal antibody therapy using murine type II collagen-induced arthritis

    PubMed Central

    Liang, Bailin; Song, Zheng; Wu, Bin; Gardner, Debra; Shealy, David; Song, Xiao-Yu; Wooley, Paul H

    2009-01-01

    Interleukin-6 is a multifunctional cytokine that is critical for T/B-cell differentiation and maturation, immunoglobulin secretion, acute-phase protein production, and macrophage/monocyte functions. Extensive research into the biology of IL-6 has implicated IL-6 in the pathophysiology and pathogenesis of RA. An anti-murine IL-6 mAb that neutralizes mouse IL-6 activities was tested in animal model of collagen-induced arthritis. Prophylactic treatment with anti-IL-6 mAb significantly reduced the incidence and severity of arthritis compared to control mAb treated mice. The mitogenic response of B and T cells isolated from the lymph nodes of anti-IL-6 treated mice was significantly reduced compared to cells isolated from control mAb treated mice. The overall histopathology score for paws from the anti-IL-6 treated mice was significantly reduced when compared to paws from mice treated with control mAb, including both inflammatory (synovitis and pannus) and erosive (erosions and architecture) parameters. Reduced loss of cartilage matrix components was also observed in the anti-IL-6 treated mice. Collectively, these data suggest that IL-6 plays a major role in the pathophysiology of rheumatoid arthritis, and thus support the potential benefit of anti-IL-6 mAb treatment in rheumatoid arthritis patients. PMID:19368720

  17. Arthritis

    MedlinePlus

    ... or have trouble moving around, you might have arthritis. Most kinds of arthritis cause pain and swelling in your joints. Joints ... joint can become severely damaged. Some kinds of arthritis can also cause problems in your organs, such ...

  18. Immune regulation and anti-inflammatory effects of isogarcinol extracted from Garcinia mangostana L. against collagen-induced arthritis.

    PubMed

    Fu, Yanxia; Zhou, Hailing; Wang, Mengqi; Cen, Juren; Wei, Qun

    2014-05-07

    Isogarcinol is a natural compound that we extracted from Garcinia mangostana L., and we were the first to report that it is a new immunosuppressant. In the present study, we investigated the immune regulation and anti-inflammatory effects of isogarcinol on collagen-induced arthritis (CIA) and explored its potential mechanism in the treatment of rheumatoid arthritis. The oral administration of isogarcinol significantly reduced clinical scores, alleviated cartilage and bone erosion, and reduced the levels of serum inflammatory cytokines in CIA mice. Isogarcinol inhibited xylene-induced mouse ear edema in vivo. In vitro, isogarcinol decreased iNOS and COX-2 mRNA expression and NO content by inhibiting NF-κB expression. Furthermore, isogarcinol decreased the activity of NFAT and inhibited IL-2 expression. The mechanism of action of isogarcinol is associated with down-regulation of both autoimmune and inflammatory reactions.

  19. Methotrexate, combined with cyclophosphamide attenuates murine collagen induced arthritis by modulating the expression level of Breg and DCs.

    PubMed

    Fan, Jinnan; Luo, Jing; Yan, Caiping; Hao, Runxi; Zhao, Xiangcong; Jia, Ruihuan; He, Jiaojiao; Xu, Dan; Miao, Miao; Li, Xiaofeng

    2017-10-01

    To explore the mechanism of methotrexate (MTX) and its combination with cyclophosphamide (CTX) in collagen-induced arthritis (CIA), we investigated the levels of several immune cells and cytokines in mice with different treatments. CIA was induced in DBA/1 mice at the age of 7 weeks by primary immunization with 100μl emulsion containing 2mg/ml bovine type II collagen which was mixed with complete Freund's adjuvant (CFA). The booster immunization was performed with 50-100μl emulsion containing 2mg/ml bovine type II collagen (CII) mixed with incomplete Freund's adjuvant (IFA). MTX, CTX or both were administrated after the booster immunization. Therapeutic effect was evaluated by arthritic scores, X-rays and assessment of histopathological joint destruction. The expression of TNF-α, IL-6, IL-23, IL-10 were also measured. The frequencies of different immune cell subsets in the lymph node, spleen and bone marrow were determined by flow cytometry analysis. Our results showed that CTX and MTX treatment attenuated the severity of arthritis of CIA mice and reduced the levels of several cytokines. CTX and MTX treated mice showed a lower frequency of B cells in bone marrow. Also, when treated the CIA mice with MTX, alone or together with CTX, the lymph nodes and spleen exhibited a decrease in regulatory B cells (Breg) and dendritic cells (DCs). Notably, the combination of MTX and CTX had a more pronounced effect. By measuring the levels of different immune cells those participated in the development of rheumatoid arthritis (RA), our experiment may help to evaluate the therapeutic effects and prognosis of arthritic diseases. Copyright © 2017. Published by Elsevier Ltd.

  20. Individual isomers of conjugated linoleic acid reduce inflammation associated with established collagen-induced arthritis in DBA/1 mice.

    PubMed

    Huebner, Shane M; Campbell, James P; Butz, Daniel E; Fulmer, Tyler G; Gendron-Fitzpatrick, Annette; Cook, Mark E

    2010-08-01

    Previously, dietary conjugated linoleic acid [(CLA), an equal mixture of cis-9, trans-11 (c9t11) and trans-10, cis-12 (t10c12) CLA isomers], was found to reduce inflammation in the murine collagen antibody-induced arthritis model, but less so in the murine collagen-induced arthritis (CIA) model, an arthritic model dependent upon acquired immunity. Because CLA is known to alter the acquired immune response, it was hypothesized that feeding CLA after the establishment of arthritis would reduce paw swelling in the CIA model. In this study, upon the establishment of arthritic symptoms, mice were randomized to the following dietary treatments: corn oil (CO) control (n = 6), 0.5% c9t11-CLA (n = 8), 0.5% t10c12-CLA (n = 6), or 1% combined CLA (1:1 c9t11:t10c12-CLA, n = 6). Paws were scored for severity of arthritis and measured for changes in thickness during an 84-d study period. Dietary c9t11- and combined-CLA similarly decreased the arthritic score (29%, P = 0.036, P = 0.049, respectively, when normalized to initial score) and paw thickness (0.11 mm, P = 0.027, P = 0.035, respectively) compared with CO. Dietary t10c12-CLA reduced the arthritic score (41%, P = 0.007 when normalized) and paw thickness (0.12 mm, P = 0.013) relative to CO. Reduced interleukin-1beta on d 7 and 21 for all CLA treatments (n = 3) relative to CO suggested that antiinflammatory effects of CLA isomers might work by common mechanisms of known pathways involved in chronic inflammation. In conclusion, dietary CLA reduced inflammation associated with CIA, and both c9t11-CLA and t10c12-CLA exhibited antiinflammatory effects.

  1. Morphological characterization of intra-articular HMGB1 expression during the course of collagen-induced arthritis

    PubMed Central

    Palmblad, Karin; Sundberg, Erik; Diez, Margarita; Söderling, Riikka; Aveberger, Ann-Charlotte; Andersson, Ulf; Harris, Helena Erlandsson

    2007-01-01

    High-mobility group chromosomal box protein 1 (HMGB1) is a structural nuclear protein that promotes inflammation when present extracellularly. Aberrant, extracellular HMGB1 expression has been demonstrated in human and experimental synovitis. The aim of the present study was to elucidate the temporal and spatial expression of HMGB1 compared to that of the central mediators tumor necrosis factor (TNF) and interleukin-1-beta (IL-1β) during the course of collagen-induced arthritis. Thus, Dark Agouti rats were immunized with homologous type II collagen and synovial tissue specimens were obtained at various time points prior to and during the course of clinical arthritis. Local cytokine responses were assessed by immunohistochemistry and by in situ hybridization. We demonstrate a distinct nuclear expression of HMGB1 at early disease-preceding time points. Preceding clinical onset by a few days, cytoplasmic HMGB1 expression was evident in synoviocytes within the non-proliferative lining layer. Pronounced cytoplasmic and additional extracellular HMGB1 expression coincided with the progression of clinical disease. In advanced arthritis, the number of cells with cytoplasmic HMGB1 expression was quantitatively comparable to that of cells expressing TNF and IL-1β. Interestingly, although HMGB1 was abundantly expressed throughout the inflamed synovium at a protein level, upregulation of HMGB1 mRNA was restricted mainly to areas of cartilage and bone destruction. In conclusion, these new findings implicate a role for HMGB1 in both inducing and perpetuating inflammatory events of significant importance in the destructive processes in chronic arthritis. PMID:17397533

  2. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

    PubMed Central

    Lu, Jian-Hua; Liu, Yi-Qian; Deng, Qiao-Wen; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-01-01

    Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 −/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 −/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 −/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance. PMID:26693483

  3. Maintained pregnancy levels of oestrogen afford complete protection from post-partum exacerbation of collagen-induced arthritis.

    PubMed Central

    Mattsson, R; Mattsson, A; Holmdahl, R; Whyte, A; Rook, G A

    1991-01-01

    Pregnancy is known to influence the course of rheumatoid arthritis (RA) in women, as well as type II collagen-induced arthritis (CIA) in DBA/1 mice. A characteristic feature is the remission during gestation and the exacerbation of the diseases during the post-partum period. In the case of CIA in DBA 1 mice, two hormonal changes have been assumed to be critical for the induction of the post-partum flare: (i) the fall in steroid hormone levels from those present during pregnancy; and (ii) surges of prolactin (PRL) release at and after delivery. Our results show that treatment with oestradiol during a short period immediately after parturition protects the mouse from a post-partum flare of the disease, and that treatment with bromocriptine, a drug known to inhibit the endogenous PRL release, has a significant though less marked effect. Studies of lactating (i.e. animals with physiological stimulation of endogenous PRL release) and non-lactating arthritic mice revealed no clear-cut differences, indicating that PRL is of minor importance for the induction of the post-partum flare. Some steroids other than oestradiol, which may be implicated in the exacerbation of arthritis, namely progesterone and hydrocortisone, had no clinical effect. Analyses of agalactosyl IgG levels in mice with CIA, and anti-collagen II antibodies in sera collected at the end of the experiments revealed no significant differences between the oestradiol and the control groups. The successful oestradiol treatment of the mice indicates that the drop in endogenous oestradiol levels prior to delivery ends the oestrogen-mediated protection against arthritis during pregnancy. PMID:2070561

  4. A Broad Blockade of Signaling from the IL-20 Family of Cytokines Potently Attenuates Collagen-Induced Arthritis.

    PubMed

    Liu, Xinyu; Zhou, Hong; Huang, Xueqin; Cui, Jingjing; Long, Tianzhen; Xu, Yang; Liu, Haipeng; Yu, Ruoxuan; Zhao, Rongchuan; Luo, Guangping; Huang, Anliang; Liang, Joshua G; Liang, Peng

    2016-10-15

    Two heterodimeric receptors consisting of either IL-20R1 or IL-22R1 in complex with a common β receptor subunit IL-20R2 are shared by three of the IL-20 family of cytokines: IL-19, IL-20, and IL-24. These proinflammatory cytokines have been implicated in the pathogenesis of some autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and atopic dermatitis. Although mAbs against IL-19 and IL-20 have each been shown to modulate disease severity of collagen-induced arthritis in animal models, and anti-IL-20 therapeutic Ab has exhibited some efficacy in the treatment of RA in clinical trials, benefits for a complete blockade of these functionally redundant cytokines remain to be explored. In this report, we show that recombinant human soluble IL-20R2-Fc fusion protein binds to IL-19, IL-20, and IL-24 with similar high affinity and blocks their signaling in vitro. In DBA/1 mouse collagen-induced arthritis model, recombinant human IL-20R2-Fc exhibits comparable efficacy as TNF blocker etanercept in the treatment of established arthritis, whereas the combined use of both biologics manifests little synergistic therapeutic effects. In situ ligand-receptor functional binding analysis shows that a large amount of immune infiltrates expressing high levels of TNFR and IL-20 subfamily cytokines congregate within the inflamed disease tissues. Colocalization experiments reveal that signals from IL-20R2 and TNF transduction pathways seem to converge in macrophages and function in tandem in orchestrating the pathogenesis of RA. Elucidation of this interaction provides a better understanding of cytokine cross-talk in RA and a rationale for more effective biologic therapies that target IL-20R2 instead of individual cytokines from IL-20 family. Copyright © 2016 by The American Association of Immunologists, Inc.

  5. Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction.

    PubMed

    Moon, Su-Jin; Park, Jin-Sil; Woo, Yun-Ju; Lim, Mi-Ae; Kim, Sung-Min; Lee, Seon-Yeong; Kim, Eun-Kyung; Lee, Hee Jin; Lee, Weon Sun; Park, Sang-Hi; Jeong, Jeong-Hee; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La; Min, Jun-Ki

    2014-04-01

    Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA. Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti-type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17-producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry. Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen-specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor-related orphan nuclear receptor γt and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice. The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway. Copyright © 2014 by the American College of

  6. Placement of a collagen glaucoma drainage device to control intraocular pressure and chronic iritis secondary to juvenile rheumatoid arthritis.

    PubMed

    Price, Francis W; Ziemba, Steven L

    2002-01-01

    A patient with juvenile rheumatoid arthritis and chronic iritis is reported with intraocular pressure near 30 mm Hg and previous episodes of intraocular pressure as high as 50 mm Hg despite maximally tolerated medical therapy. Because of the potential risk involved with a full-thickness filtration procedure, it was decided that a nonpenetrating deep sclerectomy would be appropriate, followed by placement of a collagen glaucoma drainage device to maintain aqueous outflow. Immediately postoperatively, intraocular pressure was stabilized. At 24 months postoperatively, intraocular pressure was well controlled at 15 mm Hg with patient receiving only Lotemax. No significant complications were noted at any point in the postoperative course. Because of the patient's predisposition for serious complications frequently associated with trabeculectomy, nonpenetrating deep sclerectomy with the collagen glaucoma drainage device was an effective alternative for this patient.

  7. OSCAR-collagen signaling in monocytes plays a proinflammatory role and may contribute to the pathogenesis of rheumatoid arthritis.

    PubMed

    Schultz, Heidi S; Guo, Li; Keller, Pernille; Fleetwood, Andrew J; Sun, Mingyi; Guo, Wei; Ma, Chunyan; Hamilton, John A; Bjørkdahl, Olle; Berchtold, Martin W; Panina, Svetlana

    2016-04-01

    Osteoclast-associated receptor (OSCAR) is an activating receptor expressed by human myeloid cells. Collagen type I (ColI) and collagen type II (ColII) serve as ligands for OSCAR. OSCAR-collagen interaction stimulates RANK-dependent osteoclastogenesis. We have recently reported that OSCAR promotes functional maturation of monocyte-derived dendritic cells. OSCAR is upregulated on monocytes from rheumatoid arthritis (RA) patients with active disease, and these monocytes show an increased proosteoclastogenic potential. In the current study, we have addressed a functional role for an OSCAR-collagen interaction on monocytes. We show that OSCAR-ColII signaling promoted the survival of monocytes. Moreover, ColII stimulated the release of proinflammatory cytokines by monocytes from healthy donors, which could be completely blocked by an anti-OSCAR monoclonal antibody. Mononuclear cells from the synovial fluid of RA patients plated on ColII secreted TNF-α and IL-8 in an OSCAR-dependent manner. Global RNA profiling showed that components of multiple signaling pathways relevant to RA pathogenesis are regulated at the transcriptional level by OSCAR in monocytes. Thus, OSCAR can play a proinflammatory role in monocyte-derived cells and may contribute crucially on multiple levels to RA pathogenesis.

  8. Distinct serum proteome profiles associated with collagen-induced arthritis and complete Freund's adjuvant-induced inflammation in CD38⁻/⁻ mice: The discriminative power of protein species or proteoforms.

    PubMed

    Rosal-Vela, Antonio; García-Rodríguez, Sonia; Postigo, Jorge; Iglesias, Marcos; Longobardo, Victoria; Lario, Antonio; Merino, Jesús; Merino, Ramón; Zubiaur, Mercedes; Sancho, Jaime

    2015-10-01

    Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38(-/-) than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38(-/-) versus WT mice either with arthritis (CIA(+) ), with no arthritis (CIA(-) ), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA(+) from CIA(-) mice, and WT from CD38(-/-) mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA(+) CD38(-/-) mice from CIA(+) WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38(-/-) and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071).

  9. No mixing of granulocytes and other lymphocytes in the inflamed joints of parabiosis mice with collagen-induced arthritis: possible in situ generation

    PubMed Central

    Nishizawa, Tetsuro; Kawamura, Toshihiko; Izumi, Nakao; Kawamura, Hiroki; Fujii, Katsuyuki; Abo, Toru

    2005-01-01

    Collagen-induced arthritis was evoked by an injection of lipopolysaccharide and anti-type II collagen antibody in mice. In parallel with the onset of arthritis, granulocytes with large light scatter and a Mac-1+ Gr-1+ phenotype expanded in the joints of these mice. Lymphocytes with a CD3− B220+ phenotype (i.e. B220+ B cells) were the major population among lymphocyte subsets in the joints, irrespective of disease. To determine the origin of these leucocyte populations in the joints and other organs, parabiotic experiments using CBF1Ly5.1 and CBF1Ly5.2 mice were conducted in mice with and without collagen-induced arthritis. As expected, leucocyte populations in the liver and spleen became a half-and-half mixture of their own cells and partner cells (e.g. ∼45% of Ly5.1+ cells in Ly5.2+ partner mice). However, such a mixture was extremely delayed in the joints and bone marrow, even in mice with arthritis. These results suggest that, because circulatory blood is not exchanged in the joints, granulocytes and other lymphocytes are generated in situ in the inflamed joints of mice with collagen-induced arthritis or are possibly supplied by the bone marrow. It is of interest that granulocytes in the joints expanded, even without a supply from another site, namely, the synovium. PMID:15606803

  10. Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis.

    PubMed

    Ippagunta, Sirish K; Brand, David D; Luo, Jiwen; Boyd, Kelli L; Calabrese, Christopher; Stienstra, Rinke; Van de Veerdonk, Frank L; Netea, Mihai G; Joosten, Leo A B; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi

    2010-04-16

    Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.

  11. Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

    SciTech Connect

    Antipova, Olga; Orgel, Joseph P.R.O.

    2013-04-08

    Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo.

  12. Protective effects of Huang-Lian-Jie-Du-Tang and its component group on collagen-induced arthritis in rats.

    PubMed

    Hu, Yaohua; Hu, Zhenlin; Wang, Shuping; Dong, Xinxin; Xiao, Cheng; Jiang, Miao; Lv, Aiping; Zhang, Weidong; Liu, Runhui

    2013-12-12

    Huang-Lian-Jie-Du-Tang is a famous Traditional Chinese medicine consisting of Rhizoma coptidis (Coptis chinensis Franch, Ranunculaceae), Radix scutellariae (Scutellaria baicalensis Georgi, Labiatae), Cortex phellodendri (Phellodendron amurense Rupr. Rutaceae) and Fructus gardeniae (Gardenia jasminoide Ellis, Rubiaceae) in a weight ratio of 3:2:2:3.This formula was described by Wang Tao (in the Chinese Tang Dynasty) in his treatise "Wai Tai Mi Yao". It has been used to treat inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases in the clinical practice of Traditional Chinese medicine, especially in treating inflammation for nearly two thousand years. However, the essential compounds in it have not been identified, and the mechanisms remain to be addressed. To investigate the protective effects of HLJDT and its component group (HLJDT-CG) on collagen-induced arthritis in rats. CIA was established in male Wistar rats with subcutaneous injection of type II bovine collagen at the base of the tail of animals. CIA rats were treated daily with oral administration of HLJDT aqueous extracts (270 mg/kg) or HLJDT-CG (40 mg/kg) once per day from day 6 to day 28. Rats in normal and vehicle control groups were given an equal volume of vehicle (0.9% saline) and 0.025 mg/kg Dexamethasone was given to the Standard group at the same time. The protective effect of them were assessed by measuring arthritis index, swelling, the cytokines such as TNF-α, IFN-γ and IL-17 in serum, type II collagen antibodies, splenocyte proliferation and so on. The results demonstrated that treatment of CIA rat with either HLJDT aqueous extracts or HLJDT-CG not only ameliorated the symptoms of arthritis, prevented joint damage but also reduced the serum levels of TNF-α, IFN-γ and IL-17 in CIA rats. Anti-CII antibodies showed the similar trend except that of IgG1. Furthermore, HLJDT aqueous extracts and HLJDT-CG administration also suppressed CII

  13. Collagen-induced arthritis in Biozzi mice. Joint involvement is not correlated with collagen II IgG2a autoantibodies nor restricted to only H-2q and H-2r.

    PubMed

    Bouvet, J P; Couderc, J; Bouthillier, Y; Franc, B; Decreusefond, C; Mouton, D

    1989-09-01

    High (H) and low (L) immune responder "Biozzi" mice, obtained by four different selections, were investigated for their ability to develop collagen-induced arthritis. Both LI and LII lines--characterized by their low antibody responses to a wide variety of Ag--developed arthritis though they do not bear the susceptible H-2q and H-2r haplotypes. Out of the two lines (HI and HII) selected for their high antibody responses and bearing H-2q, only one (HI) developed arthritis. Both the lines with amplified high or low antibody responses (HG and LG), and the lines differing in the levels of cell-mediated immunity (Hpha and Lpha), failed to develop arthritis. Collagen II autoantibodies were found in all the lines: the responses being high (HI and HG), low (LI, LII and LG), or intermediate (HII, Hpha and Lpha). The level of IgG2a autoantibodies, presumed to be the most pathogenic, was low in two (HI and LII) of the three arthritic lines, and was high in the unaffected HG line. These results show that this arthritis is not solely restricted to H-2q and H-2r haplotypes, and argue against a correlation between collagen autoantibody levels and disease incidence.

  14. Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis.

    PubMed

    Kiyeko, Gaëlle Wambiekele; Hatterer, Eric; Herren, Suzanne; Di Ceglie, Irene; van Lent, Peter L; Reith, Walter; Kosco-Vilbois, Marie; Ferlin, Walter; Shang, Limin

    2016-11-01

    Increased expression of endogenous Toll-like receptor 4 (TLR4) ligands (e.g., Tenascin-C, S100A8/A9, citrullinated fibrinogen (cFb) immune complexes) has been observed in patients with rheumatoid arthritis (RA). However, their roles in RA pathogenesis are not well understood. Here, we investigated the expression kinetics and role of endogenous TLR4 ligands in the murine model of collagen-induced arthritis (CIA). Tenascin-C was upregulated in blood early in CIA, and correlated positively with the clinical score at day 56. Levels of S100A8/A9 increased starting from day 28, peaking at day 42, and correlated positively with joint inflammation. Levels of anti-cFb antibodies increased during the late phase of CIA and correlated positively with both joint inflammation and cartilage damage. Blockade of TLR4 activation at the time of the first TLR4 ligand upregulation prevented clinical and histological signs of arthritis. A TLR4-dependent role was also observed for Tenascin-C and cFb immune complexes in osteoclast differentiation in vitro. Taken together, our data suggests that the pathogenic contribution of TLR4 in promoting joint inflammation and bone erosion during CIA occurs via various TLR4 ligands arising at different stages of disease. The data also suggests that Blockade of TLR4 with monoclonal antibodies is a promising strategy in RA treatment. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Anti-inflammatory activities of light emitting diode irradiation on collagen-induced arthritis in mice (a secondary publication)

    PubMed Central

    Ohta, Mitsuhiro; Sato, Yusuke; Abiko, Yoshimitsu

    2014-01-01

    Background and aims: Rheumatoid arthritis (RA) is an auto-immune disease afflicting multiple joints of the body, where as a result of the increase in inflammatory cytokines and tissue destructive factors such as matrix metalloproteinase (MMP)-3, deterioration of the bones and cartilages of the joints occurs. The present investigation was carried out to study the anti-inflammatory activities of light emitting diode (LED) irradiation on hind paw inflammation in collagen-induced arthritis (CIA) mice models. Materials and method: RA in the CIA mouse model was induced by immunization of DBA/1J mice with intradermal injections of an emulsion of bovine type II collagen and complete Freund's adjuvant. A total of 20 CIA mice were subdivided into the following groups: control group, CIA group and 2 groups of LED irradiated CIA mice (LED groups) (n=5 per group). The mouse knee joint area in the LED groups (the 570 nm and 940 nm groups) was irradiated with LED energy, three times a week for 500 s per session over 8 weeks at a dose of 5 J/cm2. The hind paw swelling was assessed by the increase in hind paw thickness. The serum levels of the inflammatory cytokines and arthritic factor MMP-3 were determined with an enzyme-linked immunosorbent assay (ELISA). Results: In the LED-570 and LED-940 groups at 4 weeks after arthritis induction, the swelling inhibition index was 18.1±4.9 and 29.3±4.0 respectively. Interleukin (IL)-1β, IL-6 and MMP-3 serum levels were significantly lower in the LED-940 group. Conclusions: LED irradiation, particularly in the near-infrared was effective for inhibition of the inflammatory reactions caused by RA. PMID:25368445

  16. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

    PubMed Central

    Malfait, A. M.; Gallily, R.; Sumariwalla, P. F.; Malik, A. S.; Andreakos, E.; Mechoulam, R.; Feldmann, M.

    2000-01-01

    The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-γ production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA. PMID:10920191

  17. Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro-inflammatory role of citrullinated BiP in collagen-induced arthritis

    PubMed Central

    2011-01-01

    Introduction Anti-citrullinated protein/peptide antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA) patients and are thought to have a close relationship with the pathogenesis of arthritis. Several proteins, including fibrinogen, vimentin, and alpha-enolase, were reported as ACPA-target antigens, and their importance in RA pathogenesis was widely proposed. We identified citrullinated immunoglobulin binding protein (citBiP) as another ACPA target in RA patients and examined its pro-inflammatory role in arthritis. Methods We measured the levels of anti-citBiP, anti-BiP, and anti-cyclic citrullinated peptide (CCP) antibodies in the serum of RA patients (n = 100), systemic lupus erythematosus (SLE) patients (n = 60), and healthy controls (n = 30) using ELISA and immunoblotting. Epitope mapping was performed using 27 citBiP-derived peptides. In the mouse study, after DBA/1J mice were immunized with BiP or citBiP, serum titers of ACPAs were measured by ELISA and immunohistochemistry. The development of collagen-induced arthritis (CIA) was observed in BiP- or citBiP-pre-immunized mice. Results The serum levels of anti-BiP and anti-citBiP antibodies were significantly increased in RA patients, although only anti-BiP antibodies were slightly increased in SLE patients. Interestingly, anti-citBiP antibody levels were higher than anti-BiP antibody levels in 72% of RA patients, whereas no significant increase in anti-citBiP antibody levels was detected in SLE patients and healthy controls. The serum levels of anti-CCP antibodies were correlated with those of anti-citBiP antibodies in RA patients (R2 = 0.41). Several citrulline residues of citBiP were determined to be major epitopes of anti-citBiP antibodies, one of which showed cross-reactivity with CCP. Immunization of DBA/1J mice with citBiP induced several kinds of ACPAs, including anti-CCP and anti-citrullinated fibrinogen antibodies. Pre-immunization with citBiP exacerbated CIA, and anti-CCP antibody levels

  18. Incidence and specificity of antibodies to types I, II, III, IV, and V collagen in rheumatoid arthritis and other rheumatic diseases as measured by 125I-radioimmunoassay

    SciTech Connect

    Stuart, J.M.; Huffstutter, E.H.; Townes, A.S.; Kang, A.H.

    1983-07-01

    Antibodies to human native and denatured types I, II, III, IV, and V collagens were measured using 125I-radioimmunoassay. Mean levels of binding by sera from 30 rheumatoid arthritis patients were significantly higher than those from 20 normal subjects against all of the collagens tested. The relative antibody concentration was higher in synovial fluid than in simultaneously obtained serum. Many patients with gout or various other rheumatic diseases also had detectable anticollagen antibodies. With a few notable exceptions, the majority of the reactivity detected in all patient groups was directed against covalent structural determinants present on all of the denatured collagens, suggesting a secondary reaction to tissue injury.

  19. Differential display analysis of murine collagen-induced arthritis: cloning of the cDNA-encoding murine ATPase inhibitor.

    PubMed Central

    Yamada, E; Ishiguro, N; Miyaishi, O; Takeuchi, A; Nakashima, I; Iwata, H; Isobe, K

    1997-01-01

    We used the differential display technique in order to detect a new gene involved in murine type II collagen-induced arthritis (CIA). In this study, we have identified a novel gene, IF1, whose expression level is increased during the natural course of CIA. Northern blot analyses suggest that IF1 is involved in the natural course of CIA but is not involved as a trigger of CIA. IF1 is considered to be the murine ATPase inhibitor gene for several reasons. First, IF1 shows an extremely high homology to the rat ATPase inhibitor; the highly conserved region between rat and bovine amino acid residues 22-45, which is the minimum sequence showing ATPase inhibitory activities, is also highly conserved in IF1. Second, IF1 possesses a histidine-rich region in the same area, which is thought to be important for regulation of mammalian inhibitors. Third, the tissue distribution of IF1 is very suggestive. The expression of IF1 was very strong in energetic organs such as the heart, brain and kidney, and the development of arthritis requires great amounts of ATP. As arthritis develops rapidly, the cellular ATP pool may be decreased. Before the ATP pool is exhausted, the ATPase inhibitor may serve as a brake for ATP hydrolysis. If the supply of free energy can be reduced, the inflammation of arthritis may in turn be restored. Our hypothesis is that the ATPase inhibitor is involved in regulating the inflammatory responses. Images Figure 1 Figure 2 Figure 4 Figure 5 PMID:9497501

  20. Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats.

    PubMed

    Earp, Justin C; Dubois, Debra C; Molano, Diana S; Pyszczynski, Nancy A; Keller, Craig E; Almon, Richard R; Jusko, William J

    2008-08-01

    A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy X-ray densitometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-alpha and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1beta, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-alpha and IL-1beta mRNA most significantly induce paw edema, whereas IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.

  1. Model studies directed toward the application of boron neutron capture therapy to rheumatoid arthritis: Boron delivery by liposomes in rat collagen-induced arthritis

    PubMed Central

    Watson-Clark, Rachel A.; Banquerigo, Mona Lisa; Shelly, Kenneth; Hawthorne, M. Frederick; Brahn, Ernest

    1998-01-01

    The application of boron neutron capture therapy to rheumatoid arthritis requires the selective delivery of the boron-10 isotope to the synovitic tissue. The use of liposomes as a boron delivery method has been explored through the measurement of the time course biodistribution of boron in rats with collagen-induced arthritis (CIA). Small unilamellar vesicles were composed of a 1:1 mixture of distearoylphosphatidylcholine and cholesterol, incorporated K[nido-7-CH3(CH2)15-7,8-C2B9H11] as an addend in the lipid bilayer and encapsulated Na3[a2-B20H17NH2CH2CH2NH2] in the aqueous core. The tissue concentration of boron delivered by liposomes was determined by inductively coupled plasma–atomic emission spectroscopy after intravenous injection of liposome suspensions into Louvain rats with CIA. With the low injected doses of boron used [13–18 mg of boron per kg (body weight)], the peak boron concentration observed in arthritic synovium was 29 μg of boron per g of tissue. The highest synovium/blood boron ratio observed was 3.0, when the synovial boron concentration was 22 μg of boron per g of tissue. In an attempt to increase the synovium/blood boron ratio by lowering the blood boron concentration, a liposomal formulation characterized by a shorter blood clearance time was examined. Thus, the biodistribution of liposomes with additional K[nido-7-CH3(CH2)15-7,8-C2B9H11] incorporated in the vesicle membrane not only demonstrated more rapid blood clearance and slightly higher synovium/blood boron ratios but also exhibited reduced boron uptake in synovial tissue. These studies with boron neutron capture therapy for CIA suggest that this form of therapy may be feasible in the treatment of rheumatoid arthritis. PMID:9482920

  2. Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance

    PubMed Central

    2012-01-01

    Introduction Endosomal toll-like receptors (TLRs) have recently emerged as potential contributors to the inflammation observed in human and rodent models of rheumatoid arthritis (RA). This study aims to evaluate the role of endosomal TLRs and in particular TLR7 in the murine collagen induced arthritis (CIA) model. Methods CIA was induced by injection of collagen in complete Freund's adjuvant. To investigate the effect of endosomal TLRs in the CIA model, mianserin was administered daily from the day of disease onset. The specific role of TLR7 was examined by inducing CIA in TLR7-deficient mice. Disease progression was assessed by measuring clinical score, paw swelling, serum anti-collagen antibodies histological parameters, cytokine production and the percentage of T regulatory (Treg) cells. Results Therapeutic administration of mianserin to arthritic animals demonstrated a highly protective effect on paw swelling and joint destruction. TLR7-/- mice developed a mild arthritis, where the clinical score and paw swelling were significantly compromised in comparison to the control group. The amelioration of arthritis by mianserin and TLR7 deficiency both corresponded with a reduction in IL-17 responses, histological and clinical scores, and paw swelling. Conclusions These data highlight the potential role for endosomal TLRs in the maintenance of inflammation in RA and support the concept of a role for TLR7 in experimental arthritis models. This study also illustrates the potential benefit that may be afforded by therapeutically inhibiting the endosomal TLRs in RA. PMID:22691272

  3. Inhalation of carbon monoxide ameliorates collagen-induced arthritis in mice and regulates the articular expression of IL-1beta and MCP-1.

    PubMed

    Takagi, Tomohisa; Naito, Yuji; Inoue, Mamoru; Akagiri, Satomi; Mizushima, Katsura; Handa, Osamu; Kokura, Satoshi; Ichikawa, Hiroshi; Yoshikawa, Toshikazu

    2009-04-01

    Carbon monoxide (CO), long considered a toxic gas, has recently been shown to mediate anti-inflammatory effects in various animal models. The aim of this study was to investigate whether the inhalation of CO ameliorated collagen-induced arthritis (CIA) in mice. CIA was induced in female DBA/1 mice by the injection of an anti-type II collagen antibody and lipopolysaccharide. The CO treatment group was exposed to CO gas at a concentration of 200 ppm in a closed cage starting on the day of the injection with an anti-type II collagen antibody and throughout the remaining study period. The clinical arthritis scores was examined daily for swelling of the paws as a sign of arthritis. For histopathology, the sections of the hind legs were evaluated by hematoxylin-eosin staining. Moreover, we evaluated the expression of interleukin (IL)-1beta and monocyte chemoattractant protein-1 (MCP-1) mRNA in the hind paws. Both clinical arthritis scores as well as histological findings of joint inflammation were significantly reduced in mice treated with CO gas inhalation compared to untreated mice. Further, CO significantly inhibited the increased expression of IL-1beta and MCP-1 mRNA in paws at day 3 after the induction of arthritis. In conclusion, the inhalation of CO protected mice from the synovial inflammation of CIA. Based on these data, the beneficial effects of CO in murine RA model may be attributed to its anti-inflammatory properties.

  4. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis

    SciTech Connect

    Londei, M.; Savill, C.M.; Verhoef, A.; Brennan, F.; Leech, Z.A.; Feldmann, M. ); Duance, V. ); Maini, R.N. )

    1989-01-01

    Rheumatoid arthritis is an autoimmune disease characterized by T-cell infiltration of the synovium of joints. Analysis of the phenotype and antigen specificity of the infiltrating cells may thus provide insight into the pathogenesis of rheumatoid arthritis. T cells were cloned with interleukin 2, a procedure that selects for in vivo-activated cells. All clones had the CD4 CDW29 phenotype. Their antigen specificity was tested by using a panel of candidate joint autoantigens. Four of 17 reacted against autologous blood mononuclear cells. Two clones proliferated in response to collagen type II. After 21 months, another set of clones was derived from synovial tissue of the same joint. One of eight clones tested showed a strong proliferative response against collagen type II. The uncloned synovial T cells of a third operation from another joint also responded to collagen type II. The persistence of collagen type II-specific T cells in active rheumatoid joints over a period of 3 years suggests that collagen type II could be one of the autoantigens involved in perpetuating the inflammatory process in rheumatoid arthritis.

  5. Oral Administration of Shark Type II Collagen Suppresses Complete Freund's Adjuvant-Induced Rheumatoid Arthritis in Rats.

    PubMed

    Chen, Lijuan; Bao, Bin; Wang, Nanping; Xie, Jing; Wu, Wenhui

    2012-03-28

    Shark type II collagen (SCII) is extracted as a glycoprotein from the cartilage of blue shark (Prionace glauca). We aim to confirm the effects of oral tolerance of SCII on inflammatory and immune responses to the ankle joint of rheumatoid-arthritis rats induced by Complete Freund's Adjuvant (CFA). The onset of rheumatoid arthritis (RA) was observed 14 ± x days after injection of CFA. Rats in the control group were treated with acetic acid by oral administration (0.05 mmol kg-1d-1, days 14-28), while rats in experimental groups were treated by oral administration with SCII (1 or 3 mg kg-1d-1, days 14-28), Tripterygium wilfordii polyglycosidium (TWP) (10 mg kg-1d-1, days 14-28), and bovine type II collagen from US (US-CII) (1 mg kg-1d-1, days 14-28), respectively. The severity of arthritis was evaluated by the articular swelling. The immunological indexes observed included delayed type hypersensitivity (DTH) reaction, the level of interleukins 10 (IL-10) in rat blood serum and morphological characterization. Mixed lymphocyte culture (MLC) was performed to investigate the relationship between T cell apoptosis and specific immune tolerance induced by SCII. Treatment with SCII for 2 weeks significantly attenuated the acute inflammation. The rats orally administrated with SCII at the level of 3 mg kg-1d-1 (SCII 3) and US-CII had decreased DTH reaction compared with rats in control group. Rats treated with SCII 3 had the highest level of IL-10 with 102 pg/mL. SCII with concentration of 10 μg/L could help to significantly enhance level of Fas/Apo-1 in T cell in vitro. The result of histological staining indicated that the recovery of the articular membranes of ankle joint in SCII 3 group was greatly enhanced. Our results suggest that appropriate dose of SCII can not only ameliorate symptoms but also modify the disease process of Complete-Freunds-Adjuvant-induced arthritis. Oral administration of SCII might be a potential candidate as a novel drug for further

  6. Oral Administration of Shark Type II Collagen Suppresses Complete Freund’s Adjuvant-Induced Rheumatoid Arthritis in Rats

    PubMed Central

    Chen, Lijuan; Bao, Bin; Wang, Nanping; Xie, Jing; Wu, Wenhui

    2012-01-01

    Objective: Shark type II collagen (SCII) is extracted as a glycoprotein from the cartilage of blue shark (Prionace glauca). We aim to confirm the effects of oral tolerance of SCII on inflammatory and immune responses to the ankle joint of rheumatoid-arthritis rats induced by Complete Freund’s Adjuvant (CFA). Materials and Methods: The onset of rheumatoid arthritis (RA) was observed 14 ± x days after injection of CFA. Rats in the control group were treated with acetic acid by oral administration (0.05 mmol kg−1d−1, days 14–28), while rats in experimental groups were treated by oral administration with SCII (1 or 3 mg kg−1d−1, days 14–28), Tripterygium wilfordii polyglycosidium (TWP) (10 mg kg−1d−1, days 14–28), and bovine type II collagen from US (US-CII) (1 mg kg−1d−1, days 14–28), respectively. The severity of arthritis was evaluated by the articular swelling. The immunological indexes observed included delayed type hypersensitivity (DTH) reaction, the level of interleukins 10 (IL-10) in rat blood serum and morphological characterization. Mixed lymphocyte culture (MLC) was performed to investigate the relationship between T cell apoptosis and specific immune tolerance induced by SCII. Results: Treatment with SCII for 2 weeks significantly attenuated the acute inflammation. The rats orally administrated with SCII at the level of 3 mg kg−1d−1 (SCII 3) and US-CII had decreased DTH reaction compared with rats in control group. Rats treated with SCII 3 had the highest level of IL-10 with 102 pg/mL. SCII with concentration of 10 μg/L could help to significantly enhance level of Fas/Apo-1 in T cell in vitro. The result of histological staining indicated that the recovery of the articular membranes of ankle joint in SCII 3 group was greatly enhanced. Conclusions: Our results suggest that appropriate dose of SCII can not only ameliorate symptoms but also modify the disease process of Complete-Freunds-Adjuvant-induced arthritis. Oral

  7. APL-1, an altered peptide ligand derived from heat-shock protein, alone or combined with methotrexate attenuates murine collagen-induced arthritis.

    PubMed

    Lorenzo, Norailys; Altruda, Fiorella; Silengo, Lorenzo; Del Carmen Dominguez, Maria

    2016-05-09

    Induction of tolerance to autoantigens in vivo is a complex process that involves several mechanisms such as the induction of regulatory T cells and changes in the cytokine and chemokine profiles. This approach represents an attractive alternative for treatment of autoimmune diseases. APL-1 is an altered peptide ligand derived from a novel CD4 + T cell epitope of human heat-shock protein of 60 kDa (HSP60), an autoantigen involved in the pathogenesis of rheumatoid arthritis (RA). We have shown previously that this peptide efficiently inhibited the course of adjuvant-induced arthritis in Lewis rats and induced regulatory T cell (Treg) in ex vivo assay with PBMC isolated from RA patients. This study was undertaken to evaluate the therapeutic effect of APL-1 and its combination with methotrexate (MTX) in collagen-induced arthritis (CIA). CIA was induced in male DBA/1 mice at 8 weeks of age by immunization with chicken collagen. APL, MTX or both were administrated beginning from arthritis onset. Therapeutic effect was evaluated by arthritis and joint pathologic scores. In addition, TNFα and IL-10 in sera were measured by ELISA. Treg induction was assessed by FACS analysis. APL-1 inhibits efficiently the course of arthritis in CIA, similar to MTX. In addition, therapy with APL-1 plus MTX reduced CIA in mice, associated with an increase in Treg. These facts reinforce the therapeutic possibilities of APL-1 as a candidate drug for treatment of RA.

  8. Alleviation of collagen-induced arthritis by the benzoxathiole derivative BOT-4-one in mice: Implication of the Th1- and Th17-cell-mediated immune responses.

    PubMed

    Kim, Byung-Hak; Yoon, Bo Ruem; Kim, Eun Kyoung; Noh, Kum Hee; Kwon, Sun-Ho; Yi, Eun Hee; Lee, Hyun Gyu; Choi, Jung Sook; Kang, Seong Wook; Park, In-Chul; Lee, Won-Woo; Ye, Sang-Kyu

    2016-06-15

    Autoimmune rheumatoid arthritis is characterized by chronic inflammation and hyperplasia in the synovial joints. Although the cause of rheumatoid arthritis is largely unknown, substantial evidence has supported the importance of immune cells and inflammatory cytokines in the initiation and progression of this disease. Herein, we demonstrated that the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) alleviated type II collagen-induced arthritis in a mouse model. The levels of pro-inflammatory cytokines are elevated in both human patients with rheumatoid arthritis and mice with collagen-induced arthritis. BOT-4-one treatment reduced the levels of pro-inflammatory cytokines in mice and endotoxin-stimulated macrophages. BOT-4-one treatment suppressed the polarization of Th1- and Th17-cell subsets by inhibiting the expression and production of their lineage-specific master transcription factors and cytokines, as well as activation of signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited mitogen-activated protein kinase and NF-kappaB signaling as well as the transcriptional activities and DNA-binding of transcription factors, including activator protein-1, cAMP response element-binding protein and NF-kappaB. Our results suggest that BOT-4-one may have therapeutic potential for the treatment of chronic inflammation associated with autoimmune rheumatoid arthritis.

  9. The natural flavonoid galangin inhibits osteoclastic bone destruction and osteoclastogenesis by suppressing NF-κB in collagen-induced arthritis and bone marrow-derived macrophages.

    PubMed

    Huh, Jeong-Eun; Jung, In-Tae; Choi, Junyoung; Baek, Yong-Hyeon; Lee, Jae-Dong; Park, Dong-Suk; Choi, Do-Young

    2013-01-05

    We investigated the effect of galangin, a natural flavonoid, on osteoclastic bone destruction in collagen-induced arthritis and examined the molecular mechanisms by which galangin affects osteoclastogenesis in bone marrow derived macrophages. In mice with collagen-induced arthritis, administration of galangin significantly reduced the arthritis clinical score, edema and severity of disease without toxicity. Interestingly, galangin treatment during a later stage of collagen-induced arthritis, using mice with a higher clinical arthritis score, still significantly slowed the progression of the disease. Extensive cartilage and bone erosive changes as well as synovial inflammation, synovial hyperplasia and pannus formation were dramatically inhibited in arthritic mice treated with galangin. Furthermore, galangin-treated arthritic mice showed a significant reduction in the concentrations of IL-1β, TNF-α and IL-17. We found that galangin inhibited osteoclastogenic factors and osteoclast formation in bone marrow-derived macrophages and osteoblast co-cultured cells, and increased osteoprotegerin (OPG) levels in osteoblasts. Galangin and NF-κB siRNA suppressed RANKL-induced phosphorylation of the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), but not AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Also, the JNK inhibitor SP600125 and p38 inhibitor SB203580 reduced RANKL-induced expressions of phospho-c-Jun, c-fos and NFATc1 genes during osteoclast development. In addition, galangin suppressed RANKL-induced phosphorylation of NF-κB, phospho-IκBα, inflammatory cytokines and osteoclast formation in bone marrow-derived macrophages. Our data suggest that galangin prevented osteoclastic bone destruction and osteoclastogenesis in osteoclast precursors as well as in collagen-induced arthritis mice without toxicity via attenuation of RANKL-induced activation of JNK, p38 and NF-κB pathways.

  10. Evaluation of anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies in patients with juvenile idiopathic arthritis

    PubMed Central

    2013-01-01

    Background To determine the prevalence and significance of anti-citrullinated vimentin and anti-citrullinated type II collagen antibodies and elucidate their role in the disease process of juvenile idiopathic arthritis (JIA). Methods Sera were obtained from 95 patients with various subtypes of JIA, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. Antibodies were measured in the sera against citrullinated and native type II collagen and vimentin (vim1-16 and vim 59-74) by enzyme-linked immunosorbent assay. Samples were compared to anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) isotypes, and our previously measured anti-citrullinated fibrinogen and α-enolase antibodies on the same patient population, in addition to erythrocyte sedimentation rate and C-reactive protein. The relationship between the anti-citrullinated antibody profile and disease activity and joint damage were also investigated. Results Twenty-three JIA patients (24%) demonstrated reactivity to anti-citrullinated type II collagen. Ten JIA patients (10.5%) demonstrated reactivity to anti-citrullinated vimentin 1–16 antibodies and 7 (7.4%) to anti-citrullinated vimentin 59–74 antibodies. One IgM RF-positive polyarticular patient was positive for all 5 of the citrullinated autoantibodies tested. Thirty-seven different subsets of patients were identified based on their anti-citrullinated autoantibody and RF isotype profile. No significant associations were noted with anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies with joint damage or disease activity. Anti-citrullinated vimentin 59–74 antibodies demonstrated the highest overall specificity at 89.7%, with anti-citrullinated vimentin 1–16 and anti-citrullinated type II collagen antibodies at 86.2%. Conclusion This study demonstrates that antibodies to multiple citrullinated epitopes are present in the sera of patients with various subtypes of JIA. It also

  11. Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent.

    PubMed

    Srinivasan, Mythily; Eri, Rajaraman; Zunt, Susan L; Summerlin, Don-John; Brand, David D; Blum, Janice S

    2007-02-01

    The CD80/CD86-CD28/CD152 costimulatory pathways transmit signals for CD4+ T cell activation and suppression and are critically involved in the pathogenesis of rheumatoid arthritis (RA). A significant number of CD4+ T cells and macrophages in the rheumatoid synovium express elevated levels of CD80, increasing the potential for costimulation in trans of naive T cells. To determine the effect of blockade of this costimulatory axis in RA, we designed novel CD80-binding peptides and evaluated their therapeutic potential in collagen-induced arthritis (CIA), an animal model of RA. The conserved MYPPPY motif of CD152 adopts a polyproline type II (PPII) helical conformation in the CD80-CD152 complex. The pairing preferences of the critical residues at the CD80-CD152 interface and their propensity to form PPII helices were integrated to design peptides with optimum PPII helical content that selectively block CD80-receptor interactions. The clinical efficacy was tested in DBA/1LacJ mice that were administered the CD80 blocking agents, called CD80-binding competitive antagonist peptides (CD80-CAPs), at the time of immunization with bovine type II collagen or 3 weeks after immunization. A single administration of select CD80-CAPs significantly reduced the clinical, radiologic, and histologic disease severity in CIA. Importantly, administration of CD80-CAPs during activated immune response significantly suppressed disease development by reducing mononuclear cell infiltration in the joints and mediating peripheral deletion of activated CD4+ T cells. A rationally designed CD80-binding peptide both prevents and suppresses CIA, suggesting a potential application in RA. Apoptosis of activated CD4+ T cells following in vivo blockade suggests that the effects of CD80-CAPs may be long-lasting.

  12. A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

    PubMed Central

    2009-01-01

    Introduction Osteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss. Methods Arthritis was induced in 64 female Sprague-Dawley rats. After the clinical onset of CIA, rats were assigned to treatment with MTX (1 mg/kg/week), ZA (100 μg/kg twice weekly), both treatments at the same regimens, or vehicle. Arthritis score and paw thickness were recorded twice weekly. The rats were sacrificed on D28 and hind paws were removed for radiographic, histological and immunohistochemical analysis. The effects of treatments on osteoclastogenesis were determined by Tartrate resistant acid phosphatase (TRAP) staining. Micro-CT of the tibia was carried out for histomorphometric analysis. Bone mass density was evaluated by densitometry. Results MTX significantly decreased the severity of CIA, whereas ZA slightly exacerbated it. When these two drugs were used in combination, MTX prevented the pro-inflammatory effect of ZA. The combination of ZA with MTX was more effective than MTX alone for reducing structural joint damage with a dramatic decrease of osteoclasts' number in the eroded joints. However, MTX alone also significantly reduced the number of osteoclasts and the number of CD68+ mononuclear cells. ZA alone, or ZA with MTX, significantly increased the systemic bone mass density measured by densitometry and bone volume on histomorphometric analysis. Conclusions A combination of MTX and ZA prevented both bone erosion and systemic bone loss in a rat model of arthritis. Both treatments independently decreased the number of osteoclasts in the eroded joint. However

  13. Dietary trans-10,cis-12 CLA reduces murine collagen-induced arthritis in a dose-dependent manner.

    PubMed

    Huebner, Shane M; Olson, Jake M; Campbell, James P; Bishop, Jeffrey W; Crump, Peter M; Cook, Mark E

    2014-02-01

    Dietary trans-10,cis-12 (t10c12) conjugated linoleic acid (CLA) has been shown to reduce inflammation in a murine collagen-induced arthritis (CA) model. To understand the anti-inflammatory potential of t10c12-CLA in the diet, the minimum dose of pure dietary t10c12-CLA capable of reducing CA was investigated. Because plasma inflammatory cytokines often do not reflect the progression of late-stage arthritis, inflamed tissue cytokine concentrations were also investigated in relation to increasing dietary t10c12-CLA amounts. Mice were randomly assigned to the following dietary treatments upon the establishment of arthritis: corn oil (CO) or 0.125%, 0.25%, 0.375%, or 0.5% t10c12-CLA (wt:wt) for 84 d. Sham mice (no arthritis) were fed CO and served as controls. Arthritic paw score, based on subjective assessment of arthritic severity, and paw thickness decreased linearly overall [16-65% (P < 0.001) and 0.5-12% (P < 0.001), respectively] as dietary t10c12-CLA increased (P < 0.001, R(2) < 0.81). Increasing dietary t10c12-CLA was associated with a decrease in plasma interleukin (IL)-1β at days 21 and 42 compared with CO-fed arthritic mice, such that mice fed ≥0.25% t10c12-CLA had IL-1β concentrations that were similar to sham mice. Plasma cytokines returned to sham mice concentrations by day 63 regardless of treatment; however, an arthritis-induced elevation in paw IL-1β decreased linearly as dietary t10c12-CLA concentrations increased at day 84 (P = 0.007, R(2) = 0.92). Similarly, increasing dietary t10c12-CLA linearly decreased paw tumor necrosis factor (TNF)-α (P = 0.05, R(2) = 0.70). In conclusion, ≥0.125% t10c12-CLA dose-dependently reduced inflammation in a murine CA model.

  14. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor.

    PubMed

    Amdekar, Sarika; Singh, Vinod; Singh, Rambir; Sharma, Poonam; Keshav, Poonam; Kumar, Avnish

    2011-04-01

    This study evaluated the therapeutic efficacy of Lactobacillus casei in treating rheumatoid arthritis using collagen-induced arthritis (CIA) animal model. Healthy female Wistar rats (weight-180-200 g) were included in this study. Oral administration of L. casei was started on the same day. Indomethacin was used as standard reference drug. Serum level of IL-6, α-TNF, and IL-10 were observed. Four-point arthritis indexes were also assessed at the end of week for 28th day. L. casei-treated rats had shown normal histopathology without any synovial infiltration, pannus formation, cartilage, and bone destruction. Arthritis score was also lower for the group treated with L. casei. Oral administration of L. casei significantly decreased the pro-inflammatory cytokines. Present study suggests that L. casei has potent antiarthritic effect in CIA model. Inhibition of COX-2 via inhibiting the pro-inflammatory cytokines is an understanding of the complex interactions involved in these pathways.

  15. Overexpression of Bcl(XL) in B cells promotes Th1 response and exacerbates collagen-induced arthritis.

    PubMed

    Zheng, Biao; Marinova, Ekaterina; Switzer, Kirsten; Wansley, Daniel; He, Hongxia; Bheekha-Escura, Roy; Behrens, Timothy W; Han, Shuhua

    2007-11-15

    B cells play a pathogenic or regulatory role in many autoimmune diseases through production of autoantibodies, cytokine production, and Ag presentation. However, the mechanisms that regulate these B cell functions under different autoimmune settings remain unclear. In the current study, we found that when B cells overexpress an antiapoptotic gene, Bcl(XL), they significantly increased production of IFN-gamma and enhanced Th1 response. Consistently, Bcl-x(L) transgenic mice developed more severe and sustained collagen-induced arthritis due to the enhanced Th1 response. The production of autoantibodies in Bcl(XL) transgenic mice was comparable to that in wild-type mice. Thus, our results indicate a novel role of Bcl(XL) in regulating B cell functions and immune responses. In patients with rheumatoid arthritis, arthritogenic B cells often up-regulate Bcl(XL) expression, which may not only render B cells resistant to apoptosis but also alter the ability of the autoreactive B cells to produce cytokines and modulate the inflammatory response. This may have therapeutic implications if Bcl(XL) expression can be down-regulated in autoreactive B cells.

  16. Nucleosides from Phlebotomus papatasi salivary gland ameliorate murine collagen-induced arthritis by impairing dendritic cell functions

    PubMed Central

    Carregaro, Vanessa; Sá-Nunes, Anderson; Cunha, Thiago M.; Grespan, Renata; Oliveira, Carlo J. F.; Junior, Djalma L.; Costa, Diego L.; Verry, Waldiceu A.; Milanezi, Cristiane M.; Pham, Van My; Brand, David D.; Valenzuela, Jesus G.; Silva, João S.; Ribeiro, José M. C.; Cunha, Fernando Q.

    2011-01-01

    Among several pharmacological compounds, Phlebotomine saliva contains substances with anti-inflammatory properties. Herein, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Phlebotomus papatasi in an experimental model of arthritis (collagen-induced arthritis [CIA]) and identified the constituents responsible for such activity. Daily administration of SGE, initiated at disease onset, attenuated the severity of CIA, reducing the joint lesion and pro-inflammatory cytokines release. In vitro incubation of dendritic cells (DC) with SGE limited specific CD4+Th17 cell response. We identified adenosine (ADO) and adenosine monophosphate (5′AMP) as the major salivary molecules responsible for anti-inflammatory activities. Pharmacologic inhibition of ADO A2A receptor or enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect. Importantly, CD73 (ecto-5′nucleotidase enzyme) is expressed on DC surface during stage of activation, suggesting that ADO is also generated by 5′AMP metabolism. Moreover, both nucleosides mimicked SGE-induced anti-inflammatory activity upon DC function in vitro and attenuated establishment of CIA in vivo. We reveal that ADO and 5′AMP are present in pharmacological amounts in P. papatasi saliva and act preferentially on DC function, consequently reducing Th17 subset activation and suppressing the autoimmune response. Thus, it is plausible that these constituents might be promising therapeutic molecules to target immune inflammatory diseases. PMID:21930966

  17. Nucleosides from Phlebotomus papatasi salivary gland ameliorate murine collagen-induced arthritis by impairing dendritic cell functions.

    PubMed

    Carregaro, Vanessa; Sá-Nunes, Anderson; Cunha, Thiago M; Grespan, Renata; Oliveira, Carlo J F; Lima-Junior, Djalma S; Costa, Diego L; Verri, Waldiceu A; Milanezi, Cristiane M; Pham, Van My; Brand, David D; Valenzuela, Jesus G; Silva, João S; Ribeiro, José M C; Cunha, Fernando Q

    2011-10-15

    Among several pharmacological compounds, Phlebotomine saliva contains substances with anti-inflammatory properties. In this article, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Phlebotomus papatasi in an experimental model of arthritis (collagen-induced arthritis [CIA]) and identified the constituents responsible for such activity. Daily administration of SGE, initiated at disease onset, attenuated the severity of CIA, reducing the joint lesion and proinflammatory cytokine release. In vitro incubation of dendritic cells (DCs) with SGE limited specific CD4(+) Th17 cell response. We identified adenosine (ADO) and 5'AMP as the major salivary molecules responsible for anti-inflammatory activities. Pharmacologic inhibition of ADO A2(A) receptor or enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect. Importantly, CD73 (ecto-5'-nucleotidase enzyme) is expressed on DC surface during stage of activation, suggesting that ADO is also generated by 5'AMP metabolism. Moreover, both nucleosides mimicked SGE-induced anti-inflammatory activity upon DC function in vitro and attenuated establishment of CIA in vivo. We reveal that ADO and 5'AMP are present in pharmacological amounts in P. papatasi saliva and act preferentially on DC function, consequently reducing Th17 subset activation and suppressing the autoimmune response. Thus, it is plausible that these constituents might be promising therapeutic molecules to target immune inflammatory diseases.

  18. Population pharmacokinetic-pharmacodynamic-disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis.

    PubMed

    Liu, Dongyang; Lon, Hoi-Kei; Dubois, Debra C; Almon, Richard R; Jusko, William J

    2011-12-01

    A population pharmacokinetic-pharmacodynamic-disease progression (PK/PD/DIS) model was developed to characterize the effects of anakinra in collagen-induced arthritic (CIA) rats and explore the role of interleukin-1β (IL-1β) in rheumatoid arthritis. The CIA rats received either vehicle, or anakinra at 100 mg/kg for about 33 h, 100 mg/kg for about 188 h, or 10 mg/kg for about 188 h by subcutaneous infusion. Plasma concentrations of anakinra were assayed by enzyme-linked immunosorbent assay. Swelling of rat hind paws was measured. Population PK/PD/DIS parameters were computed for the various groups using non-linear mixed-effects modeling software (NONMEM® Version VI). The final model was assessed using visual predictive checks and nonparameter stratified bootstrapping. A two-compartment PK model with two sequential absorption processes and linear elimination was used to capture PK profiles of anakinra. A transduction-based feedback model incorporating logistic growth rate captured disease progression and indirect response model I captured drug effects. The PK and paw swelling versus time profiles in CIA rats were fitted well. Anakinra has modest effects (I ( max ) = 0.28) on paw edema in CIA rats. The profiles are well-described by our PK/PD/DIS model which provides a basis for future mechanism-based assessment of anakinra dynamics in rheumatoid arthritis.

  19. Decreased severity of collagen antibody and lipopolysaccharide-induced arthritis in human IL-32β overexpressed transgenic mice.

    PubMed

    Park, Mi Hee; Yoon, Do-Young; Ban, Jung Ok; Kim, Dae Hwan; Lee, Dong Hun; Song, Sukgil; Kim, Youngsoo; Han, Sang-Bae; Lee, Hee Pom; Hong, Jin Tae

    2015-11-17

    Interleukin (IL)-32, mainly produced by T-lymphocytes, natural killer cells, epithelial cells, and blood monocytes, is dominantly known as a pro-inflammatory cytokine. However, the role of IL-32 on inflammatory disease has been doubtful according to diverse conflicting results. This study was designed to examine the role of IL-32β on the development of collagen antibody (CAIA) and lipopolysaccharide (LPS)-induced inflammatory arthritis. Our data showed that the paw swelling volume and clinical score were significantly reduced in the CAIA and LPS-treated IL-32β transgenic mice compared with non-transgenic mice. The populations of cytotoxic T, NK and dendritic cells was inhibited and NF-κB and STAT3 activities were significantly lowered in the CAIA and LPS-treated IL-32β transgenic mice. The expression of pro-inflammatory proteins was prevented in the paw tissues of CAIA and LPS-treated IL-32β transgenic mice. In addition, IL-32β altered several cytokine levels in the blood, spleen and paw joint. Our data indicates that IL-32β comprehensively inhibits the inflammation responses in the CAIA and LPS-induced inflammatory arthritis model.

  20. Extracts of Bauhinia championii (Benth.) Benth. attenuate the inflammatory response in a rat model of collagen-induced arthritis

    PubMed Central

    XU, WEI; HUANG, MINGQING; ZHANG, YUQIN; LI, HUANG; ZHENG, HAIYIN; YU, LISHUANG; CHU, KEDAN; LIN, YU; CHEN, LIDIAN

    2016-01-01

    Rheumatoid arthritis is considered a serious public health problem, which is commonly treated with traditional Chinese or herbal medicine. The present study evaluated the effects of Bauhinia championii (Benth.) Benth. extraction (BCBE) on a type II collagen-induced arthritis (CIA) rat model. Wistar rats with CIA received either 125 or 500 mg/kg BCBE, after which, paw swelling was markedly suppressed compared with in the model group. In addition, BCBE significantly ameliorated pathological joint alterations, including synovial hyperplasia, and cartilage and bone destruction. The protein and mRNA expression levels of interleukin (IL)-6, IL-8, tumor necrosis factor-α and nuclear factor-κB in synovial tissue were determined by immunohistochemical staining, western blot analysis and reverse transcription-polymerase chain reaction. The results demonstrated that the expression levels of these factors were significantly downregulated in the BCBE-treated group compared with in the model group. These results indicated that BCBE may exert an inhibitory effect on the CIA rat model, and its therapeutic potential is associated with its anti-inflammatory action. PMID:27035125

  1. Pharmacokinetic and pharmacodynamic study of triptolide-loaded liposome hydrogel patch under microneedles on rats with collagen-induced arthritis

    PubMed Central

    Chen, Gui; Hao, Baohua; Ju, Dahong; Liu, Meijie; Zhao, Hongyan; Du, Zhongping; Xia, Jizi

    2015-01-01

    Triptolide (TP), a major active component of Tripterygium wilfordii Hook.F. (TWHF), is used to treat rheumatoid arthritis (RA). However, it has a narrow therapeutic window due to its serious toxicities. To increase the therapeutic index, a new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (TP-LHP), has been developed. In this paper, we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis (CIA). The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a one-compartment open model. The relationship equation between plasma concentration and time was C=303.59×(e−0.064t−e−0.287t). The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1, fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium. Other indicators were also reduced by TP-LHP, including hyperfunction of immune, interleukin-1β and interleukin-6 levels in serum. The therapeutic mechanism of TP-LHP might be regulation of the balance between Th1 and Th2, as well as inhibition of the expression and biological effects of vascular endothelial growth factor. PMID:26713272

  2. Phenotypic changes in dorsal root ganglion and spinal cord in the collagen antibody-induced arthritis mouse model.

    PubMed

    Su, Jie; Gao, Tianle; Shi, Tiejun; Xiang, Qiong; Xu, Xiaojun; Wiesenfeld-Hallin, Zsuzsanna; Hökfelt, Tomas; Svensson, Camilla I

    2015-07-01

    The mechanisms underlying rheumatoid arthritis (RA)-induced pain are still not fully elucidated, and accumulating data indicate that peripheral inflammation is not the only factor driving pain in these patients. The focus of our work is to investigate the molecular basis for long-term alterations in nociceptive pathways induced by polyarthritis using the collagen antibody-induced arthritis (CAIA) mouse model. In this model, mechanical hypersensitivity outlasts the joint inflammation by weeks. Here we examined expression levels of neuropeptides, ion channels, and nerve injury markers associated with neuropathic and/or inflammatory pain in dorsal root ganglia (DRGs) and spinal cord both during the peak of inflammation (day 15) and when the inflammation has resolved but the hypersensitivity persists (days 45-47). No apparent differences were observed in substance P, calcitonin gene-related peptide, or neuropeptide Y protein expression in DRGs and spinal cord of CAIA mice. However, the neuropeptide galanin, the ATP-gated ion channel P2X3, and calcium channel subunit α2δ1 were significantly increased in the CAIA DRGs as compared to controls, both 15 and 47 days after induction of arthritis. On day 15 there was an increase in expression of two factors associated with nerve injury and cell stress, activating transcription factor 3 and growth-associated protein 43 in DRGs, whereby the latter was still dramatically upregulated after 47 days. In conclusion, this study suggests that long-term joint inflammation has an impact on DRG neurons that resembles both inflammation and nerve injury-induced pain states. Thus, antibody-driven inflammation generates a pain state with a unique neurochemical profile. © 2015 Wiley Periodicals, Inc.

  3. Ethyl pyruvate therapy attenuates experimental severe arthritis caused by type II collagen (CII) in the mouse (CIA).

    PubMed

    Di Paola, R; Mazzon, E; Galuppo, M; Esposito, E; Bramanti, P; Fink, M P; Cuzzocrea, S

    2010-01-01

    This study tested the hypothesis that ethyl pyruvate (EP), a simple aliphatic ester with anti-inflammatory effects, can reduce type II collagen-induced mouse arthritis (CIA). DBA/1J mice were used for the study, developing erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund?s adjuvant (CFA). The incidence of CIA was 100 percent by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint margins. EP-treatment (40 mg/kg/day i.p.) starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26-35 and improved histological status in the joint and paw. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS) revealed a positive staining in inflamed joints from mice subjected to CIA, while no staining was observed for HO-1 and Nrf-2 in the same group. The degree of staining for nitrotyrosine, PAR, iNOS, was significantly reduced in CII-challenged mice treated with the EP. Immuno-positive-staining for HO-1 and Nrf-2 was observed instead, in joints obtained from the EP-treated group. Plasma levels of TNF-α, IL-6 and the joint tissue levels of macrophage inflammatory protein (MIP)-1α and MIP-2 were also significantly reduced by EP treatment. Thirty-five days after immunization, EP-treatment significantly increased plasma levels of IL-10. These data demonstrate that EP treatment exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.

  4. The Effects of Platycodin D, a Saponin Purified from Platycodi Radix, on Collagen-Induced DBA/1J Mouse Rheumatoid Arthritis

    PubMed Central

    Kwon, O. Gon; Ku, Sae Kwang; An, Hee Duk

    2014-01-01

    The object of this study is to observe the effects of platycodin D, a saponin purified from Platycodi Radix, on mice collagen-induced arthritis (CIA). A daily dose of 200, 100, and 50 mg/kg platycodin D was administered orally to male DBA/1J mice for 40 days after initial collagen immunization. To ascertain the effects administering the collagen booster, CIA-related features (including body weight, poly-arthritis, knee and paw thickness, and paw weight increase) was measured from histopathological changes in the spleen, left popliteal lymph node, third digit, and the knee joint regions. CIA-related bone and cartilage damage improved significantly in the platycodin D-administered CIA mice. Additionally, myeloperoxidase (MPO) levels in the paw were reduced in platycodin D-treated CIA mice compared to CIA control groups. The level of malondialdehyde (MDA), an indicator of oxidative stress, decreased in a dose-dependent manner in the platycodin D group. Finally, the production of IL-6 and TNF-α, involved in rheumatoid arthritis pathogenesis, was suppressed by treatment with platycodin D. Taken together, these results suggest that platycodin D is a promising new effective antirheumatoid arthritis agent, exerting anti-inflammatory, antioxidative and immunomodulatory effects in CIA mice. PMID:24511322

  5. Moxibustion at mingmen reduces inflammation and decreases IL-6 in a collagen-induced arthritis mouse model.

    PubMed

    Kogure, Morihiro; Mimura, Naomi; Ikemoto, Hideshi; Ishikawa, Shintaro; Nakanishi-Ueda, Takako; Sunagawa, Masataka; Hisamitsu, Tadashi

    2012-02-01

    The purpose of this study was to compare the effectiveness of moxibustion (MOX) treatment at the GV4 and CV12 acupoints, and to determine the correlations between MOX treatment and interleukin (IL)-6 and corticosterone levels in a collagen-induced arthritis (CIA) mouse model. CIA mice were immunized twice intradermally over a 3-week interval with bovine type II collagen. After the second immunization (day 21), MOX was applied to the mouse equivalent of the GV4 and CV12 acupoints with a 1mg moxa cone five times/day. Clinical symptoms of CIA were observed three times/week until day 35. The concentrations of IL-6 and corticosterone in the blood samples were measured by immunoassay kits. At day 35, the incidence of CIA was significantly decreased in mice treated with MOX at the GV4 acupoint (78%, n=23, p<0.05), compared to untreated CIA mice (100%) and mice treated with MOX at the CV12 acupoint (100%). IL-6 and corticosterone levels were significantly increased by immunization. IL-6 levels significantly decreased in mice treated with MOX at the GV4 acupoint. These results suggest that MOX treatment suppressed CIA at the GV4 acupoint, not at the CV12 acupoint, possibly through inhibition of IL-6 production.

  6. CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis

    PubMed Central

    Sancho, David; Gómez, Manuel; Viedma, Fernando; Esplugues, Enric; Gordón-Alonso, Mónica; Angeles García-López, María; de la Fuente, Hortensia; Martínez-A, Carlos; Lauzurica, Pilar; Sánchez-Madrid, Francisco

    2003-01-01

    CD69 is induced after activation of leukocytes at inflammatory sites, but its physiological role during inflammation remains unknown. We explored the role of CD69 in autoimmune reactivity by analyzing a model of collagen-induced arthritis (CIA) in WT and CD69-deficient mice. CD69–/– mice showed higher incidence and severity of CIA, with exacerbated T and B cell immune responses to type II collagen. Levels of TGF-β1 and TGF-β2, which act as protective agents in CIA, were reduced in CD69–/– mice inflammatory foci, correlating with the increase in the proinflammatory cytokines IL-1β and RANTES. Local injection of blocking anti–TGF-β antibodies increased CIA severity and proinflammatory cytokine mRNA levels in CD69+/+ but not in CD69–/– mice. Moreover, in vitro engagement of CD69 induced total and active TGF-β1 production in Concanavalin A–activated splenocyte subsets, mouse and human synovial leukocytes, and Jurkat stable transfectants of human CD69 but not in the parental CD69 negative cell line. Our results show that CD69 is a negative modulator of autoimmune reactivity and inflammation through the synthesis of TGF-β, a cytokine that in turn downregulates the production of various proinflammatory mediators. PMID:12975472

  7. IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4.

    PubMed

    Canetti, Claudio A; Leung, Bernard P; Culshaw, Shauna; McInnes, Iain B; Cunha, Fernando Q; Liew, Foo Y; Cannetti, Claudio A

    2003-07-15

    IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB(4) that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.

  8. [Experimental study on effects of acupoint application with Leima type II plaster on collagen-induced arthritis in rats].

    PubMed

    Li, Peng; Fang, Jian-Qiao; Zhou, Ya-Feng

    2011-09-01

    To observe the therapeutic effect of acupoint application with Leima type II plaster on collagen-induced arthritis (CIA) in rats and probe its mechanism. Bovine type II collagen was injected intradermally into the middle line of the back to induce CIA model with 48 Wistar rats. Then the rats were randomly divided into a model control group (group A), a matrix control group (group B), acupoint application group with plaster of low concentration (group C) and high concentration plaster group (group D), 12 rats in each group. Group C and group D were treated with low and high concentration of Leima type II plaster, and "Shenzhu" (GV 12), "Zhiyang" (GV 9) and "Mingmen" (GV 4) were selected, each application for about 15 hours, once each day for 30 days. Group B was used the same method of acupoint application except using non-drug matrix plaster, and group A was not given any treatment. The morphous and the histopathological changes of affection joint were observed. The paw edema volume after 30 days treatment in group C was significantly lower than that in group B (P < 0.01), and the anti-type II collagen antibody level after 15 days treatment in group C was significantly lower than that in group A (P < 0.05), and the synoviocytes proliferation of the knee joint in group C was significantly lower than that in group A and group B (both P < 0.01). The paw edema volume after 25 days treatment, arthritic index after 20 days treatment, pathological change of the paw and the synoviocytes proliferation of the knee joint in group D were significantly lower than those in group A and group B (P < 0.01, P < 0.05), and the anti-type II collagen antibody level after 15 days treatment in group D was significantly lower than that in group A (P < 0.05), and the paw edema volume and the arthritic index after 25 days treatment in group D were significantly lower than those in group C (P < 0.05, P < 0.01). Acupoint application with Leima type II plaster has a good therapeutic effect on

  9. Inhibitory effect of the extract of Phellodendron amurense Ruprecht root on collagen-induced arthritis in mice.

    PubMed

    Jung, Hyo Won; Kim, Kyung-Ho; Park, Yong-Ki

    2016-07-26

    To investigated whether the dried root of Phellodendron amurense Ruprecht (Phellodendri cortex; PC) extract improves arthritic symptoms through anti-inflammatory and immune-modulatory effects in collagen-induced arthritis in mice. Rheumatoid arthritis (RA) was induced in male DBA/1 mice by immunization with type II collagen (ColII). CIA mice were divided into 5 groups (n=10 per a group) with normal, CIA control, PC extract (50 mg/kg and 100 mg/kg)-treated, and meloxicam (50 mg/kg)-treated as the reference drug. The PC extract or meloxicam were administered orally in CIA mice once a day for 14 days after arthritis induction. Arthritic score, levels of anti-ColII IgG2a antibody, prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, and interleukin (IL)-17 in the sera of CIA mice were measured. Histopathological changes in the ankle joints of CIA mice were also analyzed by staining with hematoxylin and eosin (H and E), safranin-O and immunohistochemistry using anti-TNF-α and anti-IL-17 antibodies. The arthritic score was increased in CIA mice in a time-dependent manner, as were the serum levels of anti-ColII IgG2a antibody, PGE2, TNF-α, and IL-17. However, the oral administration of PC extract at 50 and 100 mg/kg in CIA mice significantly decreased the arthritic scores, and the serum levels of anti-ColII IgG2a, PGE2, TNF-α, and IL-17 compared with those in the CIA group (P<0.05 or P<0.01). Furthermore, histopathological improvement of the joint architecture in CIA mice was observed after administration of PC extract. PC extract also significantly inhibited the expression of TNF-α and IL-17 in the joints of CIA mice by suppressing the expression of their mRNA and proteins. PC extract may improve the pathological progression of RA through the inhibition of joint destruction by synovial inflammation and immune-stimulation, therefore, it would be a potential anti-arthritic agent in RA.

  10. Sustained Release Myofascial Release as Treatment for a Patient with Complications of Rheumatoid Arthritis and Collagenous Colitis: A Case Report

    PubMed Central

    Cubick, Erin E.; Quezada, Vanessa Y.; Schumer, Ariel D.; Davis, Carol M.

    2011-01-01

    Background: Myofascial release (MFR) is a manual therapeutic technique used to release fascial restrictions, which may cause neuromusculoskeletal and systemic pathology. Purpose: This case report describes the use of sustained release MFR techniques in a patient with a primary diagnosis of rheumatoid arthritis (RA) and a secondary diagnosis of collagenous colitis. Changes in pain, cervical range of motion, fatigue, and gastrointestinal tract function, as well as the impact of RA on daily activities, were assessed. Methods: A 54-year-old white woman presented with signs and symptoms attributed to RA and collagenous colitis. Pre and post measurements were taken with each treatment and during the interim between the initial and final treatment series. The patient recorded changes in pain, fatigue, gastrointestinal tract function, and quality of life. Cervical range of motion was assessed. Six sustained release MFR treatment sessions were provided over a 2-week period. Following an 8-week interim, two more treatments were performed. Results: The patient showed improvements in pain, fatigue, gastrointestinal tract function, cervical range of motion, and quality of life following the initial treatment series of six sessions. The patient maintained positive gains for 5 weeks following the final treatment, after which her symptoms returned to near baseline measurements. Following two more treatments, positive gains were achieved once again. Conclusions: In a patient with RA and collagenous colitis, the application of sustained release MFR techniques in addition to standard medical treatment may provide short-term and long-term improvements in comorbid symptoms and overall quality of life. PMID:22016756

  11. Apoptotic cell infusion treats ongoing collagen-induced arthritis, even in the presence of methotrexate, and is synergic with anti-TNF therapy.

    PubMed

    Bonnefoy, Francis; Daoui, Anna; Valmary-Degano, Séverine; Toussirot, Eric; Saas, Philippe; Perruche, Sylvain

    2016-08-11

    Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy. The effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen. The number and functions of antigen-presenting cells (APC), regulatory CD4(+) T cells (Treg), and circulating anti-collagen auto-antibodies were analyzed in CIA mice. Treatment of arthritic mice with i.v. apoptotic cell infusion significantly reduced the arthritis clinical score. This therapeutic approach modified T cell responses against the collagen auto-antigen with selective induction of collagen-specific Treg. In addition, we observed that APC from apoptotic-cell-treated animals were resistant to toll-like receptor ligand activation and favored ex vivo Treg induction, indicating APC reprogramming. Apoptotic cell injection-induced arthritis modulation was dependent on transforming growth factor (TGF)-β, as neutralizing anti-TGF-β antibody prevented the effects of apoptotic cells. Methotrexate did not interfere, while anti-TNF therapy was synergic with apoptotic-cell-based therapy. Overall, our data demonstrate that apoptotic-cell-based therapy is efficient in treating ongoing CIA, compatible with current RA treatments, and needs to be evaluated in humans in the treatment of RA.

  12. T cells stimulated with an analog peptide of type II collagen require the Fc receptor γ-chain to secrete interleukin-4 and suppress autoimmune arthritis in mice.

    PubMed

    Myers, Linda K; Cullins, David L; Brand, David D; Kleinau, Sandra; Stuart, John M; Kang, Andrew H

    2011-09-01

    To explore the characteristics of the T cell population that responds to an analog peptide (A9) of type II collagen and regulates autoimmunity, using the collagen-induced arthritis (CIA) model. Analog peptide A9 is a 26-amino acid peptide analogous to the sequence of a segment of type II collagen (CII245-270) but with substitutions at amino acid positions 260 (alanine for isoleucine), 261 (hydroxyproline for alanine), and 263 (asparagine for phenylalanine). We previously showed that A9 profoundly suppressed CIA and immune responses to type II collagen. In order to determine the mechanism of suppression, we used transgenic mice whose T cells express a type II collagen-specific receptor (T cell receptor) and performed passive cell transfer experiments. The results demonstrated that suppression of CIA by A9 is dependent on T cells. Using multiparameter flow cytometry, we determined that the cells responsible for suppression were CD4+ and expressed high levels of Fcε receptor Iγ chain (FcRγ). To establish the significance of this finding, we obtained mice genetically deficient in FcRγ in order to perform passive transfer experiments. The resulting FcRγ-/- CD4+ T cells, when primed by culture with A9, could not transfer the suppression of arthritis or secrete cytokines in response to A9. Taken together, the results of this study suggest that the suppression of arthritis and the Th2 cytokine profile elicited by A9 is dependent on the presence of FcRγ in T cells. These findings are novel and may have therapeutic potential for patients with autoimmune arthritis. Copyright © 2011 by the American College of Rheumatology.

  13. Muscle wasting associated with pathologic change is a risk factor for the exacerbation of joint swelling in collagen-induced arthritis in cynomolgus monkeys.

    PubMed

    Horai, Naoto; Nagaoka, Takaharu; Higuchi, Itsuro; Kasai, Hayato; Yoshioka, Takako; Umekita, Yoshihisa; Fukuzaki, Koichiro; Nagata, Ryoichi; Miyata, Atsuro; Abeyama, Kazuhiro

    2013-07-09

    Not only joint destruction but also muscle wasting due to rheumatoid cachexia has been problem in terms of quality of life of patients with rheumatoid arthritis (RA). In the present study, we performed histopathological examination and assessed relationships between characteristic parameters relating to muscle and joint swelling in a collagen-induced arthritis (CIA) model using cynomolgus monkeys (CMs). Female CMs were used and CIA was induced by twice immunizations using bovine type II collagen with Freund's complete adjuvant. Arthritis level was evaluated from the degree of swelling at the peripheral joints of the fore and hind limbs. Food consumption, body weight, and serum biochemical parameters were measured sequentially. Five or 6 animals per time point were sacrificed at 2, 3, 5 and 9 weeks after the first immunization to obtain quadriceps femoris specimens for histopathology. Pimonidazole hydrochloride was intravenously administered to determine tissue hypoxia in skeletal muscle. Gradual joint swelling was observed and the maximum arthritis score was noted at Week 5. In histopathology, necrosis of muscle fiber in the quadriceps femoris was observed only at Week 2 and the most significant findings such as degeneration, atrophy, and regeneration of muscle fiber were mainly observed at Week 5. Food consumption was decreased up to Week 4 but recovered thereafter. Body weight decreased up to Week 5 and did not completely recover thereafter. A biphasic increase in serum cortisol was also observed at Weeks 2 and 5. Histopathology showed that muscle lesions were mainly composed of degeneration and atrophy of the muscle fibers, and ATPase staining revealed that the changes were more pronounced in type II muscle fiber than type I muscle fiber. In the pimonidazole experiment, mosaic pattern in skeletal muscle was demonstrated in the intact animal, but not the CIA animal. Increased arthritis score was accompanied by a decrease in serum creatinine, a marker that

  14. Dietary Conjugated Linoleic Acid-c9t11 Prevents Collagen-Induced Arthritis, Whereas Conjugated Linoleic Acid-t10c12 Increases Arthritic Severity.

    PubMed

    Muhlenbeck, Jessica A; Butz, Daniel E; Olson, Jake M; Uribe-Cano, Daniela; Cook, Mark E

    2017-04-01

    Two conjugated linoleic acid (CLA) isomers, cis-9, trans-11 (CLAc9t11) and trans-10, cis-12 (CLAt10c12), reduce inflammation in a number of animal models, including collagen-induced arthritis (CA). However, little is known about the ability of individual CLA isomers to prevent autoimmune disease onset. Evidence that mixed isomer CLA drives T helper cell (Th) 1 responses suggests that CLA, or a specific isomer, exacerbates onset of Th1 autoimmune diseases. In two experiments, we examined if prior dietary exposure to CLAt10c12 (experiment 1) or CLAc9t11 (experiment 2) affected the incidence or severity of CA. DBA/1 mice were fed a semi purified diet with either 6% corn oil (CO, w/w), 5.75% CO plus 0.25% CLAt10c12, or 5.5% CO plus 0.5% CLAc9t11 prior to arthritis development. Arthritis incidence and severity, anti-collagen antibodies, paw cytokines, and hepatic fatty acids were measured. CLAt10c12 had no effect on arthritis incidence but increased arthritic severity (42%, P = 0.02); however, CLAc9t11 decreased arthritis incidence 39% compared to CO fed mice (P = 0.01), but had no effect on disease severity. CLAt10c12-induced increase in anti-collagen type II IgG antibodies may be a mechanism by which this isomer increased arthritic severity, and CLAc9t11-induced increase in Th2 paw cytokines (IL-4 and IL-10, P ≤ 0.04) may explain how CLAc9t11 reduced the arthritis incidence. While both isomers are well known to reduce inflammation in arthritic mice, these new data suggest isomer differences when fed prior to autoimmune disease.

  15. Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

    PubMed

    Juan, Long; Xiao, Zhao; Song, Yun; Zhijian, Zhang; Jing, Jin; Kun, Yu; Yuna, Hao; Dongfa, Dai; Lili, Ding; Liuxin, Tan; Fei, Liang; Nan, Liu; Fang, Yuan; Yuying, Sun; Yongzhi, Xi

    2015-01-01

    Current clinically available treatments for rheumatoid arthritis (RA) fail to cure the disease or unsatisfactorily halt disease progression. To overcome these limitations, the development of therapeutic DNA vaccines and boosters may offer new promising strategies. Because type II collagen (CII) as a critical autoantigen in RA and native chicken type II collagen (nCCII) has been used to effectively treat RA, we previously developed a novel therapeutic DNA vaccine encoding CCII (pcDNA-CCOL2A1) with efficacy comparable to that of the current "gold standard", methotrexate(MTX). Here, we systemically evaluated the safety and immunogenicity of the pcDNA-CCOL2A1 vaccine in normal Wistar rats. Group 1 received only a single intramuscular injection into the hind leg with pcDNA-CCOL2A1 at the maximum dosage of 3 mg/kg on day 0; Group 2 was injected with normal saline (NS) as a negative control. All rats were monitored daily for any systemic adverse events, reactions at the injection site, and changes in body weights. Plasma and tissues from all experimental rats were collected on day 14 for routine examinations of hematology and biochemistry parameters, anti-CII IgG antibody reactivity, and histopathology. Our results indicated clearly that at the maximum dosage of 3 mg/kg, the pcDNA-CCOL2A1 vaccine was safe and well-tolerated. No abnormal clinical signs or deaths occurred in the pcDNA-CCOL2A1 group compared with the NS group. Furthermore, no major alterations were observed in hematology, biochemistry, and histopathology, even at the maximum dose. In particularly, no anti-CII IgG antibodies were detected in vaccinated normal rats at 14 d after vaccination; this was relevant because we previously demonstrated that the pcDNA-CCOL2A1 vaccine, when administered at the therapeutic dosage of 300 μg/kg alone, did not induce anti-CII IgG antibody production and significantly reduced levels of anti-CII IgG antibodies in the plasma of rats with established collagen-induced arthritis

  16. Safety and immunogenicity of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats

    PubMed Central

    Juan, Long; Xiao, Zhao; Song, Yun; Zhijian, Zhang; Jing, Jin; Kun, Yu; Yuna, Hao; Dongfa, Dai; Lili, Ding; Liuxin, Tan; Fei, Liang; Nan, Liu; Fang, Yuan; Yuying, Sun; Yongzhi, Xi

    2015-01-01

    Current clinically available treatments for rheumatoid arthritis (RA) fail to cure the disease or unsatisfactorily halt disease progression. To overcome these limitations, the development of therapeutic DNA vaccines and boosters may offer new promising strategies. Because type II collagen (CII) as a critical autoantigen in RA and native chicken type II collagen (nCCII) has been used to effectively treat RA, we previously developed a novel therapeutic DNA vaccine encoding CCII (pcDNA-CCOL2A1) with efficacy comparable to that of the current “gold standard”, methotrexate(MTX). Here, we systemically evaluated the safety and immunogenicity of the pcDNA-CCOL2A1 vaccine in normal Wistar rats. Group 1 received only a single intramuscular injection into the hind leg with pcDNA-CCOL2A1 at the maximum dosage of 3 mg/kg on day 0; Group 2 was injected with normal saline (NS) as a negative control. All rats were monitored daily for any systemic adverse events, reactions at the injection site, and changes in body weights. Plasma and tissues from all experimental rats were collected on day 14 for routine examinations of hematology and biochemistry parameters, anti-CII IgG antibody reactivity, and histopathology. Our results indicated clearly that at the maximum dosage of 3 mg/kg, the pcDNA-CCOL2A1 vaccine was safe and well-tolerated. No abnormal clinical signs or deaths occurred in the pcDNA-CCOL2A1 group compared with the NS group. Furthermore, no major alterations were observed in hematology, biochemistry, and histopathology, even at the maximum dose. In particularly, no anti-CII IgG antibodies were detected in vaccinated normal rats at 14 d after vaccination; this was relevant because we previously demonstrated that the pcDNA-CCOL2A1 vaccine, when administered at the therapeutic dosage of 300μg/kg alone, did not induce anti-CII IgG antibody production and significantly reduced levels of anti-CII IgG antibodies in the plasma of rats with established collagen

  17. Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice

    PubMed Central

    Andersson, Ellen Christina; Hansen, Bjarke Endel; Jacobsen, Helle; Madsen, Lars S.; Andersen, Claus B.; Engberg, Jan; Rothbard, Jonathan B.; McDevitt, Grete Sønderstrup; Malmström, Vivianne; Holmdahl, Rikard; Svejgaard, Arne; Fugger, Lars

    1998-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease associated with the HLA-DR4 and DR1 alleles. The target autoantigen(s) in RA is unknown, but type II collagen (CII) is a candidate, and the DR4- and DR1-restricted immunodominant T cell epitope in this protein corresponds to amino acids 261–273 (CII 261–273). We have defined MHC and T cell receptor contacts in CII 261–273 and provide strong evidence that this peptide corresponds to the peptide binding specificity previously found for RA-associated DR molecules. Moreover, we demonstrate that HLA-DR4 and human CD4 transgenic mice homozygous for the I-Abβ0 mutation are highly susceptible to collagen-induced arthritis and describe the clinical course and histopathological changes in the affected joints. PMID:9636191

  18. An insight into the biophysical characterization of insoluble collagen aggregates: implication for arthritis.

    PubMed

    Amani, Samreen; Shamsi, Anas; Rabbani, Gulam; Naim, Aabgeena

    2014-09-01

    Misfolding and aggregation of proteins is involved in some of the most prevalent neurodegenerative disorders. The importance of collagen stems from the fact that it is one of the dominant component used for tissue engineering and drug delivery applications and is a major component of skin, tendon, bone and other connective tissues. A systematic investigation on the conformation of collagen at various concentrations of glyoxal is studied by various biophysical techniques such as Trp fluorescence, ANS binding, Circular dichroism (CD), ATR-FTIR, Congo red (CR) assay, Rayleigh light scattering and Turbidity measurements. At 60% (v/v) glyoxal, collagen retains native-like secondary structure, altered Trp environment and high ANS fluorescence, characteristic of molten globule (MG) state. At 80% (v/v) glyoxal, insoluble collagen aggregates are detected as confirmed by decrease in Trp and ANS fluorescence, increase in non-native β sheet structure as evident from far-UV CD and FTIR spectra, increase in Thioflavin T fluorescence, Rayleigh light scattering, Turbidity measurements, as well as red shift in CR absorbance.

  19. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

    PubMed Central

    2011-01-01

    Background Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. Methods To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. Results A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor

  20. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer.

    PubMed

    Roy, Lopamudra Das; Ghosh, Sriparna; Pathangey, Latha B; Tinder, Teresa L; Gruber, Helen E; Mukherjee, Pinku

    2011-08-22

    Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor progression and metastasis in

  1. Collagen-induced arthritis and related animal models: how much of their pathogenesis is auto-immune, how much is auto-inflammatory?

    PubMed

    Billiau, Alfons; Matthys, Patrick

    2011-01-01

    In this review, we discuss our studies on the pathogenesis of collagen-induced arthritis (CIA) and related mouse models for rheumatoid arthritis. Of note, these models invariably rely on the use of complete Freund's adjuvant (CFA). Our analysis has focused on explaining the dichotomous - either protective or disease-promoting - role of endogenous IFN-γ. Induction of a myelopoietic burst by CFA was identified as an important and underestimated factor in mediating the role of IFN-γ and other cytokines (IL-6, IL-17, GCP-2, RANK-L). Myelopoiesis provides an excess in precursors for joint-infiltrating neutrophils and osteoclasts. We postulate that classical CIA is primarily an auto-inflammatory disease, in part because of a strong innate immune response to the adjuvant. Superimposed on this, collagen-specific auto-immunity reinforces inflammatory reactivity in joints.

  2. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis.

    PubMed

    Lee, Jaejoon; Luria, Ayala; Rhodes, Christopher; Raghu, Harini; Lingampalli, Nithya; Sharpe, Orr; Rada, Balazs; Sohn, Dong Hyun; Robinson, William H; Sokolove, Jeremy

    2017-04-01

    The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA. We compared spontaneous and phorbol 12-myristate 13-acetate-induced NETosis between current and non-smokers by DNA release binding. Nicotine-induced NETosis from non-smokers was assessed by DNA release binding, NET-specific (myeloperoxidase (MPO)-DNA complex) ELISA and real-time fluorescence microscopy. We also used immunofluorescent staining to detect nicotinic acetylcholine receptors (nAChRs) on neutrophils and performed a functional analysis to assess the role of nAChRs in nicotine-induced NETosis. Finally, we investigated the effects of systemic nicotine exposure on arthritis severity and NETosis in the CIA mouse model. Neutrophils derived from current smokers displayed elevated levels of spontaneous and phorbol 12-myristate 13-acetate-induced NETosis. Nicotine induced dose-dependent NETosis in ex vivo neutrophils from healthy non-smokers, and co-incubation with ACPA-immune complexes or TNF-α facilitated a synergistic effect on NETosis. Real-time fluorescence microscopy revealed robust formation of NET-like structures in nicotine-exposed neutrophils. Immunofluorescent staining demonstrated the presence of the α7 subunit of the nAChR on neutrophils. Stimulation of neutrophils with an α7-specific nAChR agonist induced NETosis, whereas pretreatment with an nAChR antagonist attenuated nicotine-induced NETosis. Nicotine administration to mice with CIA exacerbated inflammatory arthritis, with higher plasma levels of NET-associated MPO-DNA complex. We demonstrate that nicotine is a potent inducer of NETosis, which may play an important role in accelerating arthritis in the CIA model. This study generates awareness of and the mechanisms by which nicotine-containing products, including e-cigarettes, may have deleterious effects on patients with RA.

  3. Anti-angiogenic effect of total saponins of Rhizoma Dioscorea nipponica on collagen induced-arthritis in rats

    PubMed Central

    Liang, Xiu-Jun; Guo, Ya-Chun; Sun, Tong-You; Song, Hong-Ru; Gao, Ya-Xian

    2016-01-01

    Rheumatoid arthritis (RA) is a common chronic autoimmune and incurable disease. The aim of the present study was to investigate the therapeutic effect and mechanism of the total saponins of Rhizoma Dioscorea nipponica (TSRDN) in RA. A collagen induced-arthritis (CIA) rat model was established. CIA rats were randomly divided into three groups and lavaged with an equal volume of solvent (CIA group), TSRDN (25 mg/kg/day, RDN group) and tripterygium (TP; 12 mg/kg/day, TP group) for 21 days, respectively. Normal rats served as a control group. Hematoxylin-eosin (HE) staining was used to observe the histopathological injury of synovial tissues. The level of CD31, which used for marking and counting, micro vessel density (MVD) and the expression levels of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription 3 (STAT3) were detected by immunohistochemical analysis. Additionally, the DNA-binding activity of nuclear factor-κB (NF-κB) was determined using an ELISA kit. HE staining showed obvious synovial hyperplasia, inflammatory cell infiltration, pannus formation, cartilage and bone erosion in the CIA group rats. In addition, compared with control group, the level of MVD, the expression of VEGF and STAT3, and the DNA-binding activity of NF-κB were all increased in CIA group rat synovial tissue (all P<0.01); however, TSRDN or tripterygium were able to inhibit these changes (all P<0.01). It was speculated that TSRDN may prevent angiogenesis by inhibiting the expression of STAT3 and the DNA-binding activity of NF-κB p65, thereby potentially improving CIA. PMID:27698704

  4. Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis

    PubMed Central

    Tanida, Atsushi; Kishimoto, Yuji; Okano, Toru; Hagino, Hiroshi

    2013-01-01

    Background Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA). Methods Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration. Results TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration. Conclusion Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis. PMID:24031147

  5. Detection of active matrix metalloproteinase-3 in serum and fibroblast-like synoviocytes of collagen-induced arthritis mice.

    PubMed

    Lee, Aeju; Choi, Sung-Jae; Park, Kyeongsoon; Park, Jong Woong; Kim, Kwangmeyung; Choi, Kuiwon; Yoon, Soo-Young; Youn, Inchan

    2013-06-19

    The activity of rheumatoid arthritis (RA) correlates with the expression of proteases. Among several proteases, matrix metalloproteinase-3 (MMP-3) is one of the biological markers used to diagnose RA. The active form of MMP-3 is a key enzyme involved in RA-associated destruction of cartilage and bone. Thus, detection of active MMP-3 in serum or in vivo is very important for early diagnosis of RA. In this study, a soluble MMP-3 probe was prepared to monitor RA progression by detecting expression of active MMP-3 in collagen-induced arthritis (CIA) mice in vivo in both serum and fibroblast-like synoviocytes (FLSs). The MMP-3 probe exhibited strong sensitivity to MMP-3 and moderate sensitivity to MMP-7 at nanomolecular concentrations, but was not sensitive to other MMPs such as MMP-2, MMP-9, and MMP-13. In an optical imaging study, the MMP-3 probe produced early and strong NIR fluorescence signals prior to observation of erythema and swelling in CIA mice. The MMP-3 probe was able to rapidly and selectively detect and monitor active MMP-3 in diluted serum from CIA mice. Furthermore, histological data demonstrated that activated FLSs in arthritic knee joints expressed active MMP-3. Together, our results demonstrated that the MMP-3 probe may be useful for detecting active MMP-3 for diagnosis of RA. More importantly, the MMP-3 probe was able to detect active MMP-3 in diluted serum with high sensitivity. Therefore, the MMP-3 probe developed in this study may be a very promising probe, useful as a biomarker for early detection and diagnosis of RA.

  6. Photobiomodulation therapy associated with treadmill training in the oxidative stress in a collagen-induced arthritis model.

    PubMed

    Dos Santos, Solange Almeida; Dos Santos Vieira, Marcia Ataize; Simões, Maira Cécilia Brandão; Serra, Andrey Jorge; Leal-Junior, Ernesto Cesar; de Carvalho, Paulo de Tarso Camillo

    2017-07-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by chronic and systemic inflammation, which leads to the destruction of the cartilage and bone and affects tissues in multiple joints. Oxidative stress has been implicated with regards to involvement in various disease conditions, such as diabetes mellitus and neurodegenerative, respiratory, cardiovascular, and RA diseases. In vivo experimental studies using photobiomodulation therapy (PBMT) have shown positive effects in reducing lipid peroxidation and in increasing antioxidant activity. The regular practice of physical exercise has also been reported to be a beneficial treatment capable of reducing oxidative damage. Thus, the aim of this study was to analyze the effects of photobiomodulation therapy at 2- and 4-J doses associated with physical exercise on oxidative stress in an experimental model of RA in protein expression involving superoxide dismutase (SOD), glutathione peroxidase (GPX), and/or catalase (CAT) on thiobarbituric acid reactive substances (TBARS). In this study, 24 male Wistar rats divided into four groups were submitted to an RA model (i.e., collagen-induced arthritis, CIA), with the first immunization performed at the base of the tail on days 0 and 7 were included. After 28 days, a third intraarticular dose was administered in both knees of the animals. After the last induction, PBMT was started immediately, transcutaneously at two points (i.e., the medial and lateral), with a total of 15 applications. Treadmill exercise was also started the day after the last induction, and lasted for 5 weeks. With respect to results, we obtained the decreases in the lipid peroxidation and the increases of the antioxidant activities of SOD, GPX and CAT, with physical exercise associated to PBMT in doses of 2 and 4 J. In conclusion, physical exercise associated with PBMT decreases lipid peroxidation and increases antioxidant activity.

  7. Time course of antibodies against IgG and type II collagen in adjuvant arthritis. Role of mycobacteria administration in antibody production.

    PubMed

    Franch, A; Cassany, S; Castellote, C; Castell, M

    1994-02-01

    The aim of this study was to elucidate, during the time course of adjuvant arthritis, the existence of antibodies directed to IgG (rheumatoid factor-like) and antibodies against type II collagen. In a second study, we also studied the relation between antibody production, arthritic process and mycobacteria administration. We have demonstrated the presence of antibodies to IgG and type II collagen by means of ELISA techniques. This reactivity appeared on day 7 post-induction, decreased later, and increased progressively from day 21 until last day studied (day 56 post-induction). We have also quantified antibodies against a soluble fraction of Mycobacterium butyricum, the inductor of the disease. Anti-mycobacteria antibodies appeared during the first seven days after induction, but from day 14, when systemic inflammation began, their levels suddenly increased. There is a positive correlation between anti-mycobacteria antibody levels and articular swelling. Anti-IgG and anti-collagen antibody production was not directly linked to arthritic process since these antibodies were synthesized when M. butyricum was administered intraperitoneally, which does not induce arthritis. Anti-mycobacteria antibody concentration was higher when arthritis induction by mycobacterial was successful than when it was unsuccessful.

  8. B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model.

    PubMed

    Dunussi-Joannopoulos, Kyri; Hancock, Gerald E; Kunz, Arthur; Hegen, Martin; Zhou, Xiaochuan X; Sheppard, Barbara J; Lamothe, Jennifer; Li, Evelyn; Ma, Hak-Ling; Hamann, Philip R; Damle, Nitin K; Collins, Mary

    2005-10-01

    We report the development of a mouse B cell-depleting immunoconjugate (anti-CD22 monoclonal antibody [mAb] conjugated to calicheamicin) and its in vivo use to characterize the kinetics of CD22+ B-cell depletion and reconstitution in murine primary and secondary lymphoid tissues. The effect of B-cell depletion was further studied in a murine collagen-induced arthritis (CIA) model and a respiratory syncytial virus (RSV) vaccination model. Our results show that (1) the immunoconjugate has B-cell-specific in vitro and in vivo cytotoxicity; (2) B-cell reconstitution starts in the bone marrow and spleen around day 30 after depletion and is completed in all tissues tested by day 50; (3) B-cell depletion inhibits the development of clinical and histologic arthritis in the CIA model; (4) depletion of type II collagen antibody levels is not necessary for clinical and histologic prevention of CIA; and (5) B-cell depletion does not adversely affect memory antibody responses after challenge nor clearance of infectious virus from lungs in the RSV vaccination model. These results demonstrate for the first time that only B-cell reduction but not type II collagen antibody levels correlate with the prevention of arthritis and represent key insights into the role of CD22-targeted B-cell depletion in mouse autoimmunity and vaccination models.

  9. Arthritis

    MedlinePlus

    ... joints Infection, most often by bacteria or virus Crystals such as uric acid or calcium pyrophosphate dihydrate ... common types of inflammatory arthritis include: Ankylosing ... calcium pyrophosphate deposition disease Juvenile rheumatoid ...

  10. Tetrandrine ameliorates collagen-induced arthritis in mice by restoring the balance between Th17 and Treg cells via the aryl hydrocarbon receptor.

    PubMed

    Yuan, Xusheng; Tong, Bei; Dou, Yannong; Wu, Xin; Wei, Zhifeng; Dai, Yue

    2016-02-01

    Tetrandrine is an alkaloid constituent of the root of Stephania tetrandra S. Moore. The long-term clinical uses of tetrandrine for treatments of rheumatalgia and arthralgia as well as the inhibition of rat adjuvant-induced arthritis imply that tetrandrine may have therapeutic potential in rheumatoid arthritis (RA). Here, we explored its anti-RA mechanism in collagen-induced arthritis (CIA) in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. DBA/1 mice were immunized with chicken type II collagen and were orally administered tetrandrine for 14 consecutive days. Then, the mice were sacrificed, their joints were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were removed to examine the Th17 and Treg cells. Tetrandrine markedly alleviated the severity of arthritis, reduced the serum levels of pro-inflammatory cytokines, and restored the Th17/Treg balance, as demonstrated by the serum levels of their related cytokines (IL-17 and IL-10) and the proportion of each cell type. Tetrandrine inhibited Th17 cell differentiation and induced Treg cell differentiation in vitro . Notably, aryl hydrocarbon receptor (AhR) was proven to play a crucial role in tetrandrine-mediated T cell differentiation. The correlation between AhR activation, regulation of Th17/Treg and amelioration of arthritis by tetrandrine was verified in the CIA mice. Moreover, tetrandrine might be a ligand of AhR because it facilitated the expression of the AhR target gene cytochrome P450 1A1 (CYP1A1) and the activation of its downstream signaling pathways. Taken together, tetrandrine exerts its anti-arthritis efficacy by restoring Th17/Treg balance via AhR.

  11. Effects of Sandimmune Neoral on Collagen-Induced Arthritis in DA Rats: Characterization by High Resolution Three-Dimensional Magnetic Resonance Imaging and by Histology

    NASA Astrophysics Data System (ADS)

    Beckmann, Nicolau; Bruttel, Konrad; Schuurman, Henk; Mir, Anis

    1998-03-01

    In the present work the time course of collagen-induced arthritis and the effect of Sandimmune Neoral in this model of arthritis were followed in the rat over an extended period of time (70 days) using high resolution three-dimensional (3D) magnetic resonance imaging (MRI). High resolution 3D gradient-echo (TR = 100 ms; TE = 3.8 ms) images with a voxel size of 94 × 81 × 60 μm3were acquired from the hind paw of DA rats (n= 21) at various time points after injection of type II bovine collagen into the tail. Eleven rats were treated with Neoral (15 mg/kg/day p.o. together with vehicle) for 42 days starting at day 14 after collagen injection. The remaining controls received vehicle. Pathomorphological changes associated with the collagen-induced arthritic process, e.g., increase of joint space and cartilage and bone erosion, could be observedin vivoin the control group. In contrast, no changes in the joint architecture were detected in Neoral-treated animals. Indeed, Neoral showed strong anti-inflammatory effects and marked protection against cartilage and bone destruction in this model. Qualitative information derived from the MR images correlated significantly with histological findings.

  12. Interleukin-35 (IL-35) inhibits proliferation and promotes apoptosis of fibroblast-like synoviocytes isolated from mice with collagen-induced arthritis.

    PubMed

    Li, Yunxia; Wu, Suqin; Li, Yuxuan; Jiang, Shenyi; Lin, Tiantian; Xia, Liping; Shen, Hui; Lu, Jing

    2016-09-01

    Rheumatoid arthritis (RA) is an inflammatory disorder of the joints that affects 0.5-1 % of adults. Excessive growth of the fibroblast-like synoviocytes (FLS) promotes hyperplasia of synovial tissues and causes its invasion into the bone and cartilage, which eventually causes deformity and dysfunction of affected joints. Interleukin 35 (IL-35) was shown to suppress the inflammatory responses to collagen-induced arthritis (CIA) via upregulation of T regulatory cells and suppression of T helper type 17 cells in a mouse model. To study the effects of IL-35 on the proliferation and apoptosis frequency of cultured FLS isolated from mice with CIA as well as to examine the effects of IL-35 on CIA in vivo. Thirty DBA/1 J mice, which are used as an animal model for RA, were divided randomly (ten mice per group) to a CIA group (collagen treatment), a CIA + IL-35 group (collagen and IL-35 treatments), and a control group (no treatment). Starting on the 24th day after collagen administration, IL-35 was injected intraperitoneally into mice of the CIA + IL-35 group once per day for 10 days. An arthritis index was calculated, and pathological analysis of synovial tissue was performed. FLS isolated from CIA mice were treated with various concentrations of IL-35 (12.5-100 ng/ml). The MTT assay was used to examine FLS proliferation, and apoptosis frequency of FLS was detected by flow cytometry. On day 24, the CIA mice began to exhibit arthritis symptoms, and the symptoms rapidly progressed with time. Treatment with IL-35 significantly alleviated arthritis symptoms and reduced the synovial tissue inflammation. In addition, IL-35 treatment inhibited proliferation and promoted apoptosis in cultured FLS from CIA mice in a dose-dependent manner. IL-35 could ameliorate the symptoms of arthritis in the CIA mouse model in vivo and inhibited FLS proliferation while promoting FLS apoptosis in vitro, thereby exhibited the potential in inhibiting the progression of RA.

  13. H2-M polymorphism in mice susceptible to collagen-induced arthritis involves the peptide binding groove

    SciTech Connect

    Walter, W.; Loos, M.; Maeurer, M.J.

    1996-12-31

    The ability to develop type II collagen (CII)-induced arthritis (CIA) in mice is associated with the major histocompatibility I-A gene and with as yet poorly defined regulatory molecules of the major histocompatibility complex (MHC) class II antigen processing and presentation pathway. H2-M molecules are thought to be involved in the loading of antigenic peptides into the MHC class II binding cleft. We sequenced H2-Ma, H2-Mb1, and H2-Mb2 genes from CIA-susceptible and -resistant mouse strains and identified four different Ma and Mb2 alleles, and three different Mb1 alleles defined by polymorphic residues within the predicted peptide binding groove. Most CIA-resistant mouse strains share common Ma, Mb1, and Mb2 alleles. In contrast, H2-M alleles designated Ma-III, Ma-IV, Mb1-III, and Mb2-IV could be exclusively identified in the CIA-susceptible H2{sup r} and H2{sup q} haplotypes, suggesting that allelic H2-M molecules may modulate the composition of different CII peptides loaded onto MHC class II molecules, presumably presenting {open_quotes}arthritogenic{close_quotes} epitopes to T lymphocytes. 42 refs., 4 figs., 3 tabs.

  14. Spontaneous ultra-weak photon emission in correlation to inflammatory metabolism and oxidative stress in a mouse model of collagen-induced arthritis.

    PubMed

    He, Min; van Wijk, Eduard; van Wietmarschen, Herman; Wang, Mei; Sun, Mengmeng; Koval, Slavik; van Wijk, Roeland; Hankemeier, Thomas; van der Greef, Jan

    2017-03-01

    The increasing prevalence of rheumatoid arthritis has driven the development of new approaches and technologies for investigating the pathophysiology of this devastating, chronic disease. From the perspective of systems biology, combining comprehensive personal data such as metabolomics profiling with ultra-weak photon emission (UPE) data may provide key information regarding the complex pathophysiology underlying rheumatoid arthritis. In this article, we integrated UPE with metabolomics-based technologies in order to investigate collagen-induced arthritis, a mouse model of rheumatoid arthritis, at the systems level, and we investigated the biological underpinnings of the complex dataset. Using correlation networks, we found that elevated inflammatory and ROS-mediated plasma metabolites are strongly correlated with a systematic reduction in amine metabolites, which is linked to muscle wasting in rheumatoid arthritis. We also found that increased UPE intensity is strongly linked to metabolic processes (with correlation co-efficiency |r| value >0.7), which may be associated with lipid oxidation that related to inflammatory and/or ROS-mediated processes. Together, these results indicate that UPE is correlated with metabolomics and may serve as a valuable tool for diagnosing chronic disease by integrating inflammatory signals at the systems level. Our correlation network analysis provides important and valuable information regarding the disease process from a system-wide perspective.

  15. Involvement of tachykinins and NK1 receptor in the joint inflammation with collagen type II-specific monoclonal antibody-induced arthritis in mice.

    PubMed

    Makino, Akira; Sakai, Atsushi; Ito, Hiromoto; Suzuki, Hidenori

    2012-01-01

    Rheumatoid arthritis (RA) is a chronic multisystem disease characterized by persistent joint inflammation associated with severe pain. Because RA is an immune-mediated joint disease and because type II collagen is considered an autoantigen, rodent models of arthritis using collagen type II-specific monoclonal antibodies are valuable for studying the pathogenesis of autoimmune arthritis and for evaluating therapeutic strategies. The tachykinin family peptides, substance P (SP) and hemokinin-1 (HK-1), are expressed in the nervous systems and in many peripheral organs and immunocompetent cells and activate tachykinin NK1 receptors with similar affinities. NK1 receptors are involved in the inflammation and hyperalgesia associated with a variety of inflammatory diseases. In the present study, we examined the involvement of SP and HK-1 in the joint inflammation and hyperalgesia in a collagen antibody-induced arthritis (CAIA) model in mice. The messenger RNA expression levels of the TAC1 gene encoding SP and of the TAC4 gene encoding HK-1 were decreased in the dorsal root ganglia and spinal cord at the peak of the inflammatory symptoms in CAIA. Systemic injection of an NK1 receptor antagonist, WIN 51708, significantly inhibited the joint swelling, but not the mechanical allodynia, on day 7 in CAIA mice. The messenger RNA expression levels of TAC1 and TAC4 in the dorsal root ganglia and dorsal spinal cord were unaffected by treatment with WIN 51708. These findings suggest that tachykinins and NK1 receptors play a key role in joint inflammation, rather than in nociceptive sensitization, in CAIA.

  16. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance.

    PubMed

    Lubberts, Erik; van den Bersselaar, Liduine; Oppers-Walgreen, Birgitte; Schwarzenberger, Paul; Coenen-de Roo, Christina J J; Kolls, Jay K; Joosten, Leo A B; van den Berg, Wim B

    2003-03-01

    IL-17 is a T cell-derived proinflammatory cytokine in experimental arthritis and is a stimulator of osteoclastogenesis in vitro. In this study, we report the effects of IL-17 overexpression (AdIL-17) in the knee joint of type II collagen-immunized mice on bone erosion and synovial receptor activator of NF-kappa B ligand (RANKL)/receptor activator of NF-kappa B/osteoprotegerin (OPG) expression. Local IL-17 promoted osteoclastic bone destruction, which was accompanied with marked tartrate-resistant acid phosphatase activity at sites of bone erosion in cortical, subchondral, and trabecular bone. Accelerated expression of RANKL and its receptor, receptor activator of NF-kappa B, was found in the synovial infiltrate and at sites of focal bone erosion, using specific immunohistochemistry. Interestingly, AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL/OPG ratio in the synovium. Comparison of arthritic mice from the AdIL-17 collagen-induced arthritis group with full-blown collagen-arthritic mice having similar clinical scores for joint inflammation revealed lower RANKL/OPG ratio and tartrate-resistant acid phosphatase activity in the latter group. Interestingly, systemic OPG treatment prevented joint damage induced by local AdIL-17 gene transfer in type II collagen-immunized mice. These findings suggest T cell IL-17 to be an important inducer of RANKL expression leading to loss of the RANKL/OPG balance, stimulating osteoclastogenesis and bone erosion in arthritis.

  17. Evaluation of the efficacy and safety of different Tripterygium preparations on collagen-induced arthritis in rats.

    PubMed

    Zhu, Xianjin; Zhang, Jie; Huo, Rongfen; Lin, Jinpiao; Zhou, Zhou; Sun, Yue; Wu, Pinru; Li, Huidan; Zhai, Tianhang; Shen, Baihua; Li, Ningli

    2014-12-02

    Tripterygium preparations (TPs), a traditional Chinese Medicines extracted from Tripterygium wilfordii Hook f., are widely used for treatment of rheumatoid arthritis (RA). However, TPs from different Pharmaceutical factory have different efficacy and side effects for RA treatment. The purpose of the current study is to evaluate the efficacy and safety of four TPs from different Pharmaceutical factory in china on the treatment of collagen-induced arthritis (CIA) rats and provide a theoretical and experimental basis for the individualized use of TPs. The model of wistar rats of CIA was made, and the rats were perfused a stomach with four TPs for 3 weeks continuously. Then arthritis severity was determined by visual examination of the paws and histopathologic changes of joint, liver, kidney and testis were determined by hematoxylin-eosin (H&E) staining. The expression of inflammatory cytokines (IL-1β, TNF-α, IL-17 and IL-6) in the joint was analyzed by real-time PCR, and the count and motion parameters (sperm motility and progressive sperm) of sperm in cauda epididymis were assessed with computer-assisted sperm analysis (CASA) system. Routine blood tests were conducted using automated hematology analyzer, and the aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, creatinine (Cr), and blood urea nitrogen (BUN) in serum of CIA rats were measured using a UniCel DxC 880i autoanalyzer. All of tested TPs could reduce inflammatory score, histopathological arthritis severity and joint׳s inflammatory cytokines (IL-1β, TNF-α, IL-17 and IL-6) expression in CIA rats, however, TP-D showed stronger inhibitory effect for inflammatory score compared with other three TPs in vivo. All of tested TPs did not show hepatotoxicity and nephrotoxicity and also had little effect for the concentration of hemoglobin (Hb) and the count of white blood cell (WBC). Analysis of red blood cell (RBC) number showed that TP-C and TP-D could reverse lower RBC number in

  18. Protective effect of higenamine ameliorates collagen-induced arthritis through heme oxygenase-1 and PI3K/Akt/Nrf-2 signaling pathways

    PubMed Central

    Duan, Wenjiang; Chen, Jianmin; Wu, Yu; Zhang, Yong; Xu, Yuansheng

    2016-01-01

    Existing in Ranunculaceae Aconitum and tomato, with the chemical name 1-phydroxybenzyl-1,2,3,4-tetrahy-droisoquinoline, higenamine is widely distributed in China. Higenamine's anti-inflammatory, antioxidant and anti-apoptotic effects have been identified in previous studies. The present study attempted to determine the protective effect of higenamine against collagen-induced arthritis through heme oxygenase-1 (HO-1) and PI3K/Akt/Nrf-2 signaling pathways. A type II collagen (CII)-induced arthritis (CIA) model was established and clinical arthritis scores were used to appraise the curative effect of higenamine. Inflammatory reactions, oxidative damage and caspase-3/9 activation were detected using specific ELISA kits. In addition, western blotting was used to evaluate the expression of HO-1, Akt and Nrf-2 protein in CII-induced CIA mice. In CII-induced CIA mice, the clinical arthritis scores, inflammatory reactions, oxidation damage and caspase-3/9 activation were increased and activated. The results demonstrated that treatment with higenamine significantly reduced the elevation of clinical arthritis scores (P<0.01), and suppressed the promotion of inflammatory reactions, oxidation damage and caspase-3/9 activation. Furthermore, higenamine significantly increased HO-1 protein expression (P<0.01) and upregulated the PI3K/Akt/Nrf-2 signal pathway in CII-induced CIA mice. Collectively, it is concluded that higenamine protects against CII-induced CIA through the induction of HO-1 and the upregulation of the PI3K/Akt/Nrf-2 signaling pathway. In conclusion, higenamine may be a beneficial drug for protecting against CIA. PMID:27882125

  19. Decreased Th17 and antigen-specific humoral responses in CX₃ CR1-deficient mice in the collagen-induced arthritis model.

    PubMed

    Tarrant, Teresa K; Liu, Peng; Rampersad, Rishi R; Esserman, Denise; Rothlein, Lisa R; Timoshchenko, Roman G; McGinnis, Marcus W; Fitzhugh, David J; Patel, Dhavalkumar D; Fong, Alan M

    2012-05-01

    CX(3) CR1 is a chemokine receptor that uniquely binds to its ligand fractalkine (CX(3) CL1) and has been shown to be important in inflammatory arthritis responses, largely due to its effects on cellular migration. This study was undertaken to test the hypothesis that genetic deficiency of CX(3) CR1 is protective in the chronic inflammatory arthritis model collagen-induced arthritis (CIA). Because CX(3) CR1 is expressed on T cells and antigen-presenting cells, we also examined adaptive immune functions in this model. Autoantibody formation, clinical, histologic, T cell proliferative, and cytokine responses were evaluated in wild-type and CX(3) CR1-deficient DBA/1J mice after immunization with heterologous type II collagen (CII). CX(3) CR1(-/-) mice had an ∼30% reduction in arthritis severity compared to wild-type mice, as determined by 2 independent measures, paw swelling (P < 0.01) and clinical disease score (P < 0.0001). Additionally, compared to wild-type mice, CX(3) CR1(-/-) mice had an ∼50% decrease in anti-CII autoantibody formation (P < 0.05), decreased Th17 intraarticular cytokine expression (P < 0.01 for interleukin-17 [IL-17] and P < 0.001 for IL-23), and decreased total numbers of Th17 cells in inflamed joints (P < 0.05). Our findings indicate that CX(3) CR1 deficiency is protective in inflammatory arthritis and may have effects that extend beyond migration that involve adaptive immune responses in autoimmune disease. Copyright © 2012 by the American College of Rheumatology.

  20. Betulinic acid and fluvastatin exhibits synergistic effect on toll-like receptor-4 mediated anti-atherogenic mechanism in type II collagen induced arthritis.

    PubMed

    Mathew, Limi Elizabeth; Rajagopal, Vrinda; A, Helen

    2017-09-01

    Cardiovascular disease (CVD) is a major problem during rheumatoid arthritis which leads to morbidity and mortality in arthritic patients. So the present study emphasizes combinatorial effect of Betulinic acid, a triterpenoid and fluvastatin, an HMG CoA reductase inhibitor on atherogenesis during arthritis. Arthritis was induced by bovine type II collagen dissolved in 0.01M acetic acid at a concentration of 4mg/mL and emulsified in equal volume of incomplete Freund's adjuvant. Betulinic acid (2mg/kg) and fluvastatin (5mg/kg) alone and in combination was administered orally from day 14 to 60. At the end of 60days, tissues and blood were isolated for evaluation of biochemical parameters. Treatment with betulinic acid and fluvastatin showed significant (p<0.05) reduction in Arthritic index, Rheumatoid factor, C-reactive protein (CRP), total lipids and anti-CCP (cyclic citrullinated peptide) antibody. Anti-inflammatory enzyme activities and oxidative stress were significantly decreased in the peripheral blood mononuclear cells by the administration of both betulinic acid and fluvastatin than alone treatments. Combination therapy was found to be a potential enhancer of the expression of anti-inflammatory cytokine interleukin-10 whereas it significantly blocked the expression of Toll-like receptors-2 and 4, inflammatory markers such as interleukin-1β, tumor necrosis factor-α, Interferon-γ, cell adhesion molecules and nuclear translocation of NF-kappa B in aorta than drug alone treated groups. So the present study summarizes a combination therapy of betulinic acid and fluvastatin that reduces the risk of both rheumatoid arthritis and CVD by modulating the expression of various inflammatory mediators through Toll-like receptors-4-NF-κB downstream signaling pathway, atherogenic index and oxidative stress in collagen induced arthritis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Somatic Antigens of Tropical Liver Flukes Ameliorate Collagen-Induced Arthritis in Wistar Rats

    PubMed Central

    Khan, Yasir Akhtar; Umar, Sadiq; Abidi, Syed M. A.

    2015-01-01

    Parasitic helminths polarize immune response of their vertebrate hosts towards anti-inflammatory Th2 type and therefore it is hypothesized that they may suppress the inflammatory conditions in autoimmune disorders. The present study was undertaken to investigate in vivo immunomodulatory and therapeutic potential of somatic antigens (Ag) of liver infecting digenetic trematodes [Fasciola gigantica (Fg) and Gigantocotyle explanatum (Ge)] in collagen-induced arthritic (CIA) Wistar rats. The CIA rats were administered subcutaneously with different doses (50 μg, 100 μg and 150 μg) of somatic antigens of Fg and Ge, daily for 21 days, the time period required to establish infection in natural host (Bubalus bubalis). Thereafter, the control, diseased and treated rats were compared for different parameters viz. hind paw thickness; serum interleukins, IL-4 and IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); expression level of matrix metalloproteinases (MMPs) -2, -9, -13 and nitric oxide (NO) in knee joints and patellar morphology. The CIA rats treated with different antigens, Fg-Ag and Ge-Ag, show significant amelioration of the disease by down regulation of serum TNF-α and IFN-γ (p< 0.05) and upregulation of IL-4 and IL-10 cytokines (p< 0.05); inhibition (p< 0.05) of MMPs (-2,-9,-13) and NO in knee joints and improved patellar morphology with decreased synovial hypertrophy and reduced infiltration of ploymorphonuclear cells. The activity of pro as well as active MMPs (-2 and -9) and active MMP-13 in knee joints of CIA rats was very high compared to the control and treatment groups, suggesting the extent of collagen degradation in CIA rats. Interestingly, the highest dose (150 μg) of Ge-Ag almost wiped out MMP-13 expression. The overall findings suggest that the somatic proteins of Ge-Ag appeared to be therapeutically more effective than Fg-Ag, reflecting interspecific molecular differences which could contribute to the ability of these worms to

  2. Differential effect of severe and moderate social stress on blood immune and endocrine measures and susceptibility to collagen type II arthritis in male rats.

    PubMed

    Stefanski, Volker; Hemschemeier, Susanne K; Schunke, Kerstin; Hahnel, Anja; Wolff, Christine; Straub, Rainer H

    2013-03-01

    The effects of social stress on several blood immune measures and collagen-induced arthritis (CIA) were investigated in Wistar rats using the resident-intruder confrontation paradigm to induce stress of different intensity. Male intruders were exposed for one week to a dominant opponent either repeatedly for 4h daily (moderate stress) or continuously (severe stress). Arthritis was induced by intradermal injection of collagen type II (CII) into the tail skin at the end of day 3 of confrontation. Only severe stress was associated with decreased CD4 and CD8 T cells, and the increase in granulocyte numbers and body mass loss was more pronounced under these conditions. Only severe stress reduced the susceptibility to arthritis by about 50%. Severity scores did not differ in the first five days after disease onset between all groups. Subsequent experiments focused on severely stressed rats indicated that disease progressed until day 10 only in control animals, but not in severely stressed males. Stressor exposure resulted in increased blood monocyte numbers, but these males failed to accumulate macrophages into the skin at the site of CII injection. High numbers of attacks experienced by intruders correlated with delayed disease onset in severely stressed rats. We hypothesize that severe stress persisting after disease induction exhibits beneficial effects on the susceptibility of CIA and propose that the specific endocrine and immunological profile associated with severe stress is an important factor for disease outcome--a factor which probably explains many of the conflicting data of previous stress studies on CIA.

  3. Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model.

    PubMed

    Chagas, Pietro M; Fulco, Bruna C W; Sari, Marcel H M; Roehrs, Juliano A; Nogueira, Cristina W

    2017-08-01

    Bis(phenylimidazoselenazolyl) diselenide (BPIS) is an organoselenium with acute antinociceptive and antioxidant properties. The aim of this study was to investigate BPIS effect on a collagen-induced arthritis (CIA) model in mice. Protocol of exposure consisted in arthritis induction by chicken collagen type II on day 0 with booster injection on day 21. On day 60 after collagen injection, incidence of mechanic allodynia (Von Frey test) or thermal hyperalgesia (hot plate test) was evaluated. During following 5 days, mice were treated with BPIS (0.1-1 mg/kg; p.o.; daily) or vehicle. On day 65, mice were killed, and paws and spinal cord were removed for analyses. Mice submitted to CIA model developed both mechanical allodynia and thermal hyperalgesia, which were reversed by BPIS at the highest dose. In paw, BPIS reversed the increase in myeloperoxidase activity in the CIA group. In the spinal cord, BPIS decreased NOx and NFkB levels increased in the CIA group. BPIS-treated animals had lower cyclooxygenase-2 levels in the spinal cord. The myeloperoxidase activity in paw and NOx and NFkB levels in spinal cord are related to antinociceptive properties of BPIS in CIA model. © 2017 Royal Pharmaceutical Society.

  4. [Regulation effect of scorpio and scolopendra on CD4 + CD25 + FoxP3 + Treg cell in peripheral blood from rats with collagen-induced arthritis (CIA)].

    PubMed

    Liu, Duan-Yong; Zhao, Hai-Mei; Huang, Xiao-Ying; Zuo, Zhi-Qin; Wang, Yan-Hui; Cheng, Shao-Min

    2012-04-01

    To study the regulation effect of Scorpio and Scolopendra on CD4 + CD25 + FoxP3 + Treg Cell in peripheral blood from rats with collagen-induced arthritis. Sixty female Wistar rats were randomly divided into 6 groups, normal control group, model control group, low-dose, middle-dose and high-dose Scorpio and Scolopendra group,and the type II collagen group. Rats' arthritis was induced by collagen. The number of CD4 + CD25 + FoxP3 + Treg cell in peripheral blood was tested by flow cytometry, and the level of IL-2 in serum was detected by enzyme linked immunosorbent assay. Compared with the model groups,the levels of CD4 + CD25 + Treg cell and CD4 + CD25 + FoxP3 + Treg cell were increased obviously in the high and low dose of Scorpio and Scolopendra groups (P < 0.05 or P < 0.01), while the level of IL-2 in serum was decreased remarkably in the middle and low dose of Scorpio and Scolopendra groups (P < 0.05 or P < 0.01). It is realized that Scorpio and Scolopendra effectively treat RA by regulating the level of CD4 + CD25 + FoxP3 + Treg cell to restore immunological tolerance.

  5. Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis.

    PubMed

    Li, Xiaonan; DuBois, Debra C; Almon, Richard R; Jusko, William J

    2017-05-01

    Naproxen (NPX) is a frequently used nonsteroidal anti-inflammatory drug for rheumatoid arthritis (RA). Lack of quantitative information about the drug exposure-response relationship has resulted in empirical dosage regimens for use of NPX in RA. Few studies to date have included sex as a factor, although RA predominates in women. A pharmacokinetic, pharmacodynamic, and disease progression model described the anti-inflammatory effects of NPX in collagen-induced arthritic (CIA) male and female rats. Three groups of rats were included for each sex: healthy animals, CIA controls, and CIA rats given a single 50-mg/kg dose of NPX intraperitoneally. Paw volumes of healthy rats indicated natural growth, and disease status was measured by paw edema. An innovative minimal physiologically based pharmacokinetic (mPBPK) model incorporating nonlinear albumin binding of NPX in both plasma and interstitial fluid (ISF) was applied. Arthritic rats exhibited lower plasma and ISF albumin concentrations and reduced clearances of unbound drug to explain pharmacokinetic profiles. The unbound ISF NPX concentrations predicted by the mPBPK model were used as the driving force for pharmacological effects of NPX. A logistic growth function accounting for natural paw growth and an indirect response model for paw edema and drug effects (inhibition of kin) was applied. Female rats showed a higher incidence of CIA, earlier disease onset, and more severe symptoms. NPX had stronger effects in males, owing to higher unbound ISF NPX concentrations and lower IC50 values. The model described the pharmacokinetics, unbound NPX in ISF, time course of anti-inflammatory effects, and sex differences in CIA rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Inhibitory effects of deer antler aqua-acupuncture, the pilose antler of Cervus Korean TEMMINCK var mantchuricus Swinhoe, on type II collagen-induced arthritis in rats.

    PubMed

    Kim, Yeon-Kye; Kim, Kyung-Sook; Chung, Kang-Hyun; Kim, Jin-Gyu; Kim, Kap-Sung; Lee, Young-Choon; Chang, Young-Chae; Kim, Cheorl-Ho

    2003-07-01

    Water extract of deer antler aqua-acupunture (DAA) prepared from the growing antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe, was used to investigate the efficacy of a traditional immunosuppressive and immuno-activating Korean aqua-acupuncture, on the development of type II collagen (CII)-induced arthritis (CIA) in rats. The onset of arthritis was observed at the 24th day after the CII-immunization in rats, and the severity of CIA was gradually developed. As compared with rats treated with saline, DAA i.p. injected at doses of more than 50 microg/kg once a day for 14 days inhibited the ability of inguinal lymph node cells to produce T cell cytokines interleukin 2 and interferon-gamma when the cells were obtained from rats 24 days after immunization and cultured in vitro with CII. Treatment with DAA also inhibited the production of macrophage cytokines interleukin-1beta, IL-6 and tumor necrosis factor alpha in response to in vitro stimulation of lymph node and macrophage cells with CII. In addition, in order to evaluate the influence of DAA on the incidence and development of arthritis in rat CIA, rats were immunized twice at a 3-week interval with bovine CII, with DAA being given i.p. once a day for 14 days with four different regimens. A 14-day course of DAA treatment at a daily dose of 100 microg/kg, which began on the day of the first CII immunization, suppressed the development of arthritis, as well as antibody formation and delayed-type hypersensitivity to CII. Treatment with DAA, which started on the same day as the booster immunization, also resulted in inhibition of development of arthritis and of immune responses to CII. However, treatment with DAA, which was prophylactically started prior to a primary immunization, did not inhibit the development of arthritis and immune response to CII. Furthermore, DAA extract did not affect the established diseases.

  7. Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

    PubMed Central

    Shakya, Akhilesh Kumar; Kumar, Ashok; Klaczkowska, Dorota; Hultqvist, Malin; Hagenow, Kristin; Holmdahl, Rikard; Nandakumar, Kutty Selva

    2011-01-01

    We established and characterized an arthritis mouse model using collagen type II (CII) and a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm). The new PNiPAAm adjuvant is TLR-independent, as all immunized TLR including MyD88-deficient mice developed an anti-CII response. Unlike other adjuvants, PNiPPAm did not skew the cytokine response (IL-1β, IFN-γ, IL-4, and IL-17), as there was no immune deviation towards any one type of immune spectrum after immunization with CII/PNiPPAm. Hence, using PNiPAAm, we studied the actual immune response to the self-protein, CII. We observed arthritis and autoimmunity development in several murine strains having different major histocompatibility complex (MHC) haplotypes after CII/PNiPAAm immunization but with a clear MHC association pattern. Interestingly, C57Bl/6 mice did not develop CII-induced arthritis, with PNiPAAm demonstrating absolute requirement for a classical adjuvant. Presence of a gene (Ncf1) mutation in the NADPH oxidation complex has a profound influence in arthritis and using PNiPAAm we could show that the high CIA severity in Ncf1 mutated mice is independent of any classical adjuvant. Macrophages, neutrophils, eosinophils, and osteoclasts but not mast cells dominated the inflamed joints. Furthermore, arthritis induction in the adjuvant-free, eosinophil-dependent Vβ12 DBA/1 mice could be shown to develop arthritis independent of eosinophils using CII/PNiPAAm. Thus, biocompatible and biodegradable PNiPAAm offers unique opportunities to study actual autoimmunity independent of TLR and a particular cytokine phenotype profile. PMID:21933654

  8. Glucose Kinetics in the Collagen-Induced Arthritis Model: An All-in-One Model to Assess Both Efficacy and Metabolic Side Effects of Glucocorticoids

    PubMed Central

    van Dijk, Theo H.; Bleeker, Aycha; Grefhorst, Aldo; Schouten, Annelies E.; Bastiaanssen, Ellen A. J.; Ballak, Dov B.; Koenders, Marije I.; van Doorn, Cindy; van der Vleuten, Monique A. J.; van Lierop, Marie-Jose C.; Groen, Albert K.; Dokter, Wim H. A.

    2014-01-01

    Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory drugs, but chronic use is hampered by metabolic side effects. Therefore, there is an urgent medical need for improved GCs that are as effective as classical GCs but have a better safety profile. A well-established model to assess anti-inflammatory efficacy is the chronic collagen-induced arthritis (CIA) model in mice, a model with features resembling rheumatoid arthritis. Models to quantify undesired effects of glucocorticoids on glucose kinetics are less well-established. Recently, we have described a model to quantify basal blood glucose kinetics using stably-labeled glucose. In the present study, we have integrated this blood glucose kinetic model in the CIA model to enable quantification of both efficacy and adverse effects in one animal model. Arthritis scores were decreased after treatment with prednisolone, confirming the anti-inflammatory properties of GCs. Both inflammation and prednisolone induced insulin resistance as insulin secretion was strongly increased whereas blood glucose concentrations and hepatic glucose production were only slightly decreased. This insulin resistance did not directly resulted in hyperglycemia, indicating a highly adaptive compensatory mechanism in these mice. In conclusion, this ‘all-in-one’ model allows for studying effects of (novel) GC compounds on the development of arthritis and glucose kinetics in a single animal. This integrative model provides a valuable tool for investigating (drug-induced) metabolic dysregulation in an inflammatory setting. PMID:25181348

  9. Glucose kinetics in the collagen-induced arthritis model: an all-in-one model to assess both efficacy and metabolic side effects of glucocorticoids.

    PubMed

    Toonen, Erik J M; Laskewitz, Anke J; van Dijk, Theo H; Bleeker, Aycha; Grefhorst, Aldo; Schouten, Annelies E; Bastiaanssen, Ellen A J; Ballak, Dov B; Koenders, Marije I; van Doorn, Cindy; van der Vleuten, Monique A J; van Lierop, Marie-Jose C; Groen, Albert K; Dokter, Wim H A

    2014-01-01

    Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory drugs, but chronic use is hampered by metabolic side effects. Therefore, there is an urgent medical need for improved GCs that are as effective as classical GCs but have a better safety profile. A well-established model to assess anti-inflammatory efficacy is the chronic collagen-induced arthritis (CIA) model in mice, a model with features resembling rheumatoid arthritis. Models to quantify undesired effects of glucocorticoids on glucose kinetics are less well-established. Recently, we have described a model to quantify basal blood glucose kinetics using stably-labeled glucose. In the present study, we have integrated this blood glucose kinetic model in the CIA model to enable quantification of both efficacy and adverse effects in one animal model. Arthritis scores were decreased after treatment with prednisolone, confirming the anti-inflammatory properties of GCs. Both inflammation and prednisolone induced insulin resistance as insulin secretion was strongly increased whereas blood glucose concentrations and hepatic glucose production were only slightly decreased. This insulin resistance did not directly resulted in hyperglycemia, indicating a highly adaptive compensatory mechanism in these mice. In conclusion, this 'all-in-one' model allows for studying effects of (novel) GC compounds on the development of arthritis and glucose kinetics in a single animal. This integrative model provides a valuable tool for investigating (drug-induced) metabolic dysregulation in an inflammatory setting.

  10. Sinomenine suppresses collagen-induced arthritis by reciprocal modulation of regulatory T cells and Th17 cells in gut-associated lymphoid tissues.

    PubMed

    Tong, Bei; Yu, Juntao; Wang, Ting; Dou, Yannong; Wu, Xin; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-05-01

    Sinomenine (SIN) has long been used as a therapeutic agent of rheumatoid arthritis (RA) in China. However, the discrepancy between low oral bioavailability and higher minimal effective concentration made its action mode mysterious. The present study aimed to gain insight into the mechanisms by which SIN suppressed collagen-induced arthritis (CIA) in rats in view of Th17 and regulatory T (Treg) cell balance. SIN was orally administered, and the clinical symptoms of CIA rats were monitored; inflammatory cytokines levels in serum were measured by ELISA; pharmacokinetic studies were performed in normal and CIA rats; Th17 and Treg cell frequencies were analyzed by flow cytometry. The data showed that SIN treatment resulted in a dramatic decrease of arthritis scores and paw volume of CIA rats, which was accompanied by down-regulation of IL-17A and up-regulation of IL-10 in rat serum. The frequency of Treg cells was increased and the frequency of Th17 cells was decreased in the gut lymphoid tissues of SIN-treated rats. Immunohistochemistry assay demonstrated that more α4β7-positive cells were detained in joint tissues after SIN treatment. Moreover, the anti-arthritis efficacy of SIN disappeared when it was given by intraperitoneal injection, further confirming the action of SIN was gut-dependent. In conclusion, SIN exerts anti-RA action probably through modulating the frequencies of Treg cells and Th17 cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from gut to joint.

  11. The gene therapy of collagen-induced arthritis in rats by intramuscular administration of the plasmid encoding TNF-binding domain of variola virus CrmB protein.

    PubMed

    Shchelkunov, S N; Taranov, O S; Tregubchak, T V; Maksyutov, R A; Silkov, A N; Nesterov, A E; Sennikov, S V

    2016-07-01

    Wistar rats with collagen-induced arthritis were intramuscularly injected with the recombinant plasmid pcDNA/sTNF-BD encoding the sequence of the TNF-binding protein domain of variola virus CrmB protein (VARV sTNF-BD) or the pcDNA3.1 vector. Quantitative analysis showed that the histopathological changes in the hind-limb joints of rats were most severe in the animals injected with pcDNA3.1 and much less severe in the group of rats injected with pcDNA/sTNF-BD, which indicates that gene therapy of rheumatoid arthritis is promising in the case of local administration of plasmids governing the synthesis of VARV immunomodulatory proteins.

  12. Differential effects of isoflurane and CO2 inhalation on plasma levels of inflammatory markers associated with collagen-induced arthritis in DBA mice.

    PubMed

    Lawrance, Christopher C; Lucas, Edralin A; Clarke, Stephen L; Smith, Brenda J; Kuvibidila, Solo

    2009-07-01

    Inhalation of CO2 or isoflurane is a commonly used method of euthanasia with mice, but information related to their effects on serum inflammatory markers in chronic models of inflammation is limited. In the current study, nineteen-week old DBA female mice with (n = 53) or without (n = 51) collagen-induced arthritis were randomly assigned to euthanization with CO2 (n = 55) or isoflurane (n = 49. Plasma was collected for the measurement of soluble intercellular adhesion molecule-1 (sICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) by ELISA. When mice without and with collagen-induced arthritis were pooled, compared to CO2, administration of isoflurane was associated with lower production of the pro-inflammatory cytokines TNF-alpha (pg/ml, mean +/- SEM) (26.1 +/- 2.82 versus 48.1 +/- 7.99) and IL-6 (25.18 +/- 2.73 versus 48.1 +/- 6.82) (ANOVA, p < 0.05). In contrast to TNF-alpha and IL-6, administration of CO2 decreased the plasma sICAM-1 level (1170+/- 50 versus 758 +/- 24 for CO2) (p < 0.00001). When data were analyzed as a function of collagen-induced arthritis, the differences between CO2 and isoflurane persisted. Low plasma sICAM-1 levels found in CO2 euthanasia group may be due to degradation. Since mice are the most common animal model for studying inflammation, researchers should be aware of these iatrogenic experimental variables before interpreting their data.

  13. Suppressive effects of Chelidonium majus methanol extract in knee joint, regional lymph nodes, and spleen on collagen-induced arthritis in mice.

    PubMed

    Lee, Young-Cheol; Kim, Seung-Hyung; Roh, Seong-Soo; Choi, Ho-Young; Seo, Young-Bae

    2007-05-30

    Chelidonium majus L. has multiple applications in Korean traditional medicine because of its anti-tumoral, cytotoxic, anti-inflammatory and anti-microbial activities and has long been known to have anti-inflammatory effects. However, no study on the anti-arthritic activity of Chelidonium majus has been reported in vivo. Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic inflammation characterized by hyperplasia of synovial cells in affected joints, which ultimately leads to the destruction of cartilage and bone. Cytokine production and gene expression were assessed during CIA (collagen-induced arthritis) model mice in knee joint, lymph node (LN), and spleen, using ELISA and competitive RT-PCR. DBA/1J mice were immunized with bovine type II collagen. After a second collagen immunization, mice were treated with CME orally at 400, 40mg/kg once a day for 4 weeks. The severity of arthritis within the knee joints was evaluated by histological assessment of cartilage destruction and pannus formation. Administration of CME significantly suppressed the progression of CIA and inhibited the production of TNF-alpha and IL-6 in spleen and lymph node. The erosion of cartilage was dramatically reduced in mouse knees after treatment with CME. In conclusion, our results demonstrates that CME significantly suppressed the progression of CIA and that this action was characterized by the decreased production of TNF-alpha, IL-6, IFN-gamma, B cells, gammadelta T cells (in spleen) and increased proportion of CD4+CD25+ regulatory T cells in vivo. In the serum of CME-treated mice, the levels of IgG and IgM RA factor were decreased.

  14. An angiogenesis inhibitor, 2-methoxyestradiol, involutes rat collagen-induced arthritis and suppresses gene expression of synovial vascular endothelial growth factor and basic fibroblast growth factor.

    PubMed

    Brahn, Ernest; Banquerigo, Mona L; Lee, John K; Park, Eun J; Fogler, William E; Plum, Stacy M

    2008-11-01

    Rheumatoid arthritis (RA) pannus may be dependent on angiogenesis and several critical growth factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2-Methoxyestradiol (2ME2), an endogenous metabolite with low estrogen receptor affinity, has both antiangiogenic and antiproliferative activity. 2ME2 was assessed in the rat collagen-induced arthritis (CIA) model to determine if it could prevent or involute established synovitis. Rats were immunized on Day 0 with collagen and randomized to a vehicle control or two 2ME2 prevention arms. In additional studies, multiple parallel treatment arms were initiated at Day 10 after arthritis onset. 2ME2 in preventive protocols at 30 or 100 mg/kg significantly delayed the onset and reduced the severity of clinical and radiographic CIA. In established CIA, oral 2ME2 at 50 mg/kg/bid, 100 mg/kg/day, and 300 mg/kg/day reduced severity compared to vehicle controls. Efficacy of 2ME2 delivery by osmotic pumps at 60 mg/kg/day was equivalent to 300 mg/kg/day by daily gavage. The 3 oral treatment protocols all significantly reduced radiographic scores in a dose-dependent fashion, with the greatest benefit at 300 mg/kg. 2ME2 showed marked suppression of synovial gene expression of proangiogenic bFGF and VEGF, with parallel reduction of synovial blood vessels. Serum antibody levels to native type II collagen were not reduced, suggesting that 2ME2 did not influence humoral immunity. Our results indicate that 2ME2 may represent a novel agent for the treatment of inflammatory autoimmune diseases such as RA.

  15. Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-α mediated by TNF-α converting enzyme in murine collagen-induced arthritis model.

    PubMed

    Pu, Yuzhi; Cao, Dong; Xie, Caifeng; Pei, Heying; Li, Dan; Tang, Minghai; Chen, Lijuan

    2015-07-10

    TNF-α is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-α production with an IC50 of 8.86 μM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF-α but up-regulated the precursor of TNF-α (pro-TNF-α). Then, we studied TNF-α converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-α from pro-TNF-α to soluble TNF-α. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-α, IL-6, IL-1β. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-α mediated by TACE for the first time.

  16. Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK/STAT signaling pathway

    PubMed Central

    Yang, Yongsheng; Dong, Qiumei; Li, Rongheng

    2017-01-01

    The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen-induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast-like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apop-tosis of FLS from rats

  17. Periplocoside A ameliorated type II collagen-induced arthritis in mice via regulation of the balance of Th17/Treg cells.

    PubMed

    Yang, Yang; Hu, Xudong; Cheng, Lei; Tang, Wei; Zhao, Weimin; Yang, Yifu; Zuo, Jianping

    2017-03-01

    Periplocoside A (PSA) has been extracted from the Chinese herbal medicine Periploca sepium Bge to treat rheumatoid arthritis (RA) via immune regulation. We previously found that PSA exhibits immunosuppressive activity both in vitro and in vivo. Balanced regulation of helper T 17 (Th17)/regulatory T (Treg) cells is the current therapeutic direction for the treatment of RA. The present study investigated the mechanism of PSA in treating collagen-induced arthritis (CIA). The therapeutic effects and potential pharmacological mechanisms of PSA were specifically clarified by examining its effects on CIA in DBA/1 mice. PSA administration significantly relieved the severity of the arthritis, and preventive administration of PSA reduced the incidence of arthritis in the mice with CIA and relieved joint damage in terms of morphology. PSA was also able to reduce the levels of anti-collagen II (CII) antibodies and pro-inflammatory cytokines in the serum. As a result, the proportion of Th17 cells decreased, and the proportion of Treg cells increased. A follow-up study of the ex vivo immunological reactions induced by a specific antigen found that PSA suppressed lymphocyte proliferation, inhibited the differentiation and reactivity of Th17 cells, and promoted the proportion of Treg cells among helper T cells. PSA also exhibited pharmacological effect in regulating the balance between Th17 and Treg cells in CIA through relevant signalling pathways. Thus, PSA played a specific role in CIA treatment. In particular, our results suggest that the therapeutic effects of PSA on RA are partially realized via the regulation of the balance of Th17/Treg cells.

  18. Effectiveness of the soluble form of the interleukin-1 receptor accessory protein as an inhibitor of interleukin-1 in collagen-induced arthritis.

    PubMed

    Smeets, R L; van de Loo, F A J; Joosten, L A B; Arntz, O J; Bennink, M B; Loesberg, W A; Dmitriev, I P; Curiel, D T; Martin, M U; van den Berg, W B

    2003-10-01

    To investigate whether the soluble form of interleukin-1 (IL-1) receptor accessory protein (sIL-1RAcP), whose physiologic function remains to be established, can serve as a specific inhibitor of IL-1 signaling in vitro, and to evaluate its applicability in collagen-induced arthritis (CIA). Soluble IL-1RAcP was cloned from murine liver complementary DNA and expressed by the use of either an adenoviral vector (AdRGD) for sIL-1RAcP or a stable-transfected NIH3T3 fibroblast cell line. The ability of affinity-purified sIL-1RAcP to inhibit IL-1 signaling was tested on NF-kappaB luciferase reporter fibroblasts and quantified by luminometer. To investigate therapeutic efficacy, sIL-1RAcP was both locally (knee joint) and systemically overexpressed in collagen-immunized male DBA/1 mice. Severity of arthritis was monitored visually, and the pathologic process in the joint was examined histologically. Serum was obtained from mice to quantify IL-6 and anti-bovine type II collagen (BCII) antibody levels. Incubation of the NF-kappaB reporter fibroblast with purified sIL-1RAcP protein showed a marked reduction of IL-1-induced, but not tumor necrosis factor-induced, NF-kappaB activation. This showed a novel role for sIL-1RAcP as a specific inhibitor of IL-1 signaling. Local transplantation of sIL-1RAcP-producing NIH3T3 fibroblasts into the knee before onset of CIA had little or no effect on general disease severity in these mice. Histologic evaluation of the knee joints receiving sIL-1RAcP cell transplantation showed a marked reduction in both joint inflammation and bone and cartilage erosion. Local treatment with sIL-1RAcP had no profound effect on serum levels of IL-6 and anti-BCII antibodies, which is indicative of the ongoing presence of arthritis in distal joints. In contrast to local treatment, systemic treatment with the AdRGD for sIL-1RAcP markedly ameliorated CIA in all joints. In this study we demonstrated that sIL-1RAcP is a biologically active and innovative inhibitor

  19. [Effect of allogenic mesenchymal stem cells transplantation on the expression of interleukin-22 and matrix metalloproteinase-3 in rats with collagen induced arthritis].

    PubMed

    Liu, G Y; Bian, S; Li, F; Li, X F; Fan, K; An, H Z; Jia, X X

    2017-03-07

    Objective: To study the effect of allogeneic bone marrow mesenchymal stem cells transplantation on the expression of interleukin -22 (IL-22), matrix metalloproteinase -3 (MMP-3) in serum and synovial of rats with collagen induced arthritis. Methods: Type Ⅱ collagen were injected twice to establish the collagen induced arthritis (CIA) rat model. Forty-eight rats were randomly divided into 3 groups: control group, CIA control group, CIA experiment group. Rat bone marrow mesenchymal stem cells were cultured by bone marrow method combined with adherent culture method. After identify, the remaining cells were injected in the CIA experimental group. Enzyme linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the expression of IL-22 and MMP-3 in serum and anklebone joint's synovium of rats, respectively. Synovial cells were isolated and cultured, and were treated with different concentrations of IL-22. MMP-3 protein and mRNA were detected before and after stimulation by Western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Results: After MSC transplantation, arthritis index, X-ray, HE staining of CIA rat showed that joint damage significantly reduced compared with the control group. The ELISA results showed that the expression of MMP-3 and IL-22 in CIA control group was higher than those in the control group (125.79±9.12 vs 102.00±7.63 ng/ml, P<0.05), (292.35±31.23 vs 257.27±13.99 ng/ml, P<0.05) and CIA experiment group (125.79±9.12 vs 97.94±9.50 ng/ml, P<0.05), (292.35±31.23 vs 262.16±22.02 ng/ml, P<0.05) with statistically significant difference (P<0.05). There was no significant difference between the control group and CIA experimental group. Immunohistochemical showed similar results with ELISA. Western blotting and RT-qPCR showed that MMP-3 protein and mRNA expression was increased after IL-22 stimulation in a dose-dependent manner. Conclusion: IL-22 and MMP-3 play an important role in the pathogenesis of

  20. Human embryonic stem cell-derived mesenchymal stromal cells ameliorate collagen-induced arthritis by inducing host-derived indoleamine 2,3 dioxygenase.

    PubMed

    Gonzalo-Gil, Elena; Pérez-Lorenzo, María J; Galindo, María; Díaz de la Guardia, Rafael; López-Millán, Belén; Bueno, Clara; Menéndez, Pablo; Pablos, José L; Criado, Gabriel

    2016-04-01

    The immunosuppressive and anti-inflammatory properties of mesenchymal stromal cells (MSC) have prompted their therapeutic application in several autoimmune diseases, including rheumatoid arthritis. Adult MSC are finite and their clinical use is restricted by the need for long-term expansion protocols that can lead to genomic instability. Inhibition of Smad2/3 signaling in human pluripotent stem cells (hPSC) provides an infinite source of MSC that match the phenotype and functional properties of adult MSC. Here, we test the therapeutic potential of hPSC-MSC of embryonic origin (embryonic stem cell-derived mesenchymal stromal cells, hESC-MSC) in the experimental model of collagen-induced arthritis (CIA). CIA was induced in DBA/1 mice by immunization with type II collagen (CII) in Complete Freund's Adjuvant (CFA). Mice were treated with either a single dose (10(6) cells/mouse) of hESC-MSC on the day of immunization (prophylaxis) or with three doses of hESC-MSC every other day starting on the day of arthritis onset (therapy). Arthritis severity was evaluated daily for six weeks and ten days, respectively. Frequency of Treg (FoxP3(+)), Th1 (IFNγ(+)) and Th17 (IL17(+)) CD4(+) T cells in inguinal lymph nodes (ILN) was quantified by flow cytometry. Serum levels of anti-CII antibodies were determined by ELISA. Detection of hESC-MSC and quantification of murine and human indoleamine 2,3 dioxygenase (IDO1) expression was performed by quantitative real-time PCR. Statistical differences were analyzed by ANOVA and the Mann-Whitney U test. Administration of hESC-MSC to mice with established arthritis reduced disease severity compared to control-treated mice. Analysis of CD4 T cell populations in treated mice showed an increase in FoxP3(+) Treg and IFNγ(+) Th1 cells but not in Th17 cells in the ILN. Anti-CII antibody levels were not affected by treatment. Migration of hESC-MSC to the ILN in treated mice was associated with the induction of murine IDO1. Treatment with h

  1. Mediators of inflammation are down-regulated while apoptosis is up-regulated in rheumatoid arthritis synovial tissue by polymerized collagen

    PubMed Central

    FURUZAWA-CARBALLEDA, J; RODRÍQUEZ-CALDERÓN, R; DÍAZ DE LEÓN, L; ALCOCER-VARELA, J

    2002-01-01

    The aim of the study was to determine whether collagen-polyvinylpyrrolidone (collagen-PVP) modifies some proinflammatory responses in synovium cultures from rheumatoid arthritis (RA) patients. Synovium from 10 RA patients were cultured with or without 1% collagen-PVP. Tissues on the 3rd, 5th and 7th culture day were sectioned and stained by the Herovici technique. Total collagen and type I/III collagen ratios were evaluated by the Woessner micromethod and by interrupted gel electrophoresis, respectively. Collagenolytic activity was assessed by degradation of [3H]-collagen in supernatants. TIMP-1, IL-1β and TNF-α were determined in supernatants by ELISA, and the results were normalized by DNA concentration. IL-1β, TNF-α, IL-6, IL-8, MMP-1, TIMP-1, Cox-1, VCAM-1, ICAM-1 and Fas/APO95 expression was evaluated by immunohistochemistry. Apoptosis was detected by TUNEL technique. The histological analysis and electrophoresis revealed a 1·7-fold increase of type III collagen in a time-dependent fashion in collagen-PVP-treated cultures. Proinflammatory cytokines (IL-1β: 58 ± 9 versus 22 ± 10; TNF-α: 41 ± 6 versus 11 ± 3; IL-8: 59 ± 12 versus 29 ± 9; treated versus untreated), adhesion molecule (ICAM-1: 57 ± 11 versus 29 ± 15; VCAM-1: 49 ± 7 versus 21 ± 13; treated versus untreated) as well as Cox-1 (59 ± 10 versus 20 ± 3) expression was down-regulated in RA synovium treated. Meanwhile, TIMP-1 (36 ± 7 versus 57 ± 11) and Fas expression (20 ± 10 versus 55 ± 13) and apoptosis (14 ± 3 versus 55 ± 5) were up-regulated in treated cultures compared with controls. In supernatants, the collagenolytic activity, as well as IL-1β and TNF-α, levels were all down-regulated in treated cultures (two, three, fourfold, respectively). The addition of collagen-PVP to synovium-induced down-modulation of some inflammatory parameters and an increase in apoptosis of synovial cells. Perhaps this mechanism could contribute to inhibit outgrowth of pannus formation and to

  2. APL-2, an altered peptide ligand derived from heat-shock protein 60, induces interleukin-10 in peripheral blood mononuclear cell derived from juvenile idiopathic arthritis patients and downregulates the inflammatory response in collagen-induced arthritis model.

    PubMed

    Lorenzo, Norailys; Cantera, Dolores; Barberá, Ariana; Alonso, Amaris; Chall, Elsy; Franco, Lourdes; Ancizar, Julio; Nuñez, Yanetsy; Altruda, Fiorella; Silengo, Lorenzo; Padrón, Gabriel; Del Carmen Dominguez, Maria

    2015-02-01

    Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by autoimmune arthritis of unknown cause with onset before age of 16 years. Methotrexate provides clinical benefits in JIA. For children who do not respond to methotrexate, treatment with anti-tumor necrosis factor (TNF)-α is an option. However, some patients do not respond or are intolerant to anti-TNF therapy. Induction of peripheral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases. We aimed to evaluate the potentialities of two altered peptide ligands (APLs) derived from human heat-shock protein 60, an autoantigen involved in the pathogenesis of autoimmune arthritis, in JIA patients. Interferon (IFN)-γ, TNF-α and interleukin (IL)-10 levels were determined in ex vivo assays using peripheral blood mononuclear cells (PBMC) from these patients. Wild-type peptide and one of these APLs increased IFN-γ and TNF-α levels. Unlike, the other APLs (called APL2) increased the IL-10 level without affecting IFN-γ and TNF-α levels. On the other hand, APL2 induces a marked activation of T cells since it transforms cell cycle phase's distribution of CD4+ T cells from these patients. In addition, we evaluated the therapeutic effect of APL2 in collagen-induced arthritis model. Therapy with APL2 reduced arthritis scores and histological lesions in mice. This effect was associated to a decrease in TNF-α and IL-17 levels. These results indicate a therapeutic potentiality of APL2 for JIA.

  3. Deletion of IFT20 in early stage T lymphocyte differentiation inhibits the development of collagen-induced arthritis

    PubMed Central

    Yuan, Xue; Garrett-Sinha, Lee Ann; Sarkar, Debanjan; Yang, Shuying

    2014-01-01

    IFT20 is the smallest member of the intraflagellar transport protein (IFT) complex B. It is involved in cilia formation. Studies of IFT20 have been confined to ciliated cells. Recently, IFT20 was found to be also expressed in non-ciliated T cells and have functions in immune synapse formation and signaling in vitro. However, how IFT20 regulates T-cell development and activation in vivo is still unknown. We deleted the IFT20 gene in early and later stages of T-cell development by crossing IFT20flox/flox (IFT20f/f) mice with Lck-Cre and CD4-Cre transgenic mice, and investigated the role of IFT20 in T-cell maturation and in the development of T cell-mediated collagen-induced arthritis (CIA). We found that both Lck-Cre/IFT20f/f and CD4-Cre/IFT20f/f mice were indistinguishable from their wild-type littermates in body size, as well as in the morphology and weight of the spleen and thymus. However, the number of CD4- and CD8-positive cells was significantly lower in thymus and spleen in Lck-Cre/IFT20f/f mice. Meanwhile, the incidence and severity of CIA symptoms were significantly decreased, and inflammation in the paw was significantly inhibited in Lck-Cre/IFT20f/f mice compared to Lck-Cre/IFT20+/+ littermates. Deletion IFT20 in more mature T cells of CD4-Cre/IFT20f/f mice had only mild effects on the development of T cells and CIA. The expression of IL-1β, IL-6 and TGF-β1 were significantly downregulated in the paw of Lck-Cre/IFT20f/f mice, but just slight decreased in CD4-Cre/IFT20f/f mice. These results demonstrate that deletion of IFT20 in the early stage of T-cell development inhibited CIA development through regulating T-cell development and the expression of critical cytokines. PMID:26097753

  4. Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats.

    PubMed

    Rasool, M; Varalakshmi, P

    2007-04-01

    The present investigation was carried out to evaluate the protective effect of Withania somnifera Linn. Dunal (family-Solanaceae), commonly known as Ashwagandha, on adjuvant-induced arthritic rats. Results were compared with those for Indomethacin, a nonsteroidal anti-inflammatory drug. Arthritis was induced by intradermal injection of complete Freund's adjuvant (0.1 mL) into the right hind paw of Wistar albino rats. Withania somnifera root powder (1000 mg/kg/day) and Indomethacin (3 mg/kg/day) were orally administered for 8 days (from 11th to 18th day) after adjuvant injection. The anti-arthritic effect of W. somnifera root powder was assessed by measuring changes in lipid peroxidation, antioxidant status, and glycoprotein levels in plasma and spleen of arthritic animals. In addition, cartilage degradation was also assessed by estimating bone collagen, and urinary constituents in arthritic animals. Results of the present investigation showed significant increase in the level of lipid peroxides, glycoproteins, and urinary constituents with the depletion of antioxidant status and bone collagen in arthritic animals. These biochemical alterations observed were ameliorated significantly by oral administration of W. somnifera root powder (1000 mg/kg body weight) in arthritic animals. The results of this study clearly indicate that W. somnifera root powder is capable of rectifying the above biochemical changes in adjuvant arthritis.

  5. Adenosine A2A Receptors Mediate Anti-Inflammatory Effects of Electroacupuncture on Synovitis in Mice with Collagen-Induced Arthritis

    PubMed Central

    Li, Qi-hui; Xie, Wen-xia; Li, Xiao-pei; Huang, Ka-te; Du, Zhong-heng; Cong, Wen-jie; Zhou, Long-hua; Ye, Tian-shen; Chen, Jiang-Fan

    2015-01-01

    To study the role of adenosine A2A receptor (A2AR) in mediating the anti-inflammatory effect of electroacupuncture (EA) on synovitis in collagen-induced arthritis (CIA), C57BL/6 mice were divided into five treatment groups: Sham-control, CIA-control, CIA-EA, CIA-SCH58261 (A2AR antagonist), and CIA-EA-SCH58261. All mice except those in the Sham-control group were immunized with collagen II for arthritis induction. EA treatment was administered using the stomach 36 and spleen 6 points, and stimulated with a continuous rectangular wave for 30 min daily. EA treatment and SCH58261 were administered daily from days 35 to 49 (n = 10). After treatment, X-ray radiography of joint bone morphology was established at day 60 and mouse blood was collected for ELISA determination of tumor necrosis factor alpha (TNF-α) levels. Mice were sacrificed and processed for histological examination of pathological changes of joint tissue, including hematoxylin-eosin staining and immunohistochemistry of A2AR expression. EA treatment resulted in significantly reduced pathological scores, TNF-α concentrations, and bone damage X-ray scores. Importantly, the anti-inflammatory and tissue-protective effect of EA treatment was reversed by coadministration of SCH58261. Thus, EA treatment exerts an anti-inflammatory effect resulting in significant protection of cartilage by activation of A2AR in the synovial tissue of CIA. PMID:25784951

  6. Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the Citrus flavanone naringin.

    PubMed

    Kawaguchi, Kiichiro; Maruyama, Hiroko; Hasunuma, Ryoichi; Kumazawa, Yoshio

    2011-12-01

    Rheumatoid arthritis (RA) is closely related to the pathogenesis of tumor necrosis factor α in lesions. We investigated the suppressive effects of a Citrus flavanone naringin on inflammatory responses in mice with collagen-induced arthritis (CIA), a mouse model for RA. To investigate potential preventive and therapeutic effects of naringin, mice were given naringin orally three times a week from the second immunization with collagen (day 21) and from day 31, when symptoms of CIA had reached a plateau, respectively. In both cases, inflammation-related clinical scores for knee joints were significantly reduced by administration of naringin. Histological analyses demonstrated that representative phenomena, such as damage to interchondral joints, infiltration of inflammatory cells and pannus formation, were significantly depressed by treatment with naringin. In addition, increases in the expression of high-mobility group box-1 protein in the joints of mice with CIA were suppressed by naringin. These results suggest that oral administration of naringin might be effective for treating human patients with RA.

  7. Soluble interleukin-1 receptor accessory protein ameliorates collagen-induced arthritis by a different mode of action from that of interleukin-1 receptor antagonist.

    PubMed

    Smeets, R L; Joosten, L A B; Arntz, O J; Bennink, M B; Takahashi, N; Carlsen, H; Martin, M U; van den Berg, W B; van de Loo, F A J

    2005-07-01

    To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis. Adenoviral vectors encoding either sIL-1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Anti-bovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-kappaB luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors. Adenoviral overexpression of both sIL-1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-kappaB reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-kappaB activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-kappaB luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

  8. The therapeutic effect of extracellular superoxide dismutase (EC-SOD) mouse embryonic fibroblast (MEF) on collagen-induced arthritis (CIA) mice.

    PubMed

    Yu, Dong Hoon; Kim, Myoung Ok; Kim, Sung Hyun; Shin, Mi Jung; Kim, Bong Soo; Kim, Hei Jung; Lee, Sang Ryeul; Lee, Sang Gyu; Yoo, Seung-Ah; Kim, Wan Uk; Hyun, Byung Hwa; Park, Young Sik; Kim, Tae Yoon; Ryoo, Zae Young

    2008-01-01

    Rheumatoid arthritis is a chronic inflammatory disease. The generation of reactive oxygen species (ROS) within an inflamed joint has been suggested as playing a significant pathogenic role. Extracellular superoxide dismutase (EC-SOD) is a major scavenger enzyme of ROS, which has received growing attention for its therapeutic potential. To investigate the therapeutic effect of EC-SOD in mice with collagen-induced arthritis (CIA), we used mouse embryonic fibroblast (MEF) of transgenic mice that overexpresses EC-SOD on the skin by using hK14 promoter. DBA/1 mice that had been treated with bovine type II collagen were administrated subcutaneous injections of EC-SOD transgenic MEF (each at 1.4 x 10(60 cells) on days 28, 35, and 42 after primary immunization. To test EC-SOD activity, blood samples were collected in each group on day 49. The EC-SOD activity was nearly 1.5-fold higher in the transgenic MEF-treated group than in the nontransgenic MEF-treated group (p < 0.05). The severity of arthritis in mice was scored in a double-blind manner, with each paw being assigned a separate clinical score. The severity of arthritis in EC-SOD transgenic MEF-treated mice was significantly suppressed in the arthritic clinical score (p < 0.05). To investigate the alteration of cytokine levels, ELISA was used to measure blood samples. Levels of IL-1beta and TNF-alpha were reduced in the transgenic MEF-treated group (p < 0.05). Abnormalities of the joints were examined by H&E staining. There were no signs of inflammation except for mild hyperplasia of the synovium in the transgenic MEF-treated group. The proliferation of CII-specific T cells was lower in the transgenic MEF-treated mice than in those in the other groups. The transfer of EC-SOD transgenic MEF has shown a therapeutic effect in CIA mice and this approach may be a safer and more effective form of therapy for rheumatoid arthritis.

  9. Anti-arthritic activity of Fu-Fang-Lu-Jiao-Shuang on collagen-induced arthritis in Balb/c mice and its underlying mechanisms

    PubMed Central

    Wang, Yanyan; Sun, Weiguang; Chen, Laxia; Xu, Xin; Wu, Yunxia; Zhang, Jinwen; Zhang, Yonghui

    2015-01-01

    Background: Rheumatoid arthritis (RA) is a common, autoimmune disorder characterized by progressive multiple joint destruction, deformity, disability and premature death in most patients. Fu-Fang-Lu-Jiao-Shuang (FFLJS) is an effective traditional Chinese medicine, which has long been used clinically to treat RA patients. Objective: The objective of this study is aimed to evaluate the anti-rheumatic effects of FFLJS on collagen induced arthritis (CIA) model, as well as the underlying mechanisms, which have not previously been explored. Materials and Methods: CIA was induced by immunization with type II collagen (CII) in male Balb/c mice. The mice in the onset of arthritis were treated daily with FFLJS (125 or 500 mg/kg) or 1% carboxymethyl cellulose-Na for 28 days. Paw thickness and arthritic score were evaluated to confirm the anti-arthritic effect of FFLJS on CIA in mice. Levels of anti-CII antibody, proinflammatory cytokines interleukin-1 (IL-1) β, IL-17, and tumor necrosis factor-α (TNF-α) as well as prostaglandin E-2 (PGE-2) in serum and histological changes in the ankle joint were also analyzed. In addition, expressions of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitors of matrix metalloproteases-1 (TIMP-1) in synovial tissue were also detected to further study the molecular mechanism of the anti-arthritic effects of FFLJS. Results: During therapeutic treatment, FFLJS significantly reduced paw thickness and arthritic score in CIA mice, decreased the amounts of TNF-α, IL-1 β, IL-17, PGE-2 and anti-CII antibody in serum. In addition, FFLJS treatment could prevent the bone destruction by reducing the expression of MMP-1 and MMP-3, increasing the expression of TIMP-1 in synovial tissue of CIA mice. Conclusion: These findings offer the convincing evidence for the first time that the anti-rheumatic effects of FFLJS might be related to down-regulation of TNF-α, IL-1 β, IL-17 and PGE-2 levels for acute arthritis, and regulation of MMP-1, MMP-3

  10. Effect of taurine chloramine, the product of activated neutrophils, on the development of collagen-induced arthritis in DBA 1/J mice.

    PubMed

    Kwaśny-Krochin, B; Bobek, M; Kontny, E; Gluszko, P; Biedroń, R; Chain, B M; Maśliński, W; Marcinkiewicz, J

    2002-01-01

    Taurine chloramine (TauCl), a product of neutrophil myeloperoxidase - halide system, formed by a reaction of taurine with HOCl, is known as an anti-microbial and anti-inflammatory long-lived oxidant. We previously reported that TauCl inhibits in vitro the production of proinflammatory cytokines (IL-6, IL-8) by RA synoviocytes. Therefore we performed this study to investigate the effect of TauCl treatment on the development of collagen-induced arthritis (CIA) in DBA1/J mice. Early administration of TauCl (after primary immunization) resulted in the delay of the onset of CIA, but had no effect on severity of arthritis. TauCl, given daily for 21 days after booster immunization, did not reduce the symptoms of arthritis in those mice, which already developed CIA, but significantly diminished incidence of the disease (55% vs. 90% of placebo mice). The mechanism of this effect is unknown. This is the first in vivo study suggesting that TauCl may be used for immune intervention in chronic inflammatory diseases.

  11. Carnosic acid (CA) attenuates collagen-induced arthritis in db/db mice via inflammation suppression by regulating ROS-dependent p38 pathway.

    PubMed

    Xia, Guangtao; Wang, Xia; Sun, Hongsheng; Qin, Yuhong; Fu, Min

    2017-07-01

    Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, characterized by inflammation of synovial joints. Carnosic acid (CA) is a phenolic diterpene isolated from Rosmarinus officinailis, playing a central role in cytoprotective responses to oxidative stress and inflammation response. Our study aimed to investigate the effects of CA on RA progression in diabetic animals. Carnosic acid (CA) was used to treat collagen-induced arthritis (CIA)-induced db/db mice. Blood glucose, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were investigated to explore insulin resistance. CA significantly down-regulated fasting blood glucose, glucose level in OGTT and ITT, ameliorated CIA-induced bone loss, and reduced pro-inflammatory cytokines and reactive oxygen species (ROS) in db/db mice with arthritis induced by CIA. In vitro, CA suppressed Receptor Activator for Nuclear Factor-κ B Ligand (RANKL)- and Macrophage colony-stimulating factor (M-CSF)-induced osteoclastogenesis. The osteoclastic specific markers were inhibited by CA. Signal transduction studies showed that CA significantly decreased the expression of molecules contributing to ROS and increased anti-oxidants. Additionally, CA inactivated the RANKL- and M-CSF-induced p38 mitogen activated protein kinases (MAPK), inhibited NF-κB phosphorylation, causing pro-inflammatory cytokines down-regulation. Together, CA ameliorated osteoclast formation and CIA-induced bone loss in db/db mice through inflammation suppression by regulating ROS-dependent p38 pathway. Copyright © 2017. Published by Elsevier Inc.

  12. Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice

    PubMed Central

    Fan, Zhi-Dan; Zhang, Ya-Yuan; Guo, Yi-Hong; Huang, Na; Ma, Hui-Hui; Huang, Hui; Yu, Hai-Guo

    2016-01-01

    Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4+ T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6). Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor α and γt, which were abolished by pretreatment with P2X7R antagonists. Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A. Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice. Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells. P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype. PMID:27775097

  13. ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.

    PubMed

    Aragoneses-Fenoll, L; Montes-Casado, M; Ojeda, G; Acosta, Y Y; Herranz, J; Martínez, S; Blanco-Aparicio, C; Criado, G; Pastor, J; Dianzani, U; Portolés, P; Rojo, J M

    2016-04-15

    Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110δ inhibitor than by the p110α inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-γ), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-γ better than A66. The p110α/δ inhibitor ETP-46321, or p110α plus p110δ inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells. In vivo, therapeutic administration of ETP-46321 significantly inhibited responses to protein antigen as well as collagen-induced arthritis, as measured by antigen-specific antibody responses, secretion of IL-10, IL-17A or IFN-γ, or clinical symptoms. Hence, p110α as well as p110δ Class IA PI3Ks are important to immune regulation; inhibition of both subunits may be an effective therapeutic approach in inflammatory autoimmune diseases like rheumatoid arthritis.

  14. GV1001 immunotherapy ameliorates joint inflammation in a murine model of rheumatoid arthritis by modifying collagen-specific T-cell responses and downregulating antigen-presenting cells.

    PubMed

    Choi, In Ah; Choi, Ji Yong; Jung, Sundo; Basri, Fathihah; Park, Seho; Lee, Eun Young

    2017-03-14

    This study investigated whether GV1001 may be useful for treating rheumatoid arthritis (RA). Two collagen-induced arthritis (CIA) experiments showed that therapeutic, but not preventive, GV1001 treatment reduced the severity of joint inflammation in CIA. The third CIA experiment indicated that, compared to vehicle treatment, therapeutic GV1001 treatment was associated with a significantly smaller area under the curve for the overall clinical joint score over the 98day observation period (p<0.05). GV1001 treatment was also associated with lower Day 98 serum IL-6 levels (p<0.01) and histological joint scores (p<0.05). Moreover, splenocytes harvested from the GV1001-treated mice exhibited lower basal and collagen-stimulated production of IFN-γ and IL-6 on Days 49 and 98 than the splenocytes from vehicle-treated mice. The fourth and fifth experiments indicated that earlier treatment resulted in a better response. In addition, human (THP-1) and murine (RAW 264.7) macrophages and fibroblast-like synoviocytes (FLS) from RA patients were used for in vitro analyses. GV1001 treatment of lipopolysaccharide-stimulated macrophages derived from THP-1 and RAW 264.7 monocytes significantly reduced TNF-α and IL-6 secretion (THP-1: all p<0.05; RAW 264.7: all p<0.01). However, GV1001 treatment did not affect IL-6 expression in TNFα-stimulated RA FLS. GV1001 reduced the clinical joint scores, serum IL-6 levels, and histological joint scores of mice with CIA. In addition, GV1001 lowered the collagen-stimulated IFN-γ and IL-6 production of murine T-cells and reduced the TNF-α and IL-6 production of macrophages in vitro. Thus, GV1001 may ameliorate joint inflammation by modifying T-cell reactions to the triggering autoantigen and by reducing macrophage cytokine production.

  15. Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor.

    PubMed

    Schepetkin, Igor A; Kirpotina, Liliya N; Hammaker, Deepa; Kochetkova, Irina; Khlebnikov, Andrei I; Lyakhov, Sergey A; Firestein, Gary S; Quinn, Mark T

    2015-06-01

    c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1β in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

  16. Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

    PubMed Central

    Schepetkin, Igor A.; Kirpotina, Liliya N.; Hammaker, Deepa; Kochetkova, Irina; Khlebnikov, Andrei I.; Lyakhov, Sergey A.; Firestein, Gary S.

    2015-01-01

    c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1β in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S–treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II–specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II–specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3+CD4+CD25+ regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis. PMID:25784649

  17. Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7.

    PubMed

    Gan, Ke; Xu, Lingxiao; Feng, Xiaoke; Zhang, Qiande; Wang, Fang; Zhang, Miaojia; Tan, Wenfeng

    2015-02-01

    Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound - celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteoclast differentiation and functions in RANKL-induced osteoclast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (CT). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp-9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP+ multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen-activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction.

  18. Essential Role for the Lectin Pathway in Collagen Antibody-Induced Arthritis Revealed Through Use of Adenovirus Programming Complement Inhibitor MAp44 Expression

    PubMed Central

    Banda, Nirmal K.; Mehta, Gaurav; Kjaer, Troels R.; Takahashi, Minoru; Schaack, Jerome; Morrison, Thomas E.; Thiel, Steffen; Arend, William P.; Holers, V. Michael

    2014-01-01

    Previous studies using mannose-binding lectin (MBL) and complement C4 deficient mice have suggested that the lectin pathway (LP) is not required for the development of inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) model. MBL, ficolins and collectin-11 are key LP pattern recognition molecules that associate with three serine proteases, MASP-1, MASP-2 and MASP-3, and also with two MBL-associated proteins designated sMAP and MAp44. Recent studies have shown that MAp44, an alternatively spliced product of the MASP-1/3 gene, is a competitive inhibitor of the binding of the recognition molecules to all three MASPs. In these studies we examined the effect of treatment of mice with adenovirus (Ad) programmed to express human MAp44 (AdhMAp44) on the development of CAIA. AdhMAp44 and Ad programming Green fluorescent protein (AdGFP) expression were injected intraperitoneally in C57BL/6 wild-type mice prior to the induction of CAIA. AdhMAp44 significantly reduced the clinical disease activity score (CDA) by 81% compared to mice injected with AdGFP. Similarly, histopathologic injury scores for inflammation, pannus, cartilage and bone damage, as well as C3 deposition in the cartilage and synovium, were significantly reduced by AdhMAp44 pretreatment. Mice treated with AdmMAp44, programming expression of mouse MAp44, also showed significantly decreased CDA and histopathologic injury scores. Additionally, administration of AdhMAp44 significantly diminished the severity of Ross River Virus-induced arthritis, a LP-dependent model. Our study provides conclusive evidence that an intact complement LP is essential to initiate CAIA, and that MAp44 may be an appropriate treatment for inflammatory arthritis. PMID:25070856

  19. SPA0355, a thiourea analogue, inhibits inflammatory responses and joint destruction in fibroblast-like synoviocytes and mice with collagen-induced arthritis

    PubMed Central

    Lee, YR; Hwang, JK; Lee, HS; Cheon, YJ; Ryu, JH; Lee, SI; Kwak, HB; Lee, SM; Kim, JS; Park, JW; Jeon, R; Park, BH

    2011-01-01

    BACKGROUND AND PURPOSE NF-κB has been implicated as a therapeutic target for the treatment of rheumatoid arthritis. We previously synthesized a thiourea analogue, SPA0355, which suppressed NF-κB activity. Here we have assessed the anti-inflammatory and anti-arthritic effects of SPA0355. EXPERIMENTAL APPROACH We evaluated the effects of SPA0355 on human rheumatoid fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in mice in vivo. KEY RESULTS In vitro experiments demonstrated that SPA0355 suppressed chemokine production, matrix metalloproteinase secretion and cell proliferation induced by TNF-α in rheumatoid fibroblast-like synoviocytes. In addition, SPA0355 inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and the receptor activator of NF-κB ligand, in bone marrow macrophages. Mice with CIA that were pretreated with SPA0355 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiological and histopathological findings, and inflammatory cytokine levels, than mice treated with vehicle. Mice treated with SPA0355, after the onset of CIA, also showed significantly decreased disease incidence and joint oedema. The in vitro and in vivo protective effects of SPA0355 were mediated by inhibition of the NF-κB signalling pathway. CONCLUSION AND IMPLICATIONS Taken together, these results suggested that using SPA0355 to block the NF-κB pathway in rheumatoid joints reduced both the inflammatory responses and tissue destruction. Therefore, SPA0355 may have therapeutic value in preventing or delaying joint destruction in patients with rheumatoid arthritis. PMID:21501144

  20. SH3BP2 Gain-Of-Function Mutation Exacerbates Inflammation and Bone Loss in a Murine Collagen-Induced Arthritis Model

    PubMed Central

    Mukai, Tomoyuki; Gallant, Richard; Ishida, Shu; Yoshitaka, Teruhito; Kittaka, Mizuho; Nishida, Keiichiro; Fox, David A.; Morita, Yoshitaka; Ueki, Yasuyoshi

    2014-01-01

    Objective SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. Methods CIA was induced in wild-type (Sh3bp2+/+) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2KI/+) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Results Sh3bp2KI/+ mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2+/+ and Sh3bp2KI/+ cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2+/+ and Sh3bp2KI/+ mice. In vitro experiments showed that TNF-α production in Sh3bp2KI/+ BMMs is elevated compared with Sh3bp2+/+ BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2KI/+ BMMs associated with increased NFATc1 nuclear localization. Conclusion Gain-of-function of SH3BP2 augments inflammation

  1. Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice.

    PubMed

    Lindh, Ingrid; Snir, Omri; Lönnblom, Erik; Uysal, Hüseyin; Andersson, Ida; Nandakumar, Kutty Selva; Vierboom, Michel; 't Hart, Bert; Malmström, Vivianne; Holmdahl, Rikard

    2014-07-08

    Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA. Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice. Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group. CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation.

  2. Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

    PubMed Central

    2014-01-01

    Introduction Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA. Methods Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice. Results Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group. Conclusion CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation. PMID:25005029

  3. Discovery of serum proteomic biomarkers for prediction of response to moxibustion treatment in rats with collagen-induced arthritis: an exploratory analysis.

    PubMed

    Xu, Xiao; Wang, Miao-Miao; Sun, Zhi-Ling; Zhou, Dan-Ping; Wang, Ling; Wang, Fu-Qiang; Xu, Zhi-Yang; Ma, Qian

    2016-06-01

    To examine the possible impact of moxibustion on the serum proteome of the collagen-induced arthritis (CIA) rat model. Thirty-six male Sprague-Dawley rats were included in this experiment. The CIA animal model was prepared by injection of type II bovine collagen in Freund's adjuvant on the first and seventh day. The 36 rats were randomly divided into two groups: the untreated CIA group (control), and the CIA plus treatment with moxibustion (CIA+moxi) group. Moxibustion was administered daily at ST36 and BL23 for 7, 14 or 21 days (n=12 rats each). Arthritis score was used to assess the severity of arthritis. At the end of each 7 day treatment, blood samples from the control group and the CIA+moxi group were collected. After removal of high abundance proteins from serum samples, two-dimensional gel combined with matrix-assisted laser desorption ionisation time-of-flight MS/MS (MALDI-TOF-MS/MS) techniques were performed to examine serum protein expression patterns of the CIA rat model with and without moxibustion treatment. In addition, the relevant proteins were further analysed with the use of bioinformatics analysis. Moxibustion significantly decreased arthritis severity in the rats in the CIA+moxi group, when compared with the rats in the CIA group 35 days after the first immunisation (p=0.001). Seventeen protein spots which changed >1.33 or <0.77 at p<0.05 using Bonferonni correction for multiple testing were found to be common to all three comparisons, and these proteins were used for classification of functions using the Gene Ontology method. Consequently, with the use of the Ingenuity Pathway Analysis, the top canonical pathways and a predicted proteomic network related to the moxibustion effect of CIA were established. Using the proteomics technique, we have identified novel candidate proteins that may be involved in the mechanisms of action underlying the beneficial effects of moxibustion in rats with CIA. Our findings suggest that immune responses and

  4. Expression of peptidylarginine deiminase 4 and protein tyrosine phosphatase nonreceptor type 22 in the synovium of collagen-induced arthritis rats.

    PubMed

    Xu, Yan-Bing; Wang, Nai-Zhi; Yang, Li-Li; Cui, Hua-Dong; Xue, Hong-Xia; Zhang, Ning

    2014-06-01

    To study the expression level of peptidylarginine deiminase 4 (PADI4) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in the synovium of rat model of collagen-induced arthritis, and to explore their possible therapeutic role in rheumatoid arthritis. Thirty-two female Wistar rats weighing 100±20 g were randomly assigned into 3-week collagen-induced arthritis (CIA) model group (n=8), 4-week CIA model group (n=8), 6-week CIA model group (n=8), and the control group (n=8). The body weight changes of each group were recorded. The expression levels of PADI4 and PTPN22 were detected and compared by the methods of immunohistochemical staining and Western blot. Arthritis of rat began to form 14 days after sensitization and the joint swelling reached peak at 28 days. The weights of the rats slowly grew both in CIA model groups and the control group. Immunohistochemical staining results showed that the positive expression of PADI4 and PTPN22 was mainly located in cartilage peripheral mononuclear cells, the cytoplasm of infiltrated cells, and bone marrow cavity. There were significant differences in the optical density of PADI4 and PTPN22 among CIA model groups and the control group (PADI4, 0.2898±0.012, 0.2982±0.022, 0.2974±0.031, 0.2530±0.013 in 3-week CIA model, 4-week CIA model, 6-week CIA model and control groups; PTPN22, 0.2723±0.004, 0.2781±0.010, 0.2767±0.008, 0.2422±0.019; all P <0.05). The expression bands of PADI4 were observed in Western blot 3 weeks after initial immunization, the thickest in the 4th week, and decreased in the 6th week. The expression bands of PTPN2 were observed at all the time points, with no obvious time-dependent trend. PADI4 and PTPN22 are obviously correlated with CIA in rat model. PADI4 is expressed at early stage of the disease, while the expression of PTPN22 sustains throughout the course.

  5. Effect of an herbal mixture of Cinnamon Cortex, Persicae Semen, and Natril Sulfas on collagen-induced arthritis and lipopolysaccharides-induced nuclear factor-κ B signaling.

    PubMed

    Lee, Ji-Won; Lew, Jae-Hwan; Kim, Tae-Woo; Kang, Hee

    2016-11-17

    To investigate the anti-arthritic and anti-inflammatory effects of the mixture of three herbal agents, Cinnamon Cortex, Persica Semen, and Natril Sulfas (CPN), the major ingredients of Taoren Chengqi Decoction (). Collagen-induced arthritis (CIA) was induced by immunization with bovine type II collagen on day 1 and 21. DBA/1J mice were orally administered the water extract of CPN (100 and 500 mg/kg) and indomethacin (1 mg/kg) or vehicle (water) 3 times per week for 6 weeks. Arthritic symptoms were recorded on day 29, 31, 33, 36 and 38. On sacrififi ce, serum was obtained for inflammatory markers and anti-collagen antibodies as well as arthritic joints were obtained for histologic analysis. For the evaluation of in vitro anti-inflammatory mechanism of CPN, peritoneal macrophages were isolated from thioglycollate injected C57BL/6 mice and stimulated with lipopolysaccharides (LPS) for 15 min in the presence of CPN extract. Levels of inhibitor of NF-κB α isoform (IκBα), phospho-p38, phospho-C-Jun N-terminal kinases (JNK) and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. Compared with mice in CIA group, oral administration of CPN signififi cantly reduced the clinical scores (P<0.05), histological analysis revealed the protective effect of CPN on inflamed joints. Serum levels of the pro-inflammatory markers tumor necrosis factor-α, interleukin-6 and prostaglandin E2, but not anti-collagen antibodies, were significantly reduced (P<0.05). CPN did not affect the activation of p38, JNK and ERK1/2 but inhibited LPS-induced IκBα degradation, a required event prior to the translocation of NF-κB to the nucleus. The ameliorating effect of CPN on arthritis progression seems to be mediated by its anti-inflammatory effect, without affecting antibody response. As a supplementary agent, CPN could be benefifi cial for treatment of CIA.

  6. Early changes in serum type II collagen biomarkers predict radiographic progression at one year in inflammatory arthritis patients after biologic therapy.

    PubMed

    Mullan, Ronan H; Matthews, Clare; Bresnihan, Barry; FitzGerald, Oliver; King, Lindsay; Poole, A Robin; Fearon, Ursula; Veale, Douglas J

    2007-09-01

    To investigate whether short-term changes in serum biomarkers of type II collagen degradation (C2C) and types I and II collagen degradation (C1,2C), as well as the biomarker for the synthesis of type II procollagen (CPII) can predict radiographic progression at 1 year following initiation of biologic therapy in patients with inflammatory arthritis. Serum levels of biomarkers were measured at baseline and at 1, 3, 6, 9, and 12 months after initiation of biologic therapy. A composite score reflecting changes from baseline in all 3 biomarkers (DeltaCOL) was calculated. Associations with clinical responses according to the 28-joint count Disease Activity Score and with radiographic progression according to the modified Sharp/van der Heijde score (SHS) were assessed. The 1-year increase in the SHS correlated with the 1-month change in C2C results (r = 0.311, P = 0.028) and the DeltaCOL score (r = 0.342, P = 0.015). Radiographic progression was predicted by increases in serum C2C at 1 month (P = 0.031). The DeltaCOL score was significantly associated with 1-year radiographic progression after 1 (P = 0.022), 3 (P = 0.015), 6 (P = 0.048), and 9 (P = 0.019) months of therapy. Clinical remission was predicted by 1-month decreases in serum levels of C2C (P = 0.008) and C1,2C (P = 0.036). By regression analysis, 1-month changes in C2C, C1,2C, and CPII levels were independently associated with, and correctly predicted radiographic outcome in, 88% of the patients. Short-term changes in serum levels of collagen biomarkers following initiation of biologic therapy may better predict long-term clinical and radiographic outcomes. These collagen biomarkers may therefore be valuable new early indicators of short-term biologic treatment efficacy in clinical trials and in individual patients with inflammatory erosive arthritis.

  7. Influence of polysaccharide fractions isolated from Caltha palustris L. on the cellular immune response in collagen-induced arthritis (CIA) in mice. A comparison with methotrexate.

    PubMed

    Suszko, Agnieszka; Obmińska-Mrukowicz, Bożena

    2013-01-09

    The extracts from Caltha palustris have been used in traditional Canadian and Asian medicine to treat arthritis and rheumatism. The aim of the study was to investigate the anti-arthritis and immunomodulatory activity of the polysaccharide fractions B and C of Caltha palustris L. herbal extracts in collagen-induced arthritis (CIA) mice, an animal model of rheumathoid arthritis. The results were compared with those of methotrexate (MTX) treatment. CIA was induced in male and female DBA/1J mice by intradermal injection of chicken type II collagen in Freund's complete adjuvant (cFA). Booster injection of collagen (in incomplete Freund's adjuvant) was given on day 21 of the experiment. Mice were treated daily for 21 consecutive days with investigated fractions B or C at a dose of 10mg/kg (the first dose was given 24h after the booster) or phosphate buffered saline (PBS) (negative and positive control group). MTX was administered in parallel, intraperitoneally at three weekly cycles-every 48 h for 3 weeks at a dose of 6.6 mg/kg, the first dose was given on day 22 of the experiment. The severity of arthritis was evaluated by arthritic scores. Flow cytometry was used to investigate subsets of T lymphocytes in the thymus, and T and B lymphocytes in the spleen, and in mesenteric lymph nodes. T regulatory lymphocytes in the spleen were also quantified by means of flow cytometry. The levels of IL-2, IL-6, IL-10, IFN-γ and TNF-α in serum were also measured. The results revealed that fraction B significantly reduced the severity of joint swelling and erythema to a similar degree as MTX. It was also found that B fraction and MTX inhibited leucocytosis in peripheral blood caused by CIA, however the inhibitory effect of MTX persisted longer than that of fraction B. The analysis of lymphocyte T subsets demonstrated that both investigated fractions and MTX caused a partial or complete normalization in the percentage and the absolute number of CD4(-)CD8(-) thymocytes (immature

  8. Therapeutic Effect of Ergotope Peptides on Collagen-Induced Arthritis by Downregulation of Inflammatory and Th1/Th17 Responses and Induction of Regulatory T Cells

    PubMed Central

    Niu, Xiaoyin; Deng, Shaohua; Li, Shan; Xi, Yebin; Li, Chengzhen; Wang, Li; He, Dongyi; Wang, Zhaojun; Chen, Guangjie

    2016-01-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th) 1 and 17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it is necessary to find a truly effective and convenient treatment. Several studies have intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find potential ergotope peptides and investigate their effects in treating the animal model of RA and their underlying regulatory mechanisms. First, we selected functional ergotope peptides from 25 overlapping peptides derived from the interleukin 2 receptor (IL-2R) α chain, and then used these peptides to treat collagen-induced arthritis (CIA). We showed ergotope peptides as immunomodulatory factors with great benefits at the clinical and pathologic levels. This effect was associated with inhibition of type II collagen (CII)-specific proliferation and autoantibody production as well as induction of antiergotypic immune response, downregulation of both Th1 and Th17 cells and their related components, and emergence of Treg cells that had suppressive action on autoreactive T cells. We also proved that cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and IL-10 are two important mediators that are critical to Treg suppressive function. Inhibition of Th1 and Th17 in established CIA could be attributed to ergotope-induced Treg cells. Our findings reveal that ergotope peptides induce regulatory immune responses and restore immune tolerance, suggesting that treatment with ergotope peptides may be a novel approach to therapy for RA patients and has good application prospects, with cheap, effective, convenient, wide-spectrum features. PMID:27579476

  9. Helminth antigens enable CpG-activated dendritic cells to inhibit the symptoms of collagen-induced arthritis through Foxp3+ regulatory T cells.

    PubMed

    Carranza, Franco; Falcón, Cristian Roberto; Nuñez, Nicolás; Knubel, Carolina; Correa, Silvia Graciela; Bianco, Ismael; Maccioni, Mariana; Fretes, Ricardo; Triquell, María Fernanda; Motrán, Claudia Cristina; Cervi, Laura

    2012-01-01

    Dendritic cells (DC) have the potential to control the outcome of autoimmunity by modulating the immune response. In this study, we tested the ability of Fasciola hepatica total extract (TE) to induce tolerogenic properties in CpG-ODN (CpG) maturated DC, to then evaluate the therapeutic potential of these cells to diminish the inflammatory response in collagen induced arthritis (CIA). DBA/1J mice were injected with TE plus CpG treated DC (T/C-DC) pulsed with bovine collagen II (CII) between two immunizations with CII and clinical scores CIA were determined. The levels of CII-specific IgG2 and IgG1 in sera, the histological analyses in the joints, the cytokine profile in the draining lymph node (DLN) cells and in the joints, and the number, and functionality of CD4+CD25+Foxp3+ T cells (Treg) were evaluated. Vaccination of mice with CII pulsed T/C-DC diminished the severity and incidence of CIA symptoms and the production of the inflammatory cytokine, while induced the production of anti-inflammatory cytokines. The therapeutic effect was mediated by Treg cells, since the adoptive transfer of CD4+CD25+ T cells, inhibited the inflammatory symptoms in CIA. The in vitro blockage of TGF-β in cultures of DLN cells plus CII pulsed T/C-DC inhibited the expansion of Treg cells. Vaccination with CII pulsed T/C-DC seems to be a very efficient approach to diminish exacerbated immune response in CIA, by inducing the development of Treg cells, and it is therefore an interesting candidate for a cell-based therapy for rheumatoid arthritis (RA).

  10. Herbal formula Xian-Fang-Huo-Ming-Yin regulates differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis mice.

    PubMed

    Li, Jinyu; Wei, Yi; Li, Xue; Zhu, Dashuai; Nie, Bo; Zhou, Jingwei; Lou, Lixia; Dong, Bin; Wu, Aiming; Che, Yongzhe; Chen, Meng; Zhu, Lingqun; Mu, Mingwei; Chai, Limin

    2017-01-05

    Xian-Fang-Huo-Ming-Yin (XFHM), a traditional herbal formula, has been used to treat sores and carbuncles for hundreds of years in Asia. Nowadays, its clinical effects in treatment of rheumatoid arthritis (RA) have been validated. In this study, we want to study its possible molecular mechanisms of regulating the differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis (CIA) mice for RA treatment. A high performance liquid chromatography-electrospray ionization/mass spectrometer (HPLC-ESI/MS(n)) system was used to analyze the constituents of XFHM granules. An arthritics mouse model was induced by collagen and leflunomide (LEF) was used as a positive control medicine. Pathological changes at the metatarsophalangeal joint were studied through Safranin O and immunohistochemical staining. The differentiation of T, B and NK cells was examined by flow cytometry and pro-inflammatory cytokines were assayed using an Inflammation Antibody Array assay. The expression of key molecules of the nuclear factor κB (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in spleen were studied by western-blot analysis. In our study. 21 different dominant chemical constituents were identified in XFHM. Treatment with XFHM suppressed the pathological changes in arthrosis of CIA. Additionally, XFHM down-regulated the proliferation and differentiation of CD3(+) T cells and CD3(-)CD19(+) B cells significantly. However, XFHM had no significant effect on CD3(-)NK1.1(+) NK cells. Further study showed that the production of pro-inflammatory cytokines had been suppressed by inhibiting the activation of NF-κB and JAK/STAT signaling. XFHM can regulate and maintain the immunologic balance of lymphocytic immunity and inhibit the production of pro-inflammatory cytokines, thus suppressing the pathological changes of RA. Therefore, XFHM may be used as an application of traditional medicine against RA

  11. Expression of tyrosine hydroxylase in CD4(+) T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis.

    PubMed

    Wang, Xiao-Qin; Liu, Yan; Cai, Huan-Huan; Peng, Yu-Ping; Qiu, Yi-Hua

    2016-12-01

    Tyrosine hydroxylase (TH), a rate-limiting enzyme for the synthesis of catecholamines, is expressed in T lymphocytes. However, the role of T cell-expressed TH in rheumatoid arthritis (RA) is less clear. Herein, we aimed to show the contribution of TH expression by CD4(+) T cells to alleviation of helper T (Th)17/regulatory T (Treg) imbalance in collagen-induced arthritis (CIA), a mouse model of RA. CIA was prepared by intradermal injection of collagen type II (CII) at tail base of DBA1/J mice. Expression of TH in the spleen and the ankle joints was measured by real-time polymerase chain reaction and Western blot analysis. Percentages of TH-expressing Th17 and Treg cells in splenic CD4(+) T cells were determined by flow cytometry. Overexpression and knockdown of TH gene in CD4(+) T cells were taken to evaluate effects of TH on Th17 and Treg cells in CIA. TH expression was upregulated in both the inflamed tissues (spleen and ankle joints) and the CD4(+) T cells of CIA mice. In splenic CD4(+) T cells, the cells expressing TH were increased during CIA. These cells that expressed more TH in CIA were mainly Th17 cells rather than Treg cells. TH gene overexpression in CD4(+) T cells from CIA mice reduced Th17 cell percentage as well as Th17-related transcription factor and cytokine expression and secretion, whereas TH gene knockdown enhanced the Th17 cell activity. In contrast, TH gene overexpression increased Treg-related cytokine expression and secretion in CD4(+) T cells of CIA mice, while TH gene knockdown decreased the Treg cell changes. Collectively, these findings show that CIA induces TH expression in CD4(+) T cells, particularly in Th17 cells, and suggest that the increased TH expression during CIA represents an anti-inflammatory mechanism.

  12. [Effect of electroacupuncture at "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) on collagen-induced arthritis and secretory function of knee-joint synoviocytes in rats].

    PubMed

    Fang, Jian-Qiao; Shao, Xiao-Mei; Ma, Gui-Zhi

    2009-04-01

    To observe the effect of electroacupuncture (EA) of "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) on collagen-induced arthritis (CIA) and its underlying mechanism in regulating the secretory function of knee-joint synovial cells in CIA rats. Thirty-six Wistar rats were equally randomized into control, model and EA groups. CIA model (rheumatoid arthritis) was duplicated by intradermal injection of Bovine type II collagen into the back of the anesthetized rats. EA (2 Hz, 2 mA) was applied to "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) for 30 min, once a day for 30 days. The paw volume was measured by using a Plethysmometer and hot water tail-flick tests (50 degrees C) were conducted for detecting the rats' pain threshold (PT) before and after the treatment. The contents of PGE2, IL-1beta and TNF-alpha in supernatant of the cultured joint synoviocytes were detected by enzyme linked immunosorbent assay (ELISA). In comparison with control group, the swelled paw volume, the declined PT, PGE2, TNF-alpha and IL-1beta contents in knee-joint synoviocyte supernatant were significantly higher in model group (P < 0.05). Compared with model group, PT increased obviously (P < 0.05); paw volume, supernatant PGE2, TNF-alpha and IL-1beta contents decreased obviously (P < 0.05) in EA group. EA of ST 36 and SP 6 has a pronounced therapeutic effect in relieving knee joint pain and inflammation in CIA rats, which may be related to its effect in regulating the secretory function of the knee-joint synoviocytes.

  13. Expression of tyrosine hydroxylase in CD4+ T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis

    PubMed Central

    Wang, Xiao-Qin; Liu, Yan; Cai, Huan-Huan; Qiu, Yi-Hua

    2016-01-01

    Tyrosine hydroxylase (TH), a rate-limiting enzyme for the synthesis of catecholamines, is expressed in T lymphocytes. However, the role of T cell-expressed TH in rheumatoid arthritis (RA) is less clear. Herein, we aimed to show the contribution of TH expression by CD4+ T cells to alleviation of helper T (Th)17/regulatory T (Treg) imbalance in collagen-induced arthritis (CIA), a mouse model of RA. CIA was prepared by intradermal injection of collagen type II (CII) at tail base of DBA1/J mice. Expression of TH in the spleen and the ankle joints was measured by real-time polymerase chain reaction and Western blot analysis. Percentages of TH-expressing Th17 and Treg cells in splenic CD4+ T cells were determined by flow cytometry. Overexpression and knockdown of TH gene in CD4+ T cells were taken to evaluate effects of TH on Th17 and Treg cells in CIA. TH expression was upregulated in both the inflamed tissues (spleen and ankle joints) and the CD4+ T cells of CIA mice. In splenic CD4+ T cells, the cells expressing TH were increased during CIA. These cells that expressed more TH in CIA were mainly Th17 cells rather than Treg cells. TH gene overexpression in CD4+ T cells from CIA mice reduced Th17 cell percentage as well as Th17-related transcription factor and cytokine expression and secretion, whereas TH gene knockdown enhanced the Th17 cell activity. In contrast, TH gene overexpression increased Treg-related cytokine expression and secretion in CD4+ T cells of CIA mice, while TH gene knockdown decreased the Treg cell changes. Collectively, these findings show that CIA induces TH expression in CD4+ T cells, particularly in Th17 cells, and suggest that the increased TH expression during CIA represents an anti-inflammatory mechanism. PMID:27444150

  14. A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos, attenuates collagen-induced arthritis and inhibits TLR4 signalling in rats

    PubMed Central

    Cheng, Brian Chi Yan; Yu, Hua; Guo, Hui; Su, Tao; Fu, Xiu-Qiong; Li, Ting; Cao, Hui-Hui; Tse, Anfernee Kai-Wing; Wu, Zheng-Zhi; Kwan, Hiu-Yee; Yu, Zhi-Ling

    2016-01-01

    RL, a traditional remedy for Rheumatoid arthritis (RA), comprises two edible herbs, Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. We have reported that RL could inhibit the production of inflammatory mediators in immune cells. Here we investigated the effects and the mechanism of action of RL in collagen-induced arthritis (CIA) rats. RL significantly increased food intake and weight gain of CIA rats without any observable adverse effect; ameliorated joint erythema and swelling; inhibited immune cell infiltration, bone erosion and osteophyte formation in joints; reduced joint protein expression levels of TLR4, phospho-TAK1, phospho-NF-κB p65, phospho-c-Jun and phospho-IRF3; lowered levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-17A and MCP-1 in sera and TNF-α, IL-6, IL-1β and IL-17A in joints); elevated serum IL-10 level; reinvigorated activities of antioxidant SOD, CAT and GSH-Px in the liver and serum; reduced Th17 cell proportions in splenocytes; inhibited splenocyte proliferation and activation; and lowered serum IgG level. In conclusion, RL at nontoxic doses inhibited TLR4 signaling and potently improved clinical conditions of CIA rats. These findings provide further pharmacological justifications for the traditional use of RL in RA management. PMID:26860973

  15. Xianfanghuomingyin, a Chinese Compound Medicine, Modulates the Proliferation and Differentiation of T Lymphocyte in a Collagen-Induced Arthritis Mouse Model

    PubMed Central

    Li, Xue; Wei, Yi; Chen, Meng; Zhou, Jingwei; Dong, Bin; Zhu, Lingqun

    2016-01-01

    In traditional Chinese medicine (TCM), xianfanghuomingyin (XFHM) is used to treat autoimmune diseases, including rheumatoid arthritis (RA). Here, we studied the mechanisms underlying its treatment effects, especially its anti-inflammatory effects in a collagen-induced arthritis (CIA) mouse model. We found that cartilage destruction and pannus formation were alleviated by treatment with XFHM. The abnormal differentiation of Th1 and Th17 cells was downregulated significantly by XFHM, and Th2 and Treg cells were upregulated. Moreover, the expression levels of specific cytokines and transcription factors related to Th1 cells (interferon γ [IFNγ], T-bet) and Th17 cells (interleukin- [IL-] 17) and the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ) were downregulated. Serum IL-4 and GATA-3, which contribute to Th2 cells differentiation, increased significantly after XFHM administration. These results indicate that XFHM can restore the balance of T lymphocytes and reestablish the immunological tolerance to inhibit autoinflammatory disorder of RA. Taken together, XFHM can be used as a complementary or alternative traditional medicine to treat RA. PMID:27656238

  16. MZ B cells migrate in a T-bet dependent manner and might contribute to the remission of collagen-induced arthritis by the secretion of IL-10.

    PubMed

    Huber, Krisztina; Sármay, Gabriella; Kövesdi, Dorottya

    2016-09-01

    In mice, marginal zone (MZ) B cells are found principally in the MZ of the spleen and characterized as CD23-negative cells, primarily express polyreactive BCRs, high levels of complement receptor-2 and TLRs. Collagen-induced arthritis (CIA) is a commonly used animal model of human rheumatoid arthritis, considered as a Th1-mediated disease. Although the importance of MZ B cells in the initiation of CIA is well established, their role in remission is unexplored. Besides, playing a central role in Th1 cell development, T-box transcription factor (T-bet) has important functions in B cells. T-bet is regulated by IFN-γ and through the BCR and TLR9, the signals that have an impact on regulatory IL-10 production. In this work, we aimed to analyze the contribution of T-bet to the function of IL-10-positive MZ B cells. We demonstrate that during the remission phase of CIA, MZ B cells express an elevated level of T-bet and confirm the existence of IL-10/T-bet coexpressing cells. Moreover, we show that T-bet-expressing MZ B cells migrate toward CXCR3 ligand and secrete IL-10 by inflammatory stimuli. Our data suggest that T-bet might contribute to the remission of CIA by facilitating the regulatory potential of IL-10-positive MZ B cells. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Ossicular Bone Damage and Hearing Loss in Rheumatoid Arthritis: A Correlated Functional and High Resolution Morphometric Study in Collagen-Induced Arthritic Mice

    PubMed Central

    Barbe, Mary F.

    2016-01-01

    Globally, a body of comparative case-control studies suggests that rheumatoid arthritis (RA) patients are more prone to developing hearing loss (HL). However, experimental evidence that supports this hypothesis is still lacking because the human auditory organ is not readily accessible. The aim of this study was to determine the association between bone damage to the ossicles of the middle ear and HL, using a widely accepted murine model of collagen-induced arthritis (RA mice). Diarthrodial joints in the middle ear were examined with microcomputer tomography (microCT), and hearing function was assessed by auditory brainstem response (ABR). RA mice exhibited significantly decreased hearing sensitivity compared to age-matched controls. Additionally, a significant narrowing of the incudostapedial joint space and an increase in the porosity of the stapes were observed. The absolute latencies of all ABR waves were prolonged, but mean interpeak latencies were not statistically different. The observed bone defects in the middle ear that were accompanied by changes in ABR responses were consistent with conductive HL. This combination suggests that conductive impairment is at least part of the etiology of RA-induced HL in a murine model. Whether the inner ear sustains bone erosion or other pathology, and whether the cochlear nerve sustains pathology await subsequent studies. Considering the fact that certain anti-inflammatories are ototoxic in high doses, monitoring RA patients’ auditory function is advisable as part of the effort to ensure their well-being. PMID:27690307

  18. A rice-based soluble form of a murine TNF-specific llama variable domain of heavy-chain antibody suppresses collagen-induced arthritis in mice.

    PubMed

    Abe, Michiyo; Yuki, Yoshikazu; Kurokawa, Shiho; Mejima, Mio; Kuroda, Masaharu; Park, Eun Jeong; Scheller, Jürgen; Nakanishi, Ushio; Kiyono, Hiroshi

    2014-04-10

    Tumor necrosis factor alpha (TNF) plays a pivotal role in chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although anti-TNF antibody therapy is now commonly used to treat patients suffering from these inflammatory conditions, the cost of treatment continues to be a concern. Here, we developed a rice transgenic system for the production of a llama variable domain of a heavy-chain antibody fragment (VHH) specific for mouse TNF in rice seeds (MucoRice-mTNF-VHH). MucoRice-mTNF-VHH was produced at high levels in the rice seeds when we used our most recent transgene-overexpression system with RNA interference technology that suppresses the production of major rice endogenous storage proteins while enhancing the expression of the transgene-derived protein. Production levels of mTNF-VHH in rice seeds reached an average of 1.45% (w/w). Further, approximately 91% of mTNF-VHH was released easily when the powder form of MucoRice-mTNF-VHH was mixed with PBS. mTNF-VHH purified by means of single-step gel filtration from rice PBS extract showed high neutralizing activity in an in vitro mTNF cytotoxicity assay using WEHI164 cells. In addition, purified mTNF-VHH suppressed progression of collagen-induced arthritis in mice. These results show that this rice-expression system is useful for the production of neutralizing VHH antibody specific for mTNF.

  19. Korean Red Ginseng Saponin Fraction Rich in Ginsenoside-Rb1, Rc and Rb2 Attenuates the Severity of Mouse Collagen-Induced Arthritis

    PubMed Central

    Endale, Mehari; Im, Eun Ju; Lee, Joo Young; Kim, Sung Dae; Song, Yong-Bum; Kwak, Yi-Seong; Kim, Chaekyun; Kim, Seung-Hyung; Roh, Seong-Soo; Rhee, Man Hee

    2014-01-01

    Despite a multitude of reports on anti-inflammatory properties of ginseng extracts or individual ginsenosides, data on antiarthritic effect of ginseng saponin preparation with mixed ginsenosides is limited. On the other hand, a combined therapy of safe and inexpensive plant-derived natural products such as ginsenosides can be considered as an alternative to treat arthritis. Our previous in vitro data displayed a strong anti-inflammatory action of red ginseng saponin fraction-A (RGSF-A). We, herein, report a marked antiarthritic property of RGSF-A rich in ginsenoside Rb1, Rc, and Rb2. Collagen-induced arthritic (CIA) mice were treated with RGSF-A or methotrexate (MTX) for 5 weeks. Joint pathology, serum antibody production and leukocye activation, cytokine production in the circulation, lymph nodes, and joints were examined. RGSF-A markedly reduced severity of arthritis, cellular infiltration, and cartilage damage. It suppressed CD3+/CD69+, CD4+/CD25+, CD8+ T-cell, CD19+, B220/CD23+ B-cell, MHCII+/CD11c+, and Gr-1+/CD11b+ cell activations. It further suppressed anti-CII- or anti-RF-IgG/IgM, TNF-α, IL-1β, IL-17, and IL-6 secretions but stimulated IL-10 levels in the serum, joint, or splenocyte. RGSF-A attenuated arthritis severity, modified leukocyte activations, and restored cytokine imbalances, suggesting that it can be considered as an antiarthritic agent with the capacity to ameliorate the immune and inflammatory responses in CIA mice. PMID:24833816

  20. Two Novel α7 Nicotinic Acetylcholine Receptor Ligands: In Vitro Properties and Their Efficacy in Collagen-Induced Arthritis in Mice

    PubMed Central

    van Maanen, Marjolein A.; Papke, Roger L.; Koopman, Frieda A.; Koepke, Jessica; Bevaart, Lisette; Clark, Roger; Lamppu, Diana; Elbaum, Daniel; LaRosa, Gregory J.; Tak, Paul P.; Vervoordeldonk, Margriet J.

    2015-01-01

    Introduction The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by the vagus nerve. This neurotransmitter binds to the α7 subunit of nicotinic acetylcholine receptors (α7nAChR), expressed on macrophages and other immune cells. We tested the pharmacological and functional profile of two novel compounds, PMP-311 and PMP-072 and investigated their role in modulating collagen-induced arthritis (CIA) in mice. Methods Both compounds were characterized with binding, electrophysiological, and pharmacokinetic studies. For in vivo efficacy studies in the CIA model the compounds were administered daily by oral gavage from day 20 till sacrifice at day 34. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Results Treatment with PMP-311 was effective in preventing disease onset, reducing clinical signs of arthritis, and reducing synovial inflammation and bone destruction. PMP-072 also showed a trend in arthritis reduction at all concentrations tested. The data showed that while both compounds bind to α7nAChR with high affinity, PMP-311 acts like a classical agonist of ion channel activity, and PMP-072 can actually act as an ion channel antagonist. Moreover, PMP-072 was clearly distinct from typical competitive antagonists, since it was able to act as a silent agonist. It synergizes with the allosteric modulator PNU-120596, and subsequently activates desensitized α7nAChR. However, PMP-072 was less efficacious than PMP-311 at both channel activation and desensitization, suggesting that both conducting and non-conducting states maybe of importance in driving an anti-inflammatory response. Finally, we found that the anti-arthritic effect can be observed despite limited penetration of the central nervous system. Conclusions These data provide direct evidence that the α7nAChR in immune cells does not

  1. Multi-response model for rheumatoid arthritis based on delay differential equations in collagen-induced arthritic mice treated with an anti-GM-CSF antibody.

    PubMed

    Koch, Gilbert; Wagner, Thomas; Plater-Zyberk, Christine; Lahu, Gezim; Schropp, Johannes

    2012-02-01

    Collagen-induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis, a human chronic inflammatory destructive disease. The therapeutic effect of neutralizing the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) by an antibody was examined in the mouse disease in a view of deriving a pharmacokinetic/pharmacodynamic (PKPD) model. In CIA mice the development of disease is measured by a total arthritic score (TAS) and an ankylosis score (AKS). We present a multi-response PKPD model which describes the time course of the unperturbed and perturbed TAS and AKS. The antibody acts directly on GM-CSF by binding to it. Therefore, a compartment for the cytokine GM-CSF is an essential component of the mathematical model. This compartment drives the disease development in the PKPD model. Different known properties of arthritis development in the CIA model are included in the PKPD model. Firstly, the inflammation, driven by GM-CSF, dominates at the beginning of the disease and decreases after some time. Secondly, a destructive (ankylosis) part evolves in the TAS that is delayed in time. In order to model these two properties a delay differential equation was used. The PKPD model was applied to different experiments with doses ranging from 0.1 to 100 mg/kg. The influence of the drug was modeled by a non-linear approach. The final mathematical model consists of three differential equations representing the compartments for GM-CSF, inflammation and destruction. Our mathematical model described well all available dosing schedules by a simultaneous fit. We also present an equivalent and easy reformulation as ordinary differential equation which grants the use of standard PKPD software.

  2. A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice

    PubMed Central

    Zhang, Li; Wang, Jin; Xu, Aizhang; Zhong, Conghao; Lu, Wuguang; Deng, Li; Li, Rongxiu

    2016-01-01

    The TNF-α biological inhibitors have significantly improved the clinical outcomes of many autoimmune diseases, in particular rheumatoid arthritis. However, the practical uses are limited due to high costs and the risk of anti-drug antibody responses. Attempts to develop anti-TNF-α vaccines have generated encouraging data in animal models, however, data from clinical trials have not met expectations. In present study, we designed a TNF-α epitope-scaffold immunogen DTNF7 using the transmembrane domain of diphtheria toxin, named DTT as a scaffold. Molecular dynamics simulation shows that the grafted TNF-α epitope is entirely surface-exposed and presented in a native-like conformation while the rigid helical structure of DTT is minimally perturbed, thereby rendering the immunogen highly stable. Immunization of mice with alum formulated DTNF7 induced humoral responses against native TNF-α, and the antibody titer was sustained for more than 6 months, which supports a role of the universal CD4 T cell epitopes of DTT in breaking self-immune tolerance. In a mouse model of rheumatoid arthritis, DTNF7-alum vaccination markedly delayed the onset of collagen-induced arthritis, and reduced incidence as well as clinical score. DTT is presumed safe as an epitope carrier because a catalytic inactive mutant of diphtheria toxin, CRM197 has good clinical safety records as an active vaccine component. Taken all together, we show that DTT-based epitope vaccine is a promising strategy for prevention and treatment of autoimmune diseases. PMID:27658047

  3. Type I and III collagen turnover is increased in axial spondyloarthritis and psoriatic arthritis. Associations with disease activity and diagnostic capacity.

    PubMed

    Gudmann, Natasja Stæhr; Siebuhr, Anne Sofie; Christensen, Anne Friesgaard; Ejstrup, Leif; Sørensen, Grith Lykke; Loft, Anne Gitte; Karsdal, Morten Asser; Bay-Jensen, Anne-Christine; Munk, Heidi Lausten; Junker, Peter

    2017-01-01

    To investigate the turnover of type I and III collagen by neo-epitope markers in patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). Patients with PsA (n=101) or axSpA (n=110) and healthy subjects (n=120) were included. Demographic and clinical data were recorded. Markers of type I and III collagen were quantified by RIA (ICTP) or ELISA (C1M and C3M). Non-parametric statistics were applied for intergroup comparisons and correlation studies. The diagnostic potential of these marker molecules was assessed by ROC analysis. C1M and C3M, which originate from soft connective tissues, were significantly higher in axSpA and PsA as compared with healthy control subjects. CIM and C3M correlated with ASDAS and DAS28. Overall, ICTP, which arises from bone degradation, did not differ between disease versus healthy. However, ICTP was lower in HLA-B27 positive than in HLA-B27 negative patients with axSpA. There was no association between bone and soft connective tissue collagen I markers (ICTP and C1M), while C1M and C3M were highly correlated (p<0.0001). C1M discriminated between healthy and diseased with AUCs of 0.83 for PsA and 0.79 for axSpA. C3M AUCs were 0.77 for PsA and 0.78 for axSpA. Type I and III collagen remodelling in soft connective tissue is increased in axSpA and PsA and associates with disease activity. Bone collagen degradation is lower in HLA-B27 positive compared with HLA-B27 negative axSpA, which may represent an aspect of enhanced enthesopathic bone proliferation in HLA-B27 carriers. C1M and C3M distinguish well between healthy and diseased individuals.

  4. Absence of interleukin-17 receptor a signaling prevents autoimmune inflammation of the joint and leads to a Th2-like phenotype in collagen-induced arthritis.

    PubMed

    Corneth, Odilia B J; Mus, Adriana M C; Asmawidjaja, Patrick S; Klein Wolterink, Roel G J; van Nimwegen, Menno; Brem, Maarten D; Hofman, Yara; Hendriks, Rudi W; Lubberts, Erik

    2014-02-01

    Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis. Disease incidence and severity were scored in type II collagen-treated wild-type, IL-17RA-deficient, and IL-23p19-deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA). Comparable to the findings in IL-23p19-deficient mice, IL-17RA-deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA-deficient mice exhibited an increased number of IL-4-producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA-deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation. These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint. Copyright © 2014 by the American College of Rheumatology.

  5. Changes in focal adhesion kinase expression in rats with collagen-induced arthritis and efficacy of intervention with disease modifying anti-rheumatic drugs alone or in combination.

    PubMed

    Gao, Hui-Ying; Luo, Jing; Li, Xiao-Feng; Lv, Qian; Wen, Hong-Yan; Song, Qing-Zhen; Zhao, Wen-Peng; Zhao, Xiang-Cong; Zhang, Ting-Ting; Zhang, Si-Yu; Zhi, Jian-Ming

    2015-01-01

    Focal adhesion kinase (FAK) is known to promote the proliferation, migration and survival of synovial cells and plays an important role in the occurrence, development and pathological process of rheumatoid arthritis (RA). The aim of the present study was to observe FAK changes in synovial cells of rats with collagen-induced arthritis (CIA) and after intervention with disease modifying anti-rheumatic drugs (DMARDs) alone or in combination in a CIA female SD rat model induced by collagen type II. The rats were randomized to 8 groups: normal control group, CIA model control group, methotrexate (MTX, 0.9 mg/kg/w) group, cyclophosphamide (CTX, 24 mg/kg/3 w) group, leflunomide (LEF, 1.2 mg/kg/d) group, MTX + CTX group, LEF + CTX group, and MTX + LEF group. They were intervened with DMARDs alone or in combination for six weeks. The experiment lasted a total of 9 weeks in vivo. Articular inflammation was measured during the process of drug intervention in terms of the degree of swelling degree in the right hind foot using a venire caliper. All animals were sacrificed by breaking the neck after 9 weeks. Then, the ankle was fixed, decalcified, embedded, and HE stained, and prepared into slices to observe pathological changes in the synovial tissue. FAK expression in synovial cells was assayed by immunohistochemistry and the mean optical density (OD) value was measured using the HPIAS-2000 image analysis system. It was found that FAK expression was negative in normal control group, positive in CIA model control group, and decreased in the three DMARD combination treatment groups significantly as compared with that in the three single-drug groups (P < 0.05). FAK expression in LEF + CTX group or MTX + CTX group decreased more significantly than that in MTX + LEF group (P < 0.05), and there was no statistically significant difference between LEF + CTX and MTX + CTX groups. The arthritis index and pathological change in the synovial tissue in LEF + CTX group or MTX + CTX group

  6. N-α-Benzoyl-N5-(2-Chloro-1-Iminoethyl)-L-Ornithine Amide, a Protein Arginine Deiminase Inhibitor, Reduces the Severity of Murine Collagen-Induced Arthritis

    PubMed Central

    Willis, Van C.; Gizinski, Alison M.; Banda, Nirmal K.; Causey, Corey P.; Knuckley, Bryan; Cordova, Kristen N.; Luo, Yuan; Levitt, Brandt; Glogowska, Magdalena; Chandra, Piyanka; Kulik, Liudmila; Robinson, William H.; Arend, William P.; Thompson, Paul R.; Holers, V. Michael

    2011-01-01

    Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a recently described pan-PAD inhibitor, could affect the development of arthritis and autoimmunity by treating mice in the CIA model with Cl-amidine on days 0–35. Cl-amidine treatment reduced total synovial and serum citrullination, decreased clinical disease activity by ∼50%, and significantly decreased IgG2a anti-mouse type II collagen Abs. Additionally, histopathology scores and total complement C3 deposition were significantly lower in Cl-amidine–treated mice compared with vehicle controls. Synovial microarray analyses demonstrated decreased IgG reactivity to several native and citrullinated epitopes compared with vehicle controls. Cl-amidine treatment had no ameliorative effect on collagen Ab-induced arthritis, suggesting its primary protective mechanism was not mediated through effector pathways. Reduced levels of citrullinated synovial proteins observed in mice treated with Cl-amidine are consistent with the notion that Cl-amidine derives its efficacy from its ability to inhibit the deiminating activity of PADs. In total, these results suggested that PADs are necessary participants in the autoimmune and subsequent inflammatory processes in CIA. Cl-amidine may represent a novel class of disease-modifying agents that modulate aberrant citrullination, and perhaps other immune processes, necessary for the development of inflammatory arthritis. PMID:21346230

  7. Low Dietary c9t11-Conjugated Linoleic Acid Intake from Dairy Fat or Supplements Reduces Inflammation in Collagen-Induced Arthritis.

    PubMed

    Huebner, Shane M; Olson, Jake M; Campbell, James P; Bishop, Jeffrey W; Crump, Peter M; Cook, Mark E

    2016-07-01

    Dietary cis-9,trans-11 (c9t11) conjugated linoleic acid (CLA) fed at 0.5 % w/w was previously shown to attenuate inflammation in the murine collagen-induced (CA) arthritis model, and growing evidence implicates c9t11-CLA as a major anti-inflammatory component of dairy fat. To understand c9t11-CLA's contribution to dairy fat's anti-inflammatory action, the minimum amount of dietary c9t11-CLA needed to reduce inflammation must be determined. This study had two objectives: (1) determine the minimum dietary anti-inflammatory c9t11-CLA intake level in the CA model, and (2) compare this to anti-inflammatory effects of dairy fat (non-enriched, naturally c9t11-CLA-enriched, or c9t11-CLA-supplemented). Mice received the following dietary fat treatments (w/w) post arthritis onset: corn oil (6 % CO), 0.125, 0.25, 0.375, and 0.5 % c9t11-CLA, control butter (6 % CB), c9t11-enriched butter (6 % EB), or c9t11-CLA-supplemented butter (6 % SB, containing 0.2 % c9t11-CLA). Paw arthritic severity and pad swelling were scored and measured, respectively, over an 84-day study period. All c9t11-CLA and butter diets decreased the arthritic score (25-51 %, P < 0.01) and paw swelling (8-11 %, P < 0.01). Throughout the study, plasma tumor necrosis factor (TNFα) was elevated in CO-fed arthritic mice compared to non-arthritic (NA) mice but was reduced in 0.5 % c9t11-CLA- and EB-fed mice. Interleukin-1β and IL-6 were increased in arthritic CO-fed mice compared to NA mice but were reduced in 0.5 % c9t11-CLA- and EB-fed mice through day 42. In conclusion, 0.125 % c9t11-CLA reduced clinical arthritis as effectively as higher doses, and decreased arthritis in CB-fed mice suggested that the minimal anti-inflammatory levels of c9t11-CLA might be below 0.125 %.

  8. Role of protein kinase C delta in angiotensin II induced cardiac fibrosis

    PubMed Central

    Chintalgattu, Vishnu; Katwa, Laxmansa C

    2009-01-01

    Previous studies have demonstrated a role for angiotensin II (AngII) and myofibroblasts (myoFb) in cardiac fibrosis. However, the role of PKC-δ in AngII mediated cardiac fibrosis is unclear. Therefore, the present study was designed to investigate the role of PKC-δ in AngII induced cardiac collagen expression and fibrosis. AngII treatment significantly (p<0.05) increased myoFb collagen expression, whereas PKC-δ siRNA treatment or rottlerin, a PKC-δ inhibitor abrogated (p<0.05) AngII induced collagen expression. MyoFb transfected with PKC-δ over expression vector showed significant increase (p<0.05) in the collagen expression as compared to control. Two-weeks of chronic AngII infused rats showed significant (p<0.05) increase in collagen expression compared to sham operated rats. This increase in cardiac collagen expression was abrogated by rottlerin treatment. In conclusion, both in vitro and in vivo data strongly suggest a role for PKC-δ in AngII induced cardiac fibrosis. PMID:19540196

  9. Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.

    PubMed

    De Santis, M; Ceribelli, A; Cavaciocchi, F; Generali, E; Massarotti, M; Isailovic, N; Crotti, C; Scherer, H U; Montecucco, C; Selmi, C

    2016-09-01

    The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells. © 2016 British Society for Immunology.

  10. Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis.

    PubMed

    Andersson, Annica; Bernardi, Angelina I; Stubelius, Alexandra; Nurkkala-Karlsson, Merja; Ohlsson, Claes; Carlsten, Hans; Islander, Ulrika

    2016-03-01

    RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammation-associated bone loss using CIA in mice. Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17β-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry. LAS and BZA reduced the clinical severity of arthritis as well as the grade of histologic synovitis and erosions on cartilage and bone. Moreover, SERMs protected against generalised bone loss in CIA by increasing trabecular BMD. Both SERMs decreased serum marker of cartilage destruction and LAS reduced serum IL-6 levels. SERMs did not alter Th17 cells in lymph nodes as E2 did. The anti-osteoporotic drugs LAS and BZA were found to be potent inhibitors of joint inflammation and bone destruction in experimental arthritis. This study provides new important knowledge regarding the treatment regimen of post-menopausal women with RA who suffer from increased risk for osteoporosis. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology.

  11. Lymphocyte-activation gene 3(+) (LAG3(+)) forkhead box protein 3(-) (FOXP3(-)) regulatory T cells induced by B cells alleviates joint inflammation in collagen-induced arthritis.

    PubMed

    Chen, Szu-Ying; Hsu, Wan-Tseng; Chen, Yi-Lien; Chien, Chien-Hui; Chiang, Bor-Luen

    2016-04-01

    Rheumatoid arthritis (RA) is an autoimmune disease in which dysregulated immune cells primarily target synovial joints. Despite recent advances in the treatment of RA, including the introduction of biologic therapies and employment of combination disease-modifying antirheumatic drug strategies, remission rates remain suboptimal. Previous studies have demonstrated that the adoptive transfer of induced regulatory T cells (iTregs) was effective in treating a murine model of collagen-induced arthritis (CIA). The objective of this study was to develop optimal potential iTreg-based therapy for CIA by adoptively transferring LAG3(+) Treg-of-B cells. B-cell-induced Treg-of-B cells expressed LAG3 but not Foxp3 (designated LAG3(+) Treg-of-B), and secreted IL-4, IL-10, and TGF-β. Furthermore, LAG3(+) Treg-of-B cells suppressed the proliferation of CD4(+)CD25(-) responder T cells through both LAG3 and IL-10 production. In the murine CIA model, adoptive transfer of LAG3(+) Treg-of-B cells alleviated the joint severity as well as local and systemic inflammation. Treatment with LAG3(+) Treg-of-B cells also promoted IL-10 production in lymphocytes isolated from the spleen and draining lymph nodes. Moreover, mice receiving LAG3(+) Treg-of-B cell treatment showed significantly less pronounced osteolysis in the hind footpads, which correlated with the downregulation of tartrate-resistant acid phosphatase expression. In conclusion, we identified a novel subset of Tregs for CIA treatment. This insight may facilitate exploring novel regulatory T-cell-based therapies for human autoimmune diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues.

    PubMed

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian; Chou, Guixin; Wang, Zhengtao; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3(+) cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR.

  13. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    SciTech Connect

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian; Chou, Guixin; Wang, Zhengtao; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  14. Effects of bucillamine and N-acetyl-l-cysteine on cytokine production and collagen-induced arthritis (CIA)

    PubMed Central

    Tsuji, F; Miyake, Y; Aono, H; Kawashima, Y; Mita, S

    1999-01-01

    We investigated the effects of bucillamine and N-acetyl-l-cysteine (NAC) on cytokine production and CIA. Bucillamine and NAC inhibited NF-κB activation and tumour necrosis factor-alpha (TNF-α) mRNA expression in human monocytic leukaemia cell line THP-1, and cytokine production from monocyte cell lines at concentrations >10−3 m. They also inhibited cytokine production and CIA in mice at a dose of 500 mg/kg. These results suggest that NF-κB inhibitors such as bucillamine and NAC may inhibit cytokine-related diseases, including arthritis. PMID:9933417

  15. The suppressive effects of Saposhnikovia divaricata (Fangfeng) chromone extract on rheumatoid arthritis via inhibition of nuclear factor-κB and mitogen activated proteinkinases activation on collagen-induced arthritis model.

    PubMed

    Kong, Xiangying; Liu, Chunfang; Zhang, Cun; Zhao, Juan; Wang, Jianzhu; Wan, Hongye; Zhu, Hongwei; Zhang, Ping; Chen, Weiheng; Xiao, Yongqing; Lin, Na

    2013-07-30

    Saposhnikovia divaricata (SD), called "Fangfeng" in China, is commonly used in clinical compound prescription for treatment of rheumatoid arthritis (RA), but its actions on RA have not been clarified. The present study aims to determine the anti-inflammatory activity of SD chromone extract (SCE), the major bioactive component of SD, on collagen-induced arthritis (CIA) rats, and elucidate its underlying mechanisms with regards to its molecular basis of action on human fibroblast-like synoviocytes derived from RA patients (HFLS-RA). CIA model on rats was constructed by injection of bovine type II collagen. Rats were pre-treated with different dosages of SCE from 3 days before till 35 days after model building. The progression of CIA was evaluated by macroscopic scoring, X-ray observation and hematoxylin and eosin (HE) staining of paws. HFLS-RA were pre-treated with different concentrations of SCE prior to stimulation with 10 ng/ml of tumor necrosis factor (TNF) α. By radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), levels of interleukin (IL)-1β, IL-6, TNFα and prostaglandin E2 (PGE2) were quantified respectively. Nuclear factor (NF-κB) p65 expression and DNA-binding activity were tested by immunohistochemisty and electrophoretic mobility shift assay (EMSA) respectively. Phosphorylation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPKs were examined by immunohistochemisty staining and western blot analysis. Histological examination and radiological observation demonstrated that SCE significantly reduced the inflammatory responses in the joints of CIA rats. SCE inhibited the production of TNFα, IL-1β, and IL-6 in the joint tissues and sera. The level of PGE2 in sera was also decreased by SCE. Moreover, SCE treatment in vivo was able to reduce protein level of NF-κB, the transcriptional factor closely related to the inflammatory process, in articular synovium and cartilage of CIA rats. In addition, SCE

  16. Collagen induced arthritis (CIA) in mice features regulatory transcriptional network connecting major histocompatibility complex (MHC H2) with autoantigen genes in the thymus.

    PubMed

    Donate, Paula B; Fornari, Thaís A; Junta, Cristina M; Magalhães, Danielle A; Macedo, Cláudia; Cunha, Thiago M; Nguyen, Catherine; Cunha, Fernando Q; Passos, Geraldo A

    2011-05-01

    Considering that imbalance of central tolerance in the thymus contributes to aggressive autoimmunity, we compared the expression of peripheral tissue autoantigens (PTA) genes, which are involved in self-representation in the thymic stroma, of two mouse strains; DBA-1/J (MHC-H2(q)) susceptible and DBA-2/J (MHC-H2(d)) resistant to collagen induced arthritis (CIA). We evaluate whether these strains differ in their thymic gene expression, allowing identification of genes that might play a role in susceptibility/resistance to CIA. Microarray profiling showed that 1093 PTA genes were differentially modulated between collagen immunized DBA-1/J and DBA-2/J mice. These genes were assigned to 17 different tissues/organs, including joints/bone, characterizing the promiscuous gene expression (PGE), which is implicated in self-representation. Hierarchical clustering of microarray data and quantitative RT-PCR analysis showed that Aire (autoimmune regulator), an important regulator of the PGE process, Aire-dependent (insulin), Aire-independent (Col2A1 and Gad67), and other 22 joint/bone autoantigen genes were down-regulated in DBA-1/J compared with DBA-2/J in the thymus. Considering the importance of MHC-H2 in peptide-self presentation and autoimmunity susceptibility, we reconstructed transcriptional networks of both strains based on actual microarray data. The networks clearly demonstrated different MHC-H2 transcriptional interactions with PTAs genes. DBA-1/J strain featured MHC-H2 as a node influencing downstream genes. Differently, in DBA-2/J strain network MHC-H2 was exclusively self-regulated and does not control other genes. These findings provide evidence that CIA susceptibility in mice may be a reflex of a cascade-like transcriptional control connecting different genes to MHC-H2 in the thymus.

  17. Use of biofluorescence imaging to compare the distribution of certolizumab pegol, adalimumab, and infliximab in the inflamed paws of mice with collagen-induced arthritis.

    PubMed

    Palframan, Roger; Airey, Michael; Moore, Adrian; Vugler, Alex; Nesbitt, Andrew

    2009-08-31

    Exposure to a drug at the site of inflammation may be an important consideration for the effective treatment of inflammatory disorders such as rheumatoid arthritis (RA). The purpose of this in vivo study was to identify a methodology to enable effective quantification of antibody-type reagents in normal and inflamed tissue by investigating the distribution of the tumor necrosis factor-alpha (TNF-alpha) inhibitors, certolizumab pegol, adalimumab, and infliximab, in healthy and inflamed murine tissue using a novel non-invasive biofluorescence method. Certolizumab pegol, adalimumab, and infliximab were labeled with the low molecular weight dye alexa680. The agents were administered intravenously at a dose of 2mg/kg in naïve DBA/1 mice and in DBA/1 mice with ongoing collagen-induced arthritis. Concentrations of the TNF inhibitors in the hind paws were measured using a Xenogen IVIS200 biofluorescence imager at multiple time points up to 26h post-administration. In 2 independent experiments, the distribution of certolizumab pegol was compared with that of adalimumab and infliximab. Certolizumab pegol, adalimumab, and infliximab all distributed more effectively into inflamed tissue than non-inflamed tissue in this animal model of arthritis. However, the ratio of penetration of certolizumab pegol into inflamed arthritic paws compared with normal tissue was greater than that observed with adalimumab and infliximab. Furthermore, the duration of exposure in the inflamed versus normal tissue was more prolonged for certolizumab pegol than for both adalimumab and infliximab, and the accumulation of certolizumab pegol in diseased tissue was more responsive to the severity of inflammation when compared with adalimumab and infliximab. It is probable that these features of certolizumab pegol are conferred on the molecule by PEGylation. It is important to assess exposure to drug at the site of inflammation, because distinct structural features of certain agents may affect efficacy

  18. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis.

    PubMed

    Tchetina, Elena V; Kobayashi, Masahiko; Yasuda, Tadashi; Meijers, Tineke; Pidoux, Isabelle; Poole, A Robin

    2007-05-01

    The objective of this study was to determine whether a peptide of type II collagen which can induce collagenase activity can also induce chondrocyte terminal differentiation (hypertrophy) in articulate cartilage. Full depth explants of normal adult bovine articular cartilage were cultured with or without a 24 mer synthetic peptide of type II collagen (residues 195-218) (CB12-II). Peptide CB12-II lacks any RGD sequence and is derived from the CB12 fragment of type II collagen. Type II collagen cleavage by collagenase was measured by ELISA in cartilage and medium. Real-time RT-PCR was used to analyze gene expression of the chondrocyte hypertrophy markers COL10A1 and MMP-13. Immunostaining for anti-Ki67, anti-PCNA, (proliferation markers), type X collagen, cleavage of type II collagen by collagenases (hypertrophy markers) and TUNEL staining (hypertrophy and apoptosis markers) were used to detect progressive maturational stages of chondrocyte hypertrophy. At high but naturally occurring concentrations (10 microM and up) the collagen peptide CB12-II induced an increase in the expression of MMP-13 (24 h) and cleavage of type II collagen by collagenase in the mid zone (day 4) and also in the superficial zone (day 6). Furthermore the peptide induced an increase in proliferation on day 1 in the mid and deep zones extending to the superficial zone by day 4. There was also upregulation of COL10A1 expression at day 4 and of type X staining in the mid zone extending to the superficial zone by day 6. Apoptotic cell death was increased by day 4 in the lower deep zone and also in the superficial zone at day 7. The increase in apoptosis in the deep zone was also seen in controls. Our results show that the induction of collagenase activity by a cryptic peptide sequence of type II collagen, is accompanied by chondrocyte hypertrophy and associated with cellular and matrix changes. This induction occurs in the mid and superficial zones of previously healthy articular cartilage. This

  19. Association of H2A{sup b} with resistance to collagen-induced arthritis in H2-recombinant mouse strains: An allele associated with reduction of several apparently unrelated responses

    SciTech Connect

    Mitchison, N.A.; Brunner, M.C.

    1995-02-01

    HLA class II alleles can protect against immunological diseases. Seeking an animal model for a naturally occurring protective allele, we screened a panel of H2-congenic and recombinant mouse strains for ability to protect against collagen-induced arthritis. The strains were crossed with the susceptible strain DBA/1, and the F{sub 1} hybrids immunized with cattle and chicken type II collagen. Hybrids having the H2A{sup b} allele displayed a reduced incidence and duration of the disease. They also had a reduced level of pre-disease inflammation, but not of anti-collagen antibodies. The allele is already known to be associated with reduction of other apparently unrelated immune responses, suggesting that some form of functional differentiation may operate that is not exclusively related to epitope-binding. It is suggested that this may reflect allelic variation in the class II major histocompatibility complex promoter region. 42 refs., 7 figs., 1 tab.

  20. Anti-Inflammatory Effects of the Bioactive Compound Ferulic Acid Contained in Oldenlandia diffusa on Collagen-Induced Arthritis in Rats

    PubMed Central

    Zhu, Hao; Liang, Qing-Hua; Xiong, Xin-Gui; Chen, Jiang; Wu, Dan; Yang, Bo; Zhang, Yang; Zhang, Yong; Huang, Xi

    2014-01-01

    Objectives. This study aimed to identify the active compounds in Oldenlandia diffusa (OD) decoction and the compounds absorbed into plasma, and to determine whether the absorbed compounds derived from OD exerted any anti-inflammatory effects in rats with collagen induced arthritis (CIA). Methods. The UPLC-PDA (Ultra Performance Liquid Chromatography Photo-Diode Array) method was applied to identify the active compounds both in the decoction and rat plasma. The absorbable compound was administered to the CIA rats, and the effects were dynamically observed. X-ray films of the joints and HE stain of synovial tissues were analyzed. The levels of IL-1β and TNF-α in the rats from each group were measured by means of ELISA. The absorbed compound in the plasma of CIA rats was identified as ferulic acid (FA), following OD decoction administration. Two weeks after the administration of FA solution or OD decoction, the general conditions improved compared to the model group. The anti-inflammatory effect of FA was inferior to that of the OD decoction (P < 0.05), based on a comparison of IL-1β TNF-α levels. FA from the OD decoction was absorbed into the body of CIA rats, where it elicited anti-inflammatory responses in rats with CIA. Conclusions. These results suggest that FA is the bioactive compound in OD decoction, and FA exerts its effects through anti-inflammatory pathways. PMID:24883069

  1. T-cell compartment involvement in two high antibody responder lines of mice (HI and HII Biozzi mice) respectively susceptible and resistant to collagen-induced arthritis.

    PubMed

    Lima, G C; Zyad, A; Decreusefond, C; Mevel, J C; Stiffel, C; Mouton, D; Couderc, J

    1993-08-01

    The T-cell compartment was investigated in two high antibody responder lines of mice respectively susceptible (HI) and resistant (HII) to chicken collagen (CII)-induced arthritis (CIA). Previous data had shown that both lines were high anti-CII Ab producers, without any TCR V-beta gene defect or membrane expression impairment. The present studies demonstrate that anti-CII proliferation is much lower in HII than in HI. These results are confirmed by the limiting dilution analysis of anti-CII T-precursor frequencies (1/991 in HI and 1/12175 in HII). The percentage of CD8+ T cells is constitutively higher in HII mice, this difference increasing after CII immunization. This finding suggests a suppressive effect accounting for resistance to CIA. However, no restoration of specific response was achieved by in-vivo or in-vitro depletion of CD8+ T cells. T clones specific for Chicken CII could be obtained only from primed HI mice. Four of five clones with CD8+ phenotype proliferated in vitro to native and denatured CII and showed cytotoxic function in an anti-CD3 redirected assay. The CD4+ clone was shown to proliferate on both HI and HII-pulsed APC, which rules out a major CII processing/presentation defect in HII.

  2. Biodistribution and PET imaging of a novel [68Ga]-anti-CD163-antibody conjugate in rats with collagen-induced arthritis and in controls.

    PubMed

    Eichendorff, Sascha; Svendsen, Pia; Bender, Dirk; Keiding, Susanne; Christensen, Erik I; Deleuran, Bent; Moestrup, Søren K

    2015-02-01

    The hemoglobin scavenger receptor CD163 is exclusively expressed on monocytes and tissue macrophages, also at sites of inflammation. We examined whether gallium-68 (Ga-68)-labeled anti-CD163-antibody can detect the receptor in vivo. We radiolabeled anti-CD163 antibody with Ga-68 and evaluated stability and binding specificity of the conjugate ([(68)Ga]ED2) in vitro. Furthermore, tracer biodistribution was assessed in vivo in healthy rats and rats with acute collagen-induced arthritis (CIA) by MicroPET and tissue analysis. Radiosynthesis of [(68)Ga]ED2 antibody yielded a tracer with high-specific activity and radiochemical purity. [(68)Ga]ED2 bound specifically to CD163 in vitro. In rats, [(68)Ga]ED2 rapidly accumulated in macrophage-rich tissues. The arthritic paws exhibited a low but significant [(68)Ga]ED2 uptake. Interestingly, the systemic distribution was also changed in the sense that a significantly higher liver uptake and lower spleen uptake of [(68)Ga]ED2 was measured in CIA rats that accordingly showed a corresponding change in level of CD163 expression. [(68)Ga]ED2 specifically binds CD163 in vitro and in vivo. Biodistribution studies in CIA rats suggest that this novel tool may have applications in studies of inflammatory diseases.

  3. Scavenger Receptor-Mediated Targeted Treatment of Collagen-Induced Arthritis by Dextran Sulfate-Methotrexate Prodrug.

    PubMed

    Yang, Modi; Ding, Jianxun; Feng, Xiangru; Chang, Fei; Wang, Yinan; Gao, Zhongli; Zhuang, Xiuli; Chen, Xuesi

    2017-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder implicated in multiple joint affection and even disability. The activated macrophages perform a predominant role in onset and persistence of RA. Scavenger receptor (SR), one of several receptors overexpressed on the activated macrophages, is a specific biomarker for targeted therapy of numerous chronic inflammation diseases like RA. In this work, dextran sulfate-graft-methotrexate conjugate (DS-g-MTX) is synthesized and characterized, which exhibits excellent targetability to SR on the activated RAW 264.7 cells. Additionally, the enhanced accumulation and potent inflammatory inhibition are observed in the affected joint after intravenous injection of DS-g-MTX, compared to the treatment with dextran-graft-methotrexate (Dex-g-MTX), as is confirmed by the detection of histopathology and pro-inflammatory cytokines. Our work highlights DS-g-MTX as a potential therapeutic option for RA aiming the SR-expressed activated macrophages.

  4. Scavenger Receptor-Mediated Targeted Treatment of Collagen-Induced Arthritis by Dextran Sulfate-Methotrexate Prodrug

    PubMed Central

    Yang, Modi; Ding, Jianxun; Feng, Xiangru; Chang, Fei; Wang, Yinan; Gao, Zhongli; Zhuang, Xiuli; Chen, Xuesi

    2017-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder implicated in multiple joint affection and even disability. The activated macrophages perform a predominant role in onset and persistence of RA. Scavenger receptor (SR), one of several receptors overexpressed on the activated macrophages, is a specific biomarker for targeted therapy of numerous chronic inflammation diseases like RA. In this work, dextran sulfate-graft-methotrexate conjugate (DS-g-MTX) is synthesized and characterized, which exhibits excellent targetability to SR on the activated RAW 264.7 cells. Additionally, the enhanced accumulation and potent inflammatory inhibition are observed in the affected joint after intravenous injection of DS-g-MTX, compared to the treatment with dextran-graft-methotrexate (Dex-g-MTX), as is confirmed by the detection of histopathology and pro-inflammatory cytokines. Our work highlights DS-g-MTX as a potential therapeutic option for RA aiming the SR-expressed activated macrophages. PMID:28042319

  5. The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

    PubMed

    Zhong, Ming-Chao; Veillette, André

    2013-11-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

  6. The Adaptor Molecule Signaling Lymphocytic Activation Molecule (SLAM)-associated Protein (SAP) Is Essential in Mechanisms Involving the Fyn Tyrosine Kinase for Induction and Progression of Collagen-induced Arthritis

    PubMed Central

    Zhong, Ming-Chao; Veillette, André

    2013-01-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types. PMID:24045941

  7. Cartilage collagen type II seromarker patterns in axial spondyloarthritis and psoriatic arthritis: associations with disease activity, smoking and HLA-B27.

    PubMed

    Munk, Heidi Lausten; Gudmann, Natasja Staehr; Christensen, Anne Friesgaard; Ejstrup, Leif; Sorensen, Grith Lykke; Loft, Anne Gitte; Bay-Jensen, Anne C; Siebuhr, Anne Sofie; Junker, Peter

    2016-04-01

    The aim of the study was to assess the possible association between type II collagen turnover seromarkers and disease profile in patients with axial spondyloarthritis (SpA) and psoriatic arthritis (PsA). Outpatients with axial SpA (n = 110) or PsA (n = 101) underwent clinical examination including disease activity measures and HLA-B27 typing. The procollagen IIA N-terminal peptide (PIIANP) and a matrix metalloproteinase-generated type II collagen fragment (C2M) were quantified in serum by ELISA. C2M was higher in SpA than in controls, 0.41 versus 0.36 ng/ml (p = 0.004), while PIIANP did not differ between patients and healthy subjects, 2252 versus 2142 ng/ml (p = 0.13). However, DMARD-naïve SpA patients had higher PIIANP, 2461 ng/ml (p = 0.01) and C2M, 0.44 ng/ml (p = 0.0007) levels than controls, and PIIANP correlated with CRP (ρ = 0.34). C2M was lower in SpA smokers, 0.36 ng/ml versus non-smokers, 0.43 ng/ml (p = 0.02), while PIIANP was higher in HLA-B27 positive, 2312 ng/ml versus negative patients, 2021 ng/ml (p = 0.03). In PsA, PIIANP and C2M did not differ between patients and controls, but PIIANP was elevated in patients not receiving DMARDs, 2726 ng/ml. In PsA, PIIANP and C2M did not differ according to smoking and HLA-B27. Cartilage degradation assessed by C2M is increased in SpA irrespective of treatment but not in PsA. Cartilage synthesis reflected by PIIANP is increased in untreated SpA and PsA. PIIANP correlates with CRP in SpA while not in PsA. In DMARD-naïve SpA but not in PsA, HLA-B27 positivity and smoking are associated with a chondro-proliferative metabolic pattern.

  8. Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis.

    PubMed

    Landewé, Robert; Geusens, Piet; Boers, Maarten; van der Heijde, Désirée; Lems, Willem; te Koppele, Johan; van der Linden, Sjef; Garnero, Patrick

    2004-05-01

    To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA). Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting). Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX

  9. Anti-IgD antibody attenuates collagen-induced arthritis by selectively depleting mature B-cells and promoting immune tolerance.

    PubMed

    Nguyen, Tue G; Little, Christopher B; Yenson, Vanessa M; Jackson, Christopher J; McCracken, Sharon A; Warning, Julia; Stevens, Veronica; Gallery, Eileen G; Morris, Jonathan M

    2010-08-01

    Membrane (m)IgD forms a major part of B-cell receptor complexes. Its wider role in the immune system has been enigmatic. Stimulation of mIgD with an antibody (anti-IgD) can activate B-cells and elicit a broad immune response in vivo. Given the role of B-cells in autoimmune diseases and the profound impact of anti-IgD on B-cells, the potential effects of anti-IgD on autoimmune conditions are intriguing and yet to be explored. Here we report a novel therapeutic effect of anti-IgD in the collagen-induced arthritis (CIA) mouse model. Administration of anti-IgD at the onset of early clinical symptoms as a therapeutic intervention, but not as a prophylactic treatment, significantly ameliorates disease severity and joint pathology. Anti-IgD treatment selectively depletes mature B cells while it spares regulatory B-cell subsets. This results in a significant reduction of autoantibody levels but does not affect antibody responses to a T-cell-dependent antigen. Therapeutic treatment with anti-IgD increases the numbers of regulatory B-cells and regulatory T-cells whilst it augments adaptive Th1/Th2 responses in vivo. In human PBMC samples, anti-IgD also promotes adaptive Th1/Th2 responses and modulates the innate responses toward an anti-inflammatory Th2-biased response. Collectively, anti-IgD treatment may offer a selective approach to B-cell depletion that also promotes immune tolerance and anti-inflammatory tendencies without compromising the general adaptive B-cell and T-cell responses. The multiple mechanisms of action by anti-IgD treatment suggest a wider clinical application for a number of chronic inflammatory and autoimmune conditions.

  10. Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

    PubMed Central

    Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

    2016-01-01

    The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

  11. Proteolytic activity of IgGs from blood serum of Wistar rats at experimental rheumatoid arthritis.

    PubMed

    Kit, Yu Ya; Myronovsky, S L; Kril, I I; Havrylyuk, A M; Chop'yak, V V; Stoika, R S

    2014-01-01

    The aim of this work was to study the proteolytic activity of IgGs purified from blood serum of Wistar rats at experimental rheumatoid arthritis (ERA) induced by an injection of bovine collagen of type II. Twenty rats were immunized with a preparation of bovine collagen II (Sigma-Aldrich, USA) in the presence of complete Freund's adjuvant. ERA development was determined by inflammation in limbs of treated animals. IgG preparations were isolated from blood serum of immunized and non-immunized animals by precipitation of antibodies with 33% ammonium sulfate followed by chromatography on the Protein G-Sepharose column. Human histone H1, bovine collagen II, calf thymus histones, myelin basic protein (MBP), bovine serum albumin (BSA), and bovine casein were used as substrates of the proteolytic activity of IgGs. It was found that IgG preparations from blood serum of rats with ERA were capable of cleaving histone H1 and MBP, however, they were catalytically inactive towards collagen II, casein, BSA, and core histones. IgGs from blood serum of non-immunized rats were proteolytically inactive towards all used protein substrates. Thus, we demonstrated that immunization of rats with bovine collagen II induced IgG-antibodies possessing the proteolytic activity towards histone H1 and MBP. This activity might be associated with the development of inflammatory processes in the immunized rats.

  12. Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice.

    PubMed

    Banda, Nirmal K; Hyatt, Stephanie; Antonioli, Alexandra H; White, Jason T; Glogowska, Magdalena; Takahashi, Kazue; Merkel, Tod J; Stahl, Gregory L; Mueller-Ortiz, Stacey; Wetsel, Rick; Arend, William P; Holers, V Michael

    2012-02-01

    The complement system, especially the alternative pathway, plays essential roles in the induction of injury in collagen Ab-induced arthritis (CAIA) in mice. The goal of the current study was to directly compare the roles of receptors for C3a and C5a, as well as the membrane attack complex, as effector mechanisms in the pathogenesis of CAIA. Clinical disease activity in C3aR(-/-), C5aR(-/-), and C6-deficient (C6-def) mice was decreased by 52, 94, and 65%, respectively, as compared with wild-type mice. Decreases in histopathologic injury as well as in IgG and C3 deposition paralleled the clinical disease activity. A decrease in the percentage of synovial neutrophils was observed in C3aR(-/-), C5aR(-/-), and C6-def mice, and a decrease in macrophages was observed in C3aR(-/-) and C5aR(-/-), but not in C6-def, mice. Synovial mRNA obtained by laser capture microdissection exhibited a decrease in TNF-α in C5aR(-/-) mice and in IL-1β in both C5aR(-/-) and C6-def mice, whereas C3aR(-/-) mice demonstrated no change in either cytokine. Our findings show that absent C3aR-, C5aR-, or membrane attack complex-initiated effector mechanisms each decrease susceptibility to CAIA, with clinical effects most pronounced in C5aR-deficient mice. Although the absence of C3aR, C5aR, or C6 led to differential deficiencies in effector mechanisms, decreased proximal joint IgG and C3 deposition was common to all three genotypes in comparison with wild-type mice. These data suggest the existence of positive-feedback amplification pathways downstream of all three effectors that promote additional IgG deposition and C3 activation in the joint.

  13. Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.

    PubMed

    Dahlén, Eva; Barchan, Karin; Herrlander, Daniel; Höjman, Patrik; Karlsson, Marie; Ljung, Lill; Andersson, Mats; Bäckman, Eva; Hager, Ann-Christin Malmborg; Walse, Björn; Joosten, Leo; van den Berg, Wim

    2008-04-01

    Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic

  14. Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

    PubMed Central

    Schultz, Heidi S.; Nitze, Louise M.; Zeuthen, Louise H.; Keller, Pernille; Gruhler, Albrecht; Pass, Jesper; Chen, Jianhe; Guo, Li; Fleetwood, Andrew J.; Hamilton, John A.; Berchtold, Martin W.

    2015-01-01

    Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs. PMID:25725106

  15. Interleukin-10 attenuation of collagen-induced arthritis is associated with suppression of interleukin-17 and retinoid-related orphan receptor γt production in macrophages and repression of classically activated macrophages.

    PubMed

    Ye, Liang; Wen, Zhongyang; Li, Yanqun; Chen, Bingni; Yu, Ting; Liu, Lanying; Zhang, Jinshun; Ma, Yanmei; Xiao, Shuying; Ding, Liping; Li, Li; Huang, Zhong

    2014-04-16

    Our objective in the present study was to determine the signaling pathway of interleukin 10 (IL-10) for modulating IL-17 expression in macrophages and the importance of this mediation in collagen-induced arthritis (CIA). IL-10-knockout (IL-10⁻/⁻) mice and wild-type (WT) mice were immunized with chicken type II collagen (CII) to induce arthritis. The expression levels of IL-17 and retinoid-related orphan receptor γt (RORγt) in macrophages and joint tissues of IL-10⁻/⁻ and WT mice were analyzed by enzyme-linked immunosorbent assay, quantitative RT-PCR (qRT-PCR) and Western blotting. The F4/80 macrophages and positive IL-17-producing macrophages in synovial tissues of the mice were determined by immunohistochemistry. The populations of classically activated macrophage (M1) and alternatively activated macrophage (M2) phenotypes were analyzed by flow cytometry. The expression of genes associated with M1 and M2 markers was analyzed by qRT-PCR. Compared to WT mice, IL-10⁻/⁻ mice had exacerbated CIA development, which was associated with increased production of T helper 17 cell (Th17)/Th1 proinflammatory cytokines and CII-specific immunoglobulin G2a antibody after CII immunization. Macrophages in IL-10⁻/⁻ mice had increased amounts of IL-17 and RORγt compared with the amounts in WT mice with CIA. Immunofluorescence microscopy showed that the number of IL-17-producing macrophages in synovial tissues was significantly higher in IL-10⁻/⁻ mice than in WT mice. IL-10 deficiency might promote macrophage polarization toward the proinflammatory M1 phenotype, which contributes to the rheumatoid arthritis inflammation response. IL-10 inhibits IL-17 and RORγt expression in macrophages and suppresses macrophages toward the proinflammatory M1 phenotype, which is important for the role of IL-10 in mediating the pathogenesis of CIA.

  16. TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice

    PubMed Central

    Zhuang, Chenchen; Hong, Xuezhi; Liu, Jia; Luo, Xiaohong; Mo, Hanyou

    2017-01-01

    The study aimed to investigate the relationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and a differentially mature dendritic cell (mDC) in collagen-induced arthritis (CIA) mice and to determine whether or not TRAF6 regulates the activation of an immature dendritic cell (iDC) and inhibits iDC maturation to induce immune tolerance. The mouse bone marrow stem cells were induced with recombinant granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and recombinant interleukin-4 (rmIL-4) to differentiate immature dendritic cells (DCs), which were divided into four groups with different maturation states: rmGM-CSF, rmIL-4; TNF-α; LPS; and FK506 group. The levels of the cell surfaces of CD80, CD86, and MHI-II were analyzed by flow cytometry to prove DCs at different levels of maturity. The expression of IL-12 in DCs at different maturation states was detected by enzyme-linked immunosorbent assay (ELISA). The expression of TRAF6 mRNA and protein in each group of DCs was detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. The results revealed that the differentiation of bone marrow cells into iDCs was significantly induced by cytokines (rmGM-CSF, IL-4). CD80, CD86, MHC-II were expressed in the four groups, and the difference between them was statistically significant (P<0.05). A higher degree of DC differentiation led to a gradual increase of IL-12 secretion in the four groups. The difference was statistically significant (P<0.05) for this secretion (group D, 10,620.73±276.73 pg/ml). The expression levels of TRAF6 mRNA were significantly higher in group D than those in the other three groups (P<0.01). Although there was no significant difference in the expression levels of TRAF6 mRNA between groups B and C, the expression levels of TRAF6 mRNA between groups B and C were higher than those of the control group. The TRAF6 protein expression was higher in group D than that in the other three

  17. Evaluation of humoral and cellular immune responses to a DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats.

    PubMed

    Xiao, Zhao; Juan, Long; Song, Yun; Zhijian, Zhang; Jing, Jin; Kun, Yu; Yuna, Hao; Dongfa, Dai; Lili, Ding; Liuxin, Tan; Fei, Liang; Nan, Liu; Fang, Yuan; Yuying, Sun; Yongzhi, Xi

    2015-01-01

    A major challenge in the development of effective therapies for rheumatoid arthritis (RA) is finding a method for the specific inhibition of the inflammatory disease processes without the induction of generalized immunosuppression. Of note, the development of therapeutic DNA vaccines and boosters that may restore immunological tolerance remains a high priority. pcDNA-CCOL2A1 is a therapeutic DNA vaccine encoding chicken type II collagen(CCII). This vaccine was developed by our laboratory and has been shown to exhibit efficacy comparable to that of the current "gold standard" treatment, methotrexate (MTX). Here, we used enzyme-linked immunosorbent assays with anti-CII IgG antibodies, quantified the expression levels of Th1, Th2, and Th3 cytokines, and performed flow cytometric analyses of different T-cell subsets, including Th1, Th2, Th17, Tc, Ts, Treg, and CD4(+)CD29(+)T cells to systemically evaluate humoral and cellular immune responses to pcDNA-CCOL2A1 vaccine in normal rats. Similar to our observations at maximum dosage of 3 mg/kg, vaccination of normal rats with 300 μg/kg pcDNA-CCOL2A1 vaccine did not induce the production of anti-CII IgG. Furthermore, no significant changes were observed in the expression levels of pro-inflammatory cytokines interleukin (IL)-1α, IL-5, IL-6, IL-12(IL-23p40), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, regulated on activation in normal T-cell expressed and secreted (RANTES), receptor activator for nuclear factor-κB ligand (RANKL), and granulocyte colony-stimulating factor (G-CSF) or anti-inflammatory cytokines IL-4 and IL-10 in vaccinated normal rats relative to that in controls(P > 0.05). However, transforming growth factor (TGF)-β levels were significantly increased on days 10 and 14, while interferon (IFN)-γ and tumor necrosis factor (TNF)-α levels were significantly decreased on days 28 and 35 after vaccination(P < 0.05). Similarly, there were no significant differences in the

  18. Evaluation of humoral and cellular immune responses to a DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in normal rats

    PubMed Central

    Xiao, Zhao; Juan, Long; Song, Yun; Zhijian, Zhang; Jing, Jin; Kun, Yu; Yuna, Hao; Dongfa, Dai; Lili, Ding; Liuxin, Tan; Fei, Liang; Nan, Liu; Fang, Yuan; Yuying, Sun; Yongzhi, Xi

    2015-01-01

    A major challenge in the development of effective therapies for rheumatoid arthritis (RA) is finding a method for the specific inhibition of the inflammatory disease processes without the induction of generalized immunosuppression. Of note, the development of therapeutic DNA vaccines and boosters that may restore immunological tolerance remains a high priority. pcDNA-CCOL2A1 is a therapeutic DNA vaccine encoding chicken type II collagen(CCII). This vaccine was developed by our laboratory and has been shown to exhibit efficacy comparable to that of the current “gold standard” treatment, methotrexate (MTX). Here, we used enzyme-linked immunosorbent assays with anti-CII IgG antibodies, quantified the expression levels of Th1, Th2, and Th3 cytokines, and performed flow cytometric analyses of different T-cell subsets, including Th1, Th2, Th17, Tc, Ts, Treg, and CD4+CD29+T cells to systemically evaluate humoral and cellular immune responses to pcDNA-CCOL2A1 vaccine in normal rats. Similar to our observations at maximum dosage of 3 mg/kg, vaccination of normal rats with 300 μg/kg pcDNA-CCOL2A1 vaccine did not induce the production of anti-CII IgG. Furthermore, no significant changes were observed in the expression levels of pro-inflammatory cytokines interleukin (IL)-1α, IL-5, IL-6, IL-12(IL-23p40), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, regulated on activation in normal T-cell expressed and secreted (RANTES), receptor activator for nuclear factor-κB ligand (RANKL), and granulocyte colony-stimulating factor (G-CSF) or anti-inflammatory cytokines IL-4 and IL-10 in vaccinated normal rats relative to that in controls(P > 0.05). However, transforming growth factor (TGF)-β levels were significantly increased on days 10 and 14, while interferon (IFN)-γ and tumor necrosis factor (TNF)-α levels were significantly decreased on days 28 and 35 after vaccination(P < 0.05). Similarly, there were no significant differences in the

  19. Psoriatic Arthritis

    MedlinePlus

    ... A Patient / Caregiver Diseases & Conditions Psoriatic Arthritis Psoriatic Arthritis Fast Facts Psoriatic arthritis is a chronic arthritis. ... appear before the skin disorder. What is psoriatic arthritis? Psoriasis is a disease in which scaly red ...

  20. Arthritis - resources

    MedlinePlus

    Resources - arthritis ... The following organizations provide more information on arthritis : American Academy of Orthopaedic Surgeons -- orthoinfo.aaos.org/menus/arthritis.cfm Arthritis Foundation -- www.arthritis.org Centers for Disease Control and Prevention -- www. ...

  1. Juvenile Arthritis

    MedlinePlus

    ... A Patient / Caregiver Diseases & Conditions Juvenile Arthritis Juvenile Arthritis Fast Facts Arthritis in children is treatable. It ... as fevers or rash. What is juvenile idiopathic arthritis? Several types of arthritis, all involving chronic (long- ...

  2. A novel JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl(2,6-dichlorophenyl)acetate, suppresses helper T cell differentiation in vitro and collagen-induced arthritis in vivo.

    PubMed

    Asakawa, Mayako; Yoshida, Hideyuki; Sakai, Ryota; Saeki, Keita; Okada, Masahiro; Kanamori, Mitsuhiro; Kotani, Hitoshi; Wei, Xuetao; Yoshimura, Akihiko

    2015-12-25

    Th17 cells, which have been implicated in autoimmune diseases including rheumatoid arthritis (RA), require the JAK-STAT3 pathway for their differentiation and functions. Recently, JAK inhibitors have been developed as a therapeutic drug for RA. However, the current JAK inhibitors are not optimized to STAT3 compared with other STATs. In this study, we found a new lead compound of a small molecule JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl (2,6-dichlorophenyl)acetate, which inhibits STAT3 as efficiently as other STATs. This compound, named JI069, was selected by STAT3 reporter assay in combination with an in silico docking model. JI069 inhibited gp130 signaling by inducing dissociation between gp130 and JAK1. In HEK293T cells and primary T cells, JI069 suppressed STAT3 activation as efficiently as other STATs, including STAT1, STAT5, and STAT6. JI069 effectively suppressed Th1, Th2, and Th17 differentiation while strongly promoted iTreg differentiation. JI069 suppressed symptoms of the collagen-induced arthritis (CIA) model in mice, and inhibited the cytokine production from T cells as well as the STAT3 phosphorylation of synovial cells. These data suggest that JI069 is a new type of JAK inhibitor which has potential for the treatment of immunological disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA).

    PubMed

    Berntson, Lillemor; Nordal, Ellen; Fasth, Anders; Aalto, Kristiina; Herlin, Troels; Nielsen, Susan; Rygg, Marite; Zak, Marek; Rönnelid, Johan

    2014-01-01

    Early appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA). The Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage. Elevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up. Anti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied.

  4. Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.

    PubMed

    Sakurada, Takumi; Ishizawa, Keisuke; Imanishi, Masaki; Izawa-Ishizawa, Yuki; Fujii, Shoko; Tominaga, Erika; Tsuneishi, Teppei; Horinouchi, Yuya; Kihira, Yoshitaka; Ikeda, Yasumasa; Tomita, Shuhei; Aihara, Ken-ichi; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2013-01-01

    Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22(phox), CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca(2+) increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.

  5. Interleukin-10 attenuation of collagen-induced arthritis is associated with suppression of interleukin-17 and retinoid-related orphan receptor γt production in macrophages and repression of classically activated macrophages

    PubMed Central

    2014-01-01

    Introduction Our objective in the present study was to determine the signaling pathway of interleukin 10 (IL-10) for modulating IL-17 expression in macrophages and the importance of this mediation in collagen-induced arthritis (CIA). Methods IL-10-knockout (IL-10−/−) mice and wild-type (WT) mice were immunized with chicken type II collagen (CII) to induce arthritis. The expression levels of IL-17 and retinoid-related orphan receptor γt (RORγt) in macrophages and joint tissues of IL-10−/− and WT mice were analyzed by enzyme-linked immunosorbent assay, quantitative RT-PCR (qRT-PCR) and Western blotting. The F4/80 macrophages and positive IL-17-producing macrophages in synovial tissues of the mice were determined by immunohistochemistry. The populations of classically activated macrophage (M1) and alternatively activated macrophage (M2) phenotypes were analyzed by flow cytometry. The expression of genes associated with M1 and M2 markers was analyzed by qRT-PCR. Results Compared to WT mice, IL-10−/− mice had exacerbated CIA development, which was associated with increased production of T helper 17 cell (Th17)/Th1 proinflammatory cytokines and CII-specific immunoglobulin G2a antibody after CII immunization. Macrophages in IL-10−/− mice had increased amounts of IL-17 and RORγt compared with the amounts in WT mice with CIA. Immunofluorescence microscopy showed that the number of IL-17-producing macrophages in synovial tissues was significantly higher in IL-10−/− mice than in WT mice. IL-10 deficiency might promote macrophage polarization toward the proinflammatory M1 phenotype, which contributes to the rheumatoid arthritis inflammation response. Conclusion IL-10 inhibits IL-17 and RORγt expression in macrophages and suppresses macrophages toward the proinflammatory M1 phenotype, which is important for the role of IL-10 in mediating the pathogenesis of CIA. PMID:24742125

  6. Mouse Models of Rheumatoid Arthritis.

    PubMed

    Caplazi, P; Baca, M; Barck, K; Carano, R A D; DeVoss, J; Lee, W P; Bolon, B; Diehl, L

    2015-09-01

    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.

  7. Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.

    PubMed

    Bai, Jian; Zhang, Na; Hua, Ying; Wang, Bingjian; Ling, Lin; Ferro, Albert; Xu, Biao

    2013-01-01

    Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM) in the presence or absence of metformin (10-200 µM). Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA) and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS) generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.

  8. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

    PubMed

    Galán, María; Varona, Saray; Guadall, Anna; Orriols, Mar; Navas, Miquel; Aguiló, Silvia; de Diego, Alicia; Navarro, María A; García-Dorado, David; Rodríguez-Sinovas, Antonio; Martínez-González, José; Rodriguez, Cristina

    2017-09-01

    Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H2O2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy. © FASEB.

  9. Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA)

    PubMed Central

    2014-01-01

    Background Early appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA). Methods The Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage. Results Elevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up. Conclusions Anti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied. PMID:24944545

  10. Cleavage of denatured natural collagen type II by neutrophil gelatinase B reveals enzyme specificity, post-translational modifications in the substrate, and the formation of remnant epitopes in rheumatoid arthritis.

    PubMed

    Van den Steen, Philippe E; Proost, Paul; Grillet, Bernard; Brand, David D; Kang, Andrew H; Van Damme, Jo; Opdenakker, Ghislain

    2002-03-01

    During acute inflammation, leukocytes release proteolytic enzymes including matrix metalloproteinases (MMPs), but the physiopathological mechanisms and consequences of this process are not yet fully understood. Neutrophils, the predominant leukocyte type, produce neutrophil collagenase (MMP-8) and gelatinase B (MMP-9) but not the tissue inhibitors of MMPs. After stimulation, these cells also activate MMPs chemically. In arthritic diseases, neutrophils undergo great chemoattraction to the synovium, are activated by interleukin-8, and are stimulated to release gelatinase B in vivo. Production levels and net activities of gelatinase B were found to be absent in degenerative osteoarthritis but significantly increased in rheumatoid arthritis. The cleavage sites in cartilage type II collagen by gelatinase B were determined by a combination of reverse phase high-performance liquid chromatography, Edman degradation, and mass spectrometry analysis. The analysis revealed the site specificity of proline and lysine hydroxylations and O-linked glycosylation, the cleavage specificities by gelatinase B, and the preferential absence and presence of post-translational modifications at P2' and P5', respectively. Furthermore, gelatinase B leaves the immunodominant peptides intact, which are known from studies with (autoreactive) T cells. Lysine hydroxylation was detected at a critical position for T-cell activation. These data lend support to the thesis that extracellular proteolysis and other post-translational modifications of antigenic peptides may be critical in the establishment and perpetuation of autoimmune processes.

  11. Combination of MTX and LEF attenuates inflammatory bone erosion by down-regulation of receptor activator of NF-kB ligand and interleukin-17 in type II collagen-induced arthritis rats.

    PubMed

    Yao, Yao; Ding, Cong-zhu; Fang, Yun

    2013-07-01

    The objectives of this study were to determine the effect of combination of methotrexate (MTX) and leflunomide (LEF) on type II collagen-induced arthritis rats and its mechanism. Curative effect was confirmed on CIA rats, which were randomized and divided into model, MTX, LEF and MTX + LEF group. Weights and joint swelling scores of rats were recorded. Interleukin (IL)-17, receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) concentration in serum were determined by ELISA. H&E dyeing of joint was used to estimate the inflammation and osteoclasia extent. The mechanism was investigated through fibroblast-like synoviocytes isolated from RA patients. The effect of MTX and LEF on cell viability, and RANKL and OPG expression were indicated through MTT and RT-PCR analysis, respectively. Combination therapy would be effective in treating CIA rats. Joint swelling scores and IL-17 and RANKL level in serum were decreased obviously (P < 0.05), while OPG level was elevated (P < 0.05). Anti-inflammatory and anti-osteoclasia effect would be indicated by H&E dyeing results. Moreover, FLS cell viability was inhibited by combination treatment in vitro (P < 0.05), and expression of osteoclasia-related genes (RANKL and OPG) was modified (P < 0.05). Combination therapy would relive the synovium hypertrophy through depressing cell viability and osteoclasia through decreasing RANKL and increasing OPG expression. Otherwise, combination was superior to monotherapy.

  12. Near-infrared fluorescence imaging of experimentally collagen-induced arthritis in rats using the nonspecific dye tetrasulfocyanine in comparison with gadolinium-based contrast-enhanced magnetic resonance imaging, histology, and clinical score

    NASA Astrophysics Data System (ADS)

    Gemeinhardt, Ines; Puls, Dorothee; Gemeinhardt, Ole; Taupitz, Matthias; Wagner, Susanne; Schnorr, Beatrix; Licha, Kai; Schirner, Michael; Ebert, Bernd; Petzelt, Diethard; Macdonald, Rainer; Schnorr, Jörg

    2012-10-01

    Using 15 rats with collagen-induced arthritis (30 joints) and 7 control rats (14 joints), we correlated the intensity of near-infrared fluorescence (NIRF) of the nonspecific dye tetrasulfocyanine (TSC) with magnetic resonance imaging (MRI), histopathology, and clinical score. Fluorescence images were obtained in reflection geometry using a NIRF camera system. Normalized fluorescence intensity (INF) was determined after intravenous dye administration on different time points up to 120 min. Contrast-enhanced MRI using gadodiamide was performed after NIRF imaging. Analyses were performed in a blinded fashion. Histopathological and clinical scores were determined for each ankle joint. INF of moderate and high-grade arthritic joints were significantly higher (p<0.005) than the values of control and low-grade arthritic joints between 5 and 30 min after TSC-injection. This result correlated well with post-contrast MRI signal intensities at about 5 min after gadodiamide administration. Furthermore, INF and signal increase on contrast-enhanced MRI showed high correlation with clinical and histopathological scores. Sensitivities and specificities for detection of moderate and high-grade arthritic joints were slightly lower for NIRF imaging (89%/81%) than for MRI (100%/91%). NIRF imaging using TSC, which is characterized by slower plasma clearance compared to indocyanine green (ICG), has the potential to improve monitoring of inflamed joints.

  13. Grape seed proanthocyanidin extract has potent anti-arthritic effects on collagen-induced arthritis by modifying the T cell balance.

    PubMed

    Ahmad, Sheikh Fayaz; Zoheir, Khairy M A; Abdel-Hamied, Hala E; Ashour, Abdelkader E; Bakheet, Saleh A; Attia, Sabry M; Abd-Allah, Adel R A

    2013-09-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation of the synovial joints, joint malformations, and disability. The continuous use of conventional anti-inflammatory drugs is associated with severe adverse effects. Grape seed proanthocyanidin extract (GSPE) is considered to have protective effects against several diseases. In this study based on the mouse adjuvant-induced-arthritis (AIA) model, we examined the effects of GSPE on the key mediators of arthritic inflammation, namely T cell subsets, glucocorticoid-induced tumour necrosis factor receptor (GITR) expressing cells, CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, Th17 cells, Th1/Th2 cytokines, and inflammatory mediator gene expression. We treated BALB/c mice with 25, 50, or 100 mg/kg GSPE or saline daily (14 days) per orally (p.o.) at the onset of AIA. At the peak phase of AIA (day 14), the heparinised whole blood and ankle joints of all groups were collected and tested. GSPE-treated mice showed a substantial reduction in the levels of T cell subsets, GITR-expressing cells, and Th1 cytokines as well as the inflammatory mediators (MCP-1, MIP-2, and ICAM-1) that induce them compared with the vehicle-treated (saline) and arthritic mice. However, GSPE significantly upregulated the number of Tregs and Th2 cytokine producing cell number or it also induced Th17/Treg rebalance and orchestrated various pro-inflammatory and anti-inflammatory cytokines and the gene expression of their mediators that mediate cellular infiltration into the joints. This might, contribute to its anti-arthritic activity. Our results suggest that p.o. treatment with GSPE attenuated AIA in mice might offer a promising alternative/adjunct treatment for RA.

  14. Gonococcal arthritis

    MedlinePlus

    Disseminated gonococcal infection (DGI); Disseminated gonococcemia; Septic arthritis - gonococcal arthritis ... Gonococcal arthritis is an infection of a joint. It occurs in people who have gonorrhea , which is caused by ...

  15. Viral arthritis

    MedlinePlus

    Infectious arthritis - viral ... Arthritis may be a symptom of many virus-related illnesses. It usually disappears on its own without ... the rubella vaccine, only a few people develop arthritis. No risk factors are known.

  16. Rheumatoid Arthritis

    MedlinePlus

    Rheumatoid arthritis (RA) is a form of arthritis that causes pain, swelling, stiffness and loss of function in ... wrist and fingers. More women than men get rheumatoid arthritis. It often starts in middle age and is ...

  17. Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys

    PubMed Central

    Brok, H P M; Tekoppele, J M; Hakimi, J; Kerwin, J A; Nijenhuis, E M; De Groot, C W; Bontrop, R E; ‘T Hart, B A

    2001-01-01

    CIA in the rhesus monkey is an autoimmune-based polyarthritis with inflammation and erosion of synovial joints that shares various features with human rheumatoid arthritis (RA). The close phylogenetic relationship between man and rhesus monkey makes the model very suitable for preclinical safety and efficacy testing of new therapeutics with exclusive reactivity in primates. In this study we have investigated the prophylactic and therapeutic effects of a humanized monoclonal antibody (Daclizumab) against the α-chain of the IL-2 receptor (CD25). When Daclizumab treatment was started well after immunization but before the expected onset of CIA a significant reduction of joint-inflammation and joint-erosion was observed. A therapeutic treatment, initiated as soon as the first clinical signs of CIA were observed, proved also effective since joint-degradation was abrogated. The results of this study indicate that Daclizumab has clinical potential for the treatment of RA during periods of active inflammation and suppression of the destruction of the joint tissues. PMID:11359452

  18. Differentiated all-trans retinoic acid response of naive CD4+CD25– cells isolated from rats with collagen-induced arthritis and healthy ones under in vitro conditions

    PubMed Central

    Żyromska, Edyta; Piasecki, Tomasz; Rossowska, Joanna; Kędzierska, Anna; Nowak, Marcin; Żyromski, Marcin; Chełmońska-Soyta, Anna

    2017-01-01

    Aim o the study To compare the potential of CD4+CD25– cells, isolated from both healthy rats and rats with CIA (Collagen-Induced Arthritis), for differentiation into regulatory T cells in the presence of all-trans retinoic acid in order to learn more about the activation mechanisms and therapeutic potential of regulatory T cells. Material and methods Sorted CD4+CD25– cells were cultured in vitro with/without ATRA, and then the frequency of regulatory T cells and their ability to secrete IL-10 by CD4+ FOXP3+ cells was examined. Gene expression of the foxp3, rarα, rarβ, rxrβ, and ppar β/δ and protein expression of the Rarα, Rarβ, and Rxrβ in cells after stimulation with ATRA were also investigated. Results CD4+CD25– cells isolated from healthy animals or from animals with CIA are characterised by different potential of the differentiation into CD4+CD25+ FOXP3+ cells. Retinoic acid receptor Rxrβ is present in the CD4+CD25– cells isolated from rats with CIA. Conclusions We showed that although ATRA did not increase the frequency of Treg in culture, it significantly increased expression of rarβ and rxrβ only in lymphocytes taken from diseased animals and foxp3 expression only in healthy animals. Moreover, after ATRA stimulation, the frequency of Treg-produced IL-10 tended to be lower in diseased animals than in the healthy group. The results imply that the potential of naïve cell CD4 lymphocytes to differentiate into Tregs and their putative suppressive function is dependent on the donor’s health status. PMID:28680330

  19. Juvenile Arthritis

    MedlinePlus

    Juvenile arthritis (JA) is arthritis that happens in children. It causes joint swelling, pain, stiffness, and loss of motion. It can affect any joint, but ... of JA that children get is juvenile idiopathic arthritis. There are several other forms of arthritis affecting ...

  20. Psoriatic arthritis

    SciTech Connect

    Gerber, L.H.; Espinoza, L.R.

    1985-01-01

    This book contains 11 chapters. Some of the titles are: The history and epidemiologic definition of psoriatic arthritis as a distinct entity; Psoriatic arthritis: Further epidemiologic and genetic considerations; The radiologic features of psoriatic arthritis; and Laboratory findings and pathology of psoriatic arthritis.

  1. A Comparison of the Anti-Inflammatory Effects of Cis-9, Trans-11 Conjugated Linoleic Acid to Celecoxib in the Collagen-Induced Arthritis Model.

    PubMed

    Olson, Jake M; Haas, Alexander W; Lor, Jennifer; McKee, Holly S; Cook, Mark E

    2017-02-01

    Cyclooxygenase (COX)-2 inhibitors, such as celecoxib, for chronic inflammatory disease are associated with adverse health events, while cis-9, trans-11 (c9t11) conjugated linoleic acid (CLA) is anti-inflammatory without adverse events attributed to pure intake. Mechanistically, celecoxib and c9t11 disrupt the arachidonic acid cascade; however, the equivalency of anti-inflammatory effects between these compounds is unknown. Therefore, to test the hypothesis that 0.5% dietary c9t11 reduces inflammation equivalently to a celecoxib dose intended to treat rheumatoid arthritis (RA; 5 mg/kg bw), arthritic mice received diets containing one of the following supplements: 1% corn oil (CO, w/w), 0.5% c9t11 (>91% purity) +0.5% CO, or 1% CO + 0.5, 5, or 50 mg/kg bw celecoxib, and were assessed for changes in arthritic severity over 6 weeks. Overall, arthritic severity in mice fed c9t11 was reduced (34%, P < 0.01) while celecoxib doses (0.5, 5, 50 mg/kg) reduced arthritic severity (16, 56, 48%, respectively) compared to CO-fed arthritic mice. Linear regression of the celecoxib dose-response showed 0.5% c9t11 (570 mg/kg bw) reduced arthritic severity equivalently to 1.5 mg/kg celecoxib. Interleukin-6 (IL-6) was increased in paws of arthritic mice fed CO compared to shams, but was decreased in arthritic groups fed 0.5% c9t11 and 5 mg/kg celecoxib, compared to arthritic mice fed CO (Ps ≤ 0.05). Additionally, paw and plasma IL-10 levels in arthritic mice were decreased by 5 mg/kg celecoxib, but were unaffected by c9t11 compared to CO. Results suggest dietary c9t11 may be an effective adjunct to COX-2 inhibition for treating chronic inflammation.

  2. Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

    PubMed

    Cui, Mingli; Cai, Zhaohua; Chu, Shichun; Sun, Zhe; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2016-01-01

    Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. © 2015 American Heart Association, Inc.

  3. Imaging Prostate Cancer Microenvironment by Collagen Hybridization

    DTIC Science & Technology

    2015-10-01

    undergoing normal (e.g. skeleton) and pathological (arthritis) remodeling. 2. Demonstration of the use of CMP as collagen staining agent in SDS-PAGE gel...goal of the proposed project; however musculoskeletal injuries are the number one medical issue for the DOD when it comes to encounters and...CMP can be used to detect mechanical damage to collagen in tendon which could be used for diagnostic and therapeutics of musculoskeletal injury which

  4. Bioengineered collagens

    PubMed Central

    Ramshaw, John AM; Werkmeister, Jerome A; Dumsday, Geoff J

    2014-01-01

    Mammalian collagen has been widely used as a biomedical material. Nevertheless, there are still concerns about the variability between preparations, particularly with the possibility that the products may transmit animal-based diseases. Many groups have examined the possible application of bioengineered mammalian collagens. However, translating laboratory studies into large-scale manufacturing has often proved difficult, although certain yeast and plant systems seem effective. Production of full-length mammalian collagens, with the required secondary modification to give proline hydroxylation, has proved difficult in E. coli. However, recently, a new group of collagens, which have the characteristic triple helical structure of collagen, has been identified in bacteria. These proteins are stable without the need for hydroxyproline and are able to be produced and purified from E. coli in high yield. Initial studies indicate that they would be suitable for biomedical applications. PMID:24717980

  5. TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis.

    PubMed

    Duerrschmid, Clemens; Crawford, Jeffrey R; Reineke, Erin; Taffet, George E; Trial, Joann; Entman, Mark L; Haudek, Sandra B

    2013-04-01

    Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart.

  6. Angiotensin-II Induced Hypertension and Renovascular Remodeling in TIMP2 Knockout Mice

    PubMed Central

    PUSHPAKUMAR, Sathnur; KUNDU, Sourav; PRYOR, Tyranny; GIVVIMANI, Srikanth; LEDERER, Eleanor; TYAGI, Suresh C.; SEN, Utpal

    2014-01-01

    Sustained hypertension induces renovascular remodeling by altering extracellular matrix (ECM) components. Matrix metalloproteinases (MMPs) are Zn-dependent enzymes that regulate ECM turnover in concert with their inhibitors, tissue inhibitors of metalloproteinases, TIMPs. Increased MMP-2 & -9 have been implicated in hypertensive complications; however, the contribution of individual MMPs/TIMPs in renal remodeling has not been fully elucidated. The purpose of this study was to determine the effect of TIMP2 deficiency and thus MMP-2 on Ang-II induced renal remodeling. C57BL/6J (WT) and TIMP2 knockout mice were infused with Angiotensin-II (Ang-II) at 250 ng. kg-1. min-1 for 4 weeks. Blood pressure was measured weekly and end-point laser Doppler flowmetry was done to assess cortical blood flow. Immunohistochemical staining was performed for collagen and elastin analyses. The activity of MMP-9, and -2 was determined by Gelatin zymography. Ang-II induced similar elevation in mean blood pressure in TIMP2-/- and WT mice. In TIMP2-/- mice, Ang-II treatment was associated with a greater reduction in renal cortical blood flow and barium angiography demonstrated decreased vascular density compared to Ang-II treated WT mice. Peri-glomerular and vascular collagen deposition was increased and elastin content was decreased causing increased wall-to-lumen ratio in TIMP2-/- mice compared to WT mice receiving Ang-II. Ang-II increased the expression and activity of MMP-9 predominantly in TIMP2-/- mice than in WT mice. These results suggest that TIMP2 deficiency exacerbates renovascular remodeling in agonist induced hypertension by a mechanism which may, in part, be attributed to increased activity of MMP-9. PMID:24077247

  7. Interleukin-10 deficiency aggravates angiotensin II-induced cardiac remodeling in mice.

    PubMed

    Kwon, Woo-Young; Cha, Hye-Na; Heo, Jung-Yoon; Choi, Jung-Hyun; Jang, Byung Ik; Lee, In-Kye; Park, So-Young

    2016-02-01

    This study examined the role of interleukin (IL)-10 in angiotensin II-induced cardiac remodeling. Angiotensin II was infused subcutaneously (1.1mg/kg/day) for one week in IL-10 knockout and wild-type mice, after which cardiac function and hypertrophy were assessed by echocardiogram. IL-10 gene expression in the heart was increased by angiotensin II infusion. Plasma levels of brain natriuretic peptide (BNP) and gene expression of BNP in the heart were increased by IL-10 deficiency or angiotensin II, and plasma BNP levels were further increased by IL-10 deficiency with angiotensin II. IL-10 deficiency increased the left ventricular dimension, whereas treatment with angiotensin II increased heart weight. Angiotensin II significantly reduced cardiac function in IL-10 knockout mice compared with wild-type mice. Gene expression of tumor necrosis factor-α and interleukin-6 was increased by IL-10 deficiency or angiotensin II infusion, and these increases were further enhanced by IL-10 deficiency with angiotensin II. Gene expression of collagen I/III and collagen III protein levels were increased by angiotensin II but not by IL-10 deficiency. Gene expression of matrix metalloproteinase2/9 was increased by IL-10 deficiency or angiotensin II, and this expression was further increased by IL-10 deficiency with angiotensin II. Akt phosphorylation was increased by IL-10 deficiency or angiotensin II and further increased by IL-10 deficiency with angiotensin II. Phosphorylation of p38 was increased by IL-10 deficiency. These results suggest that IL-10 deficiency causes deterioration in cardiac functions in angiotensin II-infused mice, suggesting that IL-10 plays a protective role against angiotensin II-induced cardiac remodeling. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Angiotensin II induces apoptosis in renal proximal tubular cells.

    PubMed

    Bhaskaran, Madhu; Reddy, Krishna; Radhakrishanan, Neetu; Franki, Nicholas; Ding, Guohua; Singhal, Pravin C

    2003-05-01

    ANG II has been demonstrated to play a role in the progression of tubulointerstial injury. We studied the direct effect of ANG II on apoptosis of cultured rat renal proximal tubular epithelial cells (RPTECs). ANG II promoted RPTEC apoptosis in a dose- and time-dependent manner. This effect of ANG II was attenuated by anti-transforming growth factor (TGF)-beta antibody. Moreover, TGF-beta triggered RPTEC apoptosis in a dose-dependent manner. ANG II also enhanced RPTEC expression of Fas and Fas ligand (FasL); furthermore, anti-FasL antibody attenuated ANG II-induced RPTEC apoptosis. In addition, ANG II increased RPTEC expression of Bax, a cell death protein. Both ANG II type 1 (AT(1)) and type 2 (AT(2)) receptor blockers inhibited ANG II-induced RPTEC apoptosis. SB-202190, an inhibitor of p38 MAPK phosphorylation, and caspase-3 inhibitor also attenuated ANG II-induced RPTEC apoptosis. ANG II enhanced RPTEC heme oxygenase (HO)-1 expression. Interestingly, pretreatment with hemin as well as curcumin (inducers of HO-1) inhibited the ANG II-induced tubular cell apoptosis; conversely, pretreatment with zinc protoporphyrin, an inhibitor of HO-1 expression, promoted the effect of ANG II. These results suggest that ANG II-induced apoptosis is mediated via both AT(1) and AT(2) receptors through the generation of TGF-beta, followed by the transcription of cell death genes such as Fas, FasL, and Bax. Modulation of tubular cell expression of HO-1 has an inverse relationship with the ANG II-induced tubular cell apoptosis.

  9. Infectious Arthritis

    MedlinePlus

    Most kinds of arthritis cause pain and swelling in your joints. Joints are places where two bones meet, such as your elbow or knee. Infectious arthritis is an infection in the joint. The infection ...

  10. Thumb Arthritis

    MedlinePlus

    ... Media Find a Hand Surgeon Home Anatomy Thumb Arthritis Email to a friend * required fields From * To * ... A joint is where bones connect and move. Arthritis is thinning of the cartilage, which is the ...

  11. Rheumatoid arthritis

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000431.htm Rheumatoid arthritis To use the sharing features on this page, please enable JavaScript. Rheumatoid arthritis (RA) is a long-term disease. It leads ...

  12. Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling

    PubMed Central

    ZHANG, Hangxiang; Wu, Jing; DONG, Hailong; KHAN, Shaukat A.; CHU, Mon-Li; TSUDA, Takeshi

    2014-01-01

    AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2−/− ), heterozygous (Fbln2+/− ) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2−/− showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2−/− mice. The Fbln2+/− mice consistently displayed AngII-induced effects intermediate between WT and Fbln2−/− . Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2−/− mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2−/− cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac

  13. Rheumatoid Arthritis

    MedlinePlus

    ... men. About two to three times as many women as men have the disease. Living with Rheumatoid Arthritis Video length: 2 min 54 sec Click to watch this video Learn more about how rheumatoid arthritis occurs. Effects Vary Rheumatoid arthritis affects people differently. Some people ...

  14. Modulation of autoimmune arthritis severity in mice by apolipoprotein E (ApoE) and cholesterol.

    PubMed

    Alvarez, P; Genre, F; Iglesias, M; Augustin, J J; Tamayo, E; Escolà-Gil, J C; Lavín, B; Blanco-Vaca, F; Merino, R; Merino, J

    2016-12-01

    Apolipoprotein E (ApoE) deficiency promoted an exacerbation of autoimmune arthritis in mice by inducing proinflammatory immune responses. In this study we analysed the contribution of hypercholesterolaemia and/or the absence of ApoE anti-inflammatory properties, unrelated to its function in the control of cholesterol metabolism, towards the acceleration of arthritis in these mutant animals. The induction and severity of collagen type II-induced arthritis (CIA) were compared for B10.RIII wild-type (WT), B10.RIII.ApoE(+/-) , B10.RIII.ApoE(-/-) and B10.RIII.low-density lipoprotein receptor (LDLR(-/-) ) mice with different concentrations of circulating ApoE and cholesterol. A 50-70% reduction in serum levels of ApoE was observed in heterozygous B10.RIII.ApoE(+/-) mice in comparison to B10.RIII.WT, although both strains of mice exhibited similar circulating lipid profiles. This ApoE reduction was associated with an increased CIA severity that remained lower than in homozygous B10.RIII.ApoE(-/-) mice. An important rise in circulating ApoE concentration was observed in hypercholesterolaemic B10.RIII.LDLR(-/-) mice fed with a normal chow diet, and both parameters increased further with an atherogenic hypercholesterolaemic diet. However, the severity of CIA in B10.RIII.LDLR(-/-) mice was similar to that of B10.RIII.WT controls. In conclusion, by comparing the evolution of CIA between several strains of mutant mice with different levels of serum ApoE and cholesterol, our results demonstrate that both hypercholesterolaemia and ApoE regulate the intensity of in-vivo systemic autoimmune responses. © 2016 British Society for Immunology.

  15. Fibulin-2 is Essential for Angiotensin II-Induced Myocardial Fibrosis Mediated by Transforming Growth Factor (TGF)-β

    PubMed Central

    Khan, Shaukat A.; Dong, Hailong; Joyce, Jennifer; Sasaki, Takako; Chu, Mon-Li; Tsuda, Takeshi

    2016-01-01

    Fibrosis is an ominous pathological process in failing myocardium, but its pathogenesis is poorly understood. We recently reported that loss of an extracellular matrix (ECM) protein, fibulin-2, protected against ventricular dysfunction after myocardial infarction (MI) in association with absence of activation of transforming growth factor (TGF)-β signaling and suppressed up-regulation of ECM protein expression during myocardial remodeling. Here, we investigated a role of fibulin-2 in the development of myocardial hypertrophy and fibrosis induced by continuous pressor-dosage of Ang II infusion. Both wild type (WT) and fibulin-2 null (Fbln2KO) mice developed comparable hypertension and myocardial hypertrophy by Ang II infusion. However, myocardial fibrosis with significant up-regulation of collagen type I and III mRNA was only seen in WT but not in Fbln2KO mice.Transforming growth factor (TGF)-β1 mRNA and its downstream signal, Smad2, were significantly up-regulated in WT by Ang II, whereas there were no Ang II-induced changes in Flbn2KO, suggesting fibulin-2 is necessary for Ang II-induced TGF-β signaling that induces myocardial fibrosis. To test whether fibulin-2 is sufficient for Ang II-induced TGF-β up-regulation, isolated Flbn2KO cardiac fibroblasts were treated with Ang II after transfecting with fibulin-2 expression vector or pretreating with recombinant fibulin-2 protein. Ang II-induced TGF-β signaling in Fbln2KO cells was partially rescued by exogenous fibulin-2, suggesting that fibulin-2 is required and probably sufficient for Ang II-induced TGF-β activation. Smad2 phosphorylation was induced just by adding recombinant fibulin-2 to KO cells, suggesting that extracellular interaction between fibulin-2 and latent TGF-β triggered initial TGF-β activation. Our study indicates that Ang II cannot induce TGF-β activation without fibulin-2 and that fibulin-2 plays an essential role in Ang II-induced TGF-β signaling and subsequent myocardial fibrosis

  16. CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis

    PubMed Central

    Xu, Jing; Lin, Song-Chang; Chen, Jiyuan; Miao, Yuanxin; Taffet, George E.; Entman, Mark L.

    2011-01-01

    Angiotensin II plays an important role in the development of cardiac hypertrophy and fibrosis, but the underlying cellular and molecular mechanisms are not completely understood. Recent studies have shown that bone marrow-derived fibroblast precursors are involved in the pathogenesis of cardiac fibrosis. Since bone marrow-derived fibroblast precursors express chemokine receptor, CCR2, we tested the hypothesis that CCR2 mediates the recruitment of fibroblast precursors into the heart, causing angiotensin II-induced cardiac fibrosis. Wild-type and CCR2 knockout mice were infused with angiotensin II at 1,500 ng·kg−1·min−1. Angiotensin II treatment resulted in elevated blood pressure and cardiac hypertrophy that were not significantly different between wild-type and CCR2 knockout mice. Angiotensin II treatment of wild-type mice caused prominent cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors expressing the hematopoietic markers, CD34 and CD45, and the mesenchymal marker, collagen I. However, angiotensin II-induced cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors in the heart were abrogated in CCR2 knockout mice. Furthermore, angiotensin II treatment of wild-type mice increased the levels of collagen I, fibronectin, and α-smooth muscle actin in the heart, whereas these changes were not observed in the heart of angiotensin II-treated CCR2 knockout mice. Functional studies revealed that the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and left ventricular dilatation in angiotensin II-treated CCR2 knockout mice. Our data demonstrate that CCR2 plays a pivotal role in the pathogenesis of angiotensin II-induced cardiac fibrosis through regulation of bone marrow-derived fibroblast precursors. PMID:21572015

  17. Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts.

    PubMed

    George, Mereena; Vijayakumar, Anupama; Dhanesh, Sivadasan Bindu; James, Jackson; Shivakumar, K

    2016-01-01

    Delineation of mechanisms underlying the regulation of fibrosis-related genes in the heart is an important clinical goal as cardiac fibrosis is a major cause of myocardial dysfunction. This study probed the regulation of Discoidin Domain Receptor 2 (DDR2) gene expression and the regulatory links between Angiotensin II, DDR2 and collagen in Angiotensin II-stimulated cardiac fibroblasts. Real-time PCR and western blot analyses showed that Angiotensin II enhances DDR2 mRNA and protein expression in rat cardiac fibroblasts via NADPH oxidase-dependent reactive oxygen species induction. NF-κB activation, demonstrated by gel shift assay, abolition of DDR2 expression upon NF-κB inhibition, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of DDR2 by NF-κB in Angiotensin II-treated cells. Inhibitors of Phospholipase C and Protein kinase C prevented Angiotensin II-dependent p38 MAPK phosphorylation that in turn blocked NF-κB activation. Angiotensin II also enhanced collagen gene expression. Importantly, the stimulatory effects of Angiotensin II on DDR2 and collagen were inter-dependent as siRNA-mediated silencing of one abolished the other. Angiotensin II promoted ERK1/2 phosphorylation whose inhibition attenuated Angiotensin II-stimulation of collagen but not DDR2. Furthermore, DDR2 knockdown prevented Angiotensin II-induced ERK1/2 phosphorylation, indicating that DDR2-dependent ERK1/2 activation enhances collagen expression in cells exposed to Angiotensin II. DDR2 knockdown was also associated with compromised wound healing response to Angiotensin II. To conclude, Angiotensin II promotes NF-κB activation that up-regulates DDR2 transcription. A reciprocal regulatory relationship between DDR2 and collagen, involving cross-talk between the GPCR and RTK pathways, is central to Angiotensin II-induced increase in collagen expression in cardiac fibroblasts.

  18. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  19. Arthritis and IBD

    MedlinePlus

    ... IBD Help Center Home > Resources > Arthritis Go Back Arthritis Email Print + Share Arthritis, or inflammation of the ... joints and a reduction in flexibility. TYPES OF ARTHRITIS In IBD, arthritis may appear in three different ...

  20. What Is Reactive Arthritis?

    MedlinePlus

    ... Arthritis PDF Version Size: 69 KB November 2014 What is Reactive Arthritis? Fast Facts: An Easy-to- ... Information About Reactive Arthritis and Other Related Conditions What Causes Reactive Arthritis? Sometimes, reactive arthritis is set ...

  1. Collagenous gastritis.

    PubMed

    Jin, Xiaoyi; Koike, Tomoyuki; Chiba, Takashi; Kondo, Yutaka; Ara, Nobuyuki; Uno, Kaname; Asano, Naoki; Iijima, Katsunori; Imatani, Akira; Watanabe, Mika; Shirane, Akio; Shimosegawa, Tooru

    2013-09-01

    In the present paper, we report a case of rare collagenous gastritis. The patient was a 25-year-old man who had experienced nausea, abdominal distention and epigastralgia since 2005. Esophagogastroduodenoscopy (EGD) carried out at initial examination by the patient's local doctor revealed an extensively discolored depression from the upper gastric body to the lower gastric body, mainly including the greater curvature, accompanied by residual mucosa with multiple islands and nodularity with a cobblestone appearance. Initial biopsies sampled from the nodules and accompanying atrophic mucosa were diagnosed as chronic gastritis. In August, 2011, the patient was referred to Tohoku University Hospital for observation and treatment. EGD at our hospital showed the same findings as those by the patient's local doctor. Pathological findings included a membranous collagen band in the superficial layer area of the gastric mucosa, which led to a diagnosis of collagenous gastritis. Collagenous gastritis is an extremely rare disease, but it is important to recognize its characteristic endoscopic findings to make a diagnosis.

  2. Collagenous colitis.

    PubMed Central

    Kingham, J G; Levison, D A; Morson, B C; Dawson, A M

    1986-01-01

    Clinical and pathological aspects of six patients with collagenous colitis are presented. These patients have been observed for between four and 15 years and the evolution of the condition is documented in three (cases 1, 3 and 5). Management and possible pathogenetic mechanisms of this enigmatic condition are discussed. Images Fig. 1 Fig. 2 PMID:3699567

  3. Complex pathologies of angiotensin II-induced abdominal aortic aneurysms*

    PubMed Central

    Daugherty, Alan; Cassis, Lisa A.; Lu, Hong

    2011-01-01

    Angiotensin II (AngII) is the primary bioactive peptide of the renin angiotensin system that plays a critical role in many cardiovascular diseases. Subcutaneous infusion of AngII into mice induces the development of abdominal aortic aneurysms (AAAs). Like human AAAs, AngII-induced AAA tissues exhibit progressive changes and considerable heterogeneity. This complex pathology provides an impediment to the quantification of aneurysmal tissue composition by biochemical and immunostaining techniques. Therefore, while the mouse model of AngII-induced AAAs provides a salutary approach to studying the mechanisms of the evolution of AAAs in humans, meaningful interpretation of mechanisms requires consideration of the heterogeneous nature of the diseased tissue. PMID:21796801

  4. Monoarticular Arthritis.

    PubMed

    Singh, Namrata; Vogelgesang, Scott A

    2017-05-01

    Monoarticular arthritis is inflammation characterized by joint pain, swelling, and sometimes periarticular erythema. Although chronic causes are seen, the onset is often acute. An infected joint can quickly lead to permanent damage, making it a medical emergency. However, acute gout presenting as monoarticular arthritis is often so uncomfortable it requires urgent attention. Monoarticular crystalline arthritis is common and a septic joint is a medical emergency so it is no surprise that these diagnoses come to mind with complaint of inflammation in 1 joint. However, there are many causes of monoarticular arthritis that clinicians must consider. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Effect of pine pollen extract on experimental chronic arthritis.

    PubMed

    Lee, Kyung-Hee; Choi, Eun-Mi

    2009-05-01

    The effects of pine pollen extract (PE) on Freund's complete adjuvant (FCA)-induced arthritis and collagen-induced arthritis (CIA) were investigated. The oral administration of PE (100 and 200 mg/kg per day) for 21 days after subcutaneous immunization with FCA, significantly reduced hindpaw swelling and the production of inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) compared with the FCA-induced arthritis group. Treatment with the PE (100 mg/kg) also decreased the serum levels of LDL-cholesterol and increased HDL-cholesterol contents compared with those of the arthritis group. Since CIA is a model of some types of human autoimmune rheumatoid arthritis (RA), the study examined whether PE is efficacious against CIA in mice and investigated the possible antioxidant potential of PE on CIA. Arthritis in DBA/1J mice was induced by subcutaneous immunization with bovine type II collagen. PE (100 and 200 mg/kg) was orally administered once daily for 49 days after initial immunization with type II collagen. The arthritis score and paw edema were markedly suppressed in the groups treated with PE. Moreover, administration of PE (100 mg/kg) for 49 days reduced the serum levels of rheumatoid factor, anti-type II collagen antibody, TNF-alpha, IL-1beta, IL-6, protein carbonyl, advanced glycation endproducts, malondialdehyde and LDL-cholesterol compared with that of CIA mice. These results suggest that the pine pollen might be beneficial in the treatment of chronic inflammatory disorders.

  6. IL33 in rheumatoid arthritis: potential contribution to pathogenesis.

    PubMed

    Macedo, Rafaela Bicalho Viana; Kakehasi, Adriana Maria; Melo de Andrade, Marcus Vinicius

    A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis - structural damage - functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

  7. IL33 in rheumatoid arthritis: potencial contribution to pathogenesis.

    PubMed

    Macedo, Rafaela Bicalho Viana; Kakehasi, Adriana Maria; Andrade, Marcus Vinicius Melo de

    2016-03-22

    A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis-structural damage-functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

  8. Septic Arthritis

    MedlinePlus

    ... septic arthritis. Knees are most commonly affected, but septic arthritis also can affect hips, shoulders and other joints. The infection can quickly and severely damage the cartilage and bone within the joint, so prompt treatment is crucial. Treatment involves draining the joint with ...

  9. Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review.

    PubMed

    Dhaouadi, Tarak; Sfar, Imen; Abelmoula, Leila; Jendoubi-Ayed, Salwa; Aouadi, Houda; Ben Abdellah, Taieb; Ayed, Khaled; Zouari, Rafik; Gorgi, Yousr

    2007-12-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown cause that is notorious for the chronic polyarticular synovial inflammation and progressive destruction of affected joints. Understanding the pathogenesis of RA provides the basis for optimal management of that disease in patients. The pathogenesis of RA was largely explored in many studies in human as much as in mice models with collagen II induced arthritis, nevertheless the pathogenesis puzzle is still incomplete. The aim of this systematic review was to collect the results of many observations and to put them down into an original story of RA set up. An exhaustive electronic and library search of the relevant literature was carried out through "science direct" and "interscience wiley" web sites. The key words used for the search were "rheumatoid arthritis", "pathogenesis", "apoptosis", "angiogenesis", "immune response" and "joint destruction". The suspected responsible antigen isn't yet determined although the great specificity of anti-CCP antibodies suggests that this antigen carries probably many citrullinated residues. The immuno-pathogenesis of RA involves both the innate and the adaptive immune system. In the other hand, apoptosis defect contribute to hyperplasia of rheumatoid synovium and in extended half life of fibroblast like synoviocytes (FLS), neutrophils and many other cells implied in rheumatoid synovitis. Hyperplasia of synovium leads to ischemia and that results in neo-angiogenesis with increase of proangiogenic factors such as VEGF. The last part of the pathogenesis of RA is the joint destruction resulting from increased MMP production and activation of osteoclasts which leads to the breakup of cartilage and to bone damage.

  10. The amber theory of Lyme arthritis: initial description and clinical implications.

    PubMed

    Wormser, Gary P; Nadelman, Robert B; Schwartz, Ira

    2012-06-01

    Lyme arthritis differs in many respects from other bacterial causes of arthritis. Based on an observation made for a patient with Lyme arthritis, we propose that the pathogenesis of joint swelling in Lyme arthritis is due to the introduction into the joint space of non-viable spirochetes or more likely spirochetal debris enmeshed in a host-derived fibrinous or collagenous matrix. This "amber" hypothesis can account for the clinical and laboratory features of Lyme arthritis and is amenable to experimental validation. Validation would directly impact the clinical management of patients with Lyme arthritis.

  11. Endogenous IL-22 Plays a Dual Role in Arthritis: Regulation of Established Arthritis via IFN-γ Responses

    PubMed Central

    Justa, Shivali; Zhou, Xiaoqun; Sarkar, Sujata

    2014-01-01

    Objective IL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis. Methods Collagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR. Results Collagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity. Conclusion We show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN

  12. IFN-γ production in response to in vitro stimulation with collagen type II in rheumatoid arthritis is associated with HLA-DRB1*0401 and HLA-DQ8

    PubMed Central

    Berg, Louise; Rönnelid, Johan; Sanjeevi, Carani B; Lampa, Jon; Klareskog, Lars

    2000-01-01

    Introduction: Despite much work over past decades, whether antigen-specific immune reactions occur in rheumatoid arthritis (RA) and to what extent such reactions are directed towards joint-specific autoantigens is still questionable. One strong indicator for antigenic involvement in RA is the fact that certain major histocompatibility complex (MHC) class II genotypes [human leucocyte antigen (HLA)-DR4 and HLA-DR1] predispose for the development of the disease [1]. In the present report, collagen type II (CII) was studied as a putative autoantigen on the basis of both clinical and experimental data that show an increased frequency of antibodies to CII in RA patients [2,3,4] and that show that CII can induce experimental arthritis [5]. It is evident from the literature that RA peripheral blood mononuclear cells (PBMCs) respond poorly to antigenic stimulation [6,7,8], and in particular evidence for a partial tolerization to CII has been presented [9]. The strategy of the present work has accordingly been to reinvestigate T-cell reactivity to CII in RA patients, to relate it to the response to commonly used recall antigens and to analyze IFN-γ responses as an alternative to proliferative responses. Aims: To study cellular immune reactivity to CII in patients with RA and in healthy control individuals and to correlate this reactivity to HLA class II genotypes and to the presence of antibodies to CII in serum. Methods: Forty-five patients who met the 1987 American College of Rheumatology classification criteria for RA [10] and 25 healthy control individuals of similar age and sex were included. Twenty-six of these patients who had low levels of anti-CII in serum were randomly chosen, whereas 19 patients with high anti-CII levels were identified by enzyme-linked immunosorbent assay (ELISA)-screening of 400 RA sera. Heparinized blood was density gradient separated and PBMCs were cultured at 1 × 106/ml in RPMI-10% fetal calf serum with or without antigenic stimulation

  13. Juvenile Idiopathic Arthritis

    MedlinePlus

    ... for You Healthy School Lunch Planner Juvenile Idiopathic Arthritis (JIA) KidsHealth > For Teens > Juvenile Idiopathic Arthritis (JIA) ... people under age 17. What Is Juvenile Idiopathic Arthritis? Arthritis doesn't affect young people as much ...

  14. Juvenile Idiopathic Arthritis

    MedlinePlus

    ... Is Juvenile Idiopathic Arthritis the same as Juvenile Rheumatoid Arthritis? Yes, Juvenile Idiopathic Arthritis (JIA) is a new ... of chronic inflammatory diseases that affect children. Juvenile Rheumatoid Arthritis (JRA) is the older term that was used ...

  15. Calcium pyrophosphate arthritis

    MedlinePlus

    ... disease that can cause attacks of arthritis. Like gout, crystals form in the joints. But in this ... CPPD arthritis can be confused with: Gouty arthritis (gout) Osteoarthritis Rheumatoid arthritis Exams and Tests Most arthritic ...

  16. Psoriatic Arthritis

    MedlinePlus

    ... Walk Test (SMWT) Arthritis Impact Measurement Scales (AIMS) Evidence Based Practice (EBP) Fibromyalgia Impact Questionnaire (FIQ) Fracture Risk ... Investigators Resources for Doctoral Students/Post-Doctoral Fellows Evidence-Based Practice for Academic Researchers Responsible Data Management in ...

  17. Juvenile Arthritis

    MedlinePlus

    ... Walk Test (SMWT) Arthritis Impact Measurement Scales (AIMS) Evidence Based Practice (EBP) Fibromyalgia Impact Questionnaire (FIQ) Fracture Risk ... Investigators Resources for Doctoral Students/Post-Doctoral Fellows Evidence-Based Practice for Academic Researchers Responsible Data Management in ...

  18. Septic arthritis

    MedlinePlus

    ... following conditions increase your risk for septic arthritis: Artificial joint implants Bacterial infection somewhere else in your body Presence of bacteria in your blood Chronic illness or disease (such as diabetes, rheumatoid ...

  19. Incomplete Restoration of Angiotensin II - Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats

    PubMed Central

    Frenay, Anne-Roos S.; Yazdani, Saleh; Boersema, Miriam; van der Graaf, Anne Marijn; Waanders, Femke; van den Born, Jacob; Navis, Gerjan J.; van Goor, Harry

    2015-01-01

    Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage. PMID:26061812

  20. Evodiamine inhibits angiotensin II-induced rat cardiomyocyte hypertrophy.

    PubMed

    He, Na; Gong, Qi-Hai; Zhang, Feng; Zhang, Jing-Yi; Lin, Shu-Xian; Hou, Hua-Hua; Wu, Qin; Sun, An-Sheng

    2017-09-05

    To investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms. Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 μmol/L), and Evo (0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca(2+)]i) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis. Compared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca(2+)]i) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 μmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca(2+)]i concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05). Evo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca(2+)]i concentration, and inhibition of CaN and

  1. Viral arthritis

    PubMed Central

    Marks, Michael; Marks, Jonathan L

    2016-01-01

    Acute-onset arthritis is a common clinical problem facing both the general clinician and the rheumatologist. A viral aetiology is though to be responsible for approximately 1% of all cases of acute arthritis with a wide range of causal agents recognised. The epidemiology of acute viral arthritis continues to evolve, with some aetiologies, such as rubella, becoming less common due to vaccination, while some vector-borne viruses have become more widespread. A travel history therefore forms an important part of the assessment of patients presenting with an acute arthritis. Worldwide, parvovirus B19, hepatitis B and C, HIV and the alphaviruses are among the most important causes of virally mediated arthritis. Targeted serological testing may be of value in establishing a diagnosis, and clinicians must also be aware that low-titre autoantibodies, such as rheumatoid factor and antinuclear antibody, can occur in the context of acute viral arthritis. A careful consideration of epidemiological, clinical and serological features is therefore required to guide clinicians in making diagnostic and treatment decisions. While most virally mediated arthritides are self-limiting some warrant the initiation of specific antiviral therapy. PMID:27037381

  2. Metabolomics in angiotensin II-induced cardiac hypertrophy.

    PubMed

    Mervaala, Eero; Biala, Agnieszka; Merasto, Saara; Lempiäinen, Juha; Mattila, Ismo; Martonen, Essi; Eriksson, Ove; Louhelainen, Marjut; Finckenberg, Piet; Kaheinen, Petri; Muller, Dominik N; Luft, Friedrich C; Lapatto, Risto; Oresic, Matej

    2010-02-01

    Angiotensin II (Ang II) induces mitochondrial dysfunction. We tested whether Ang II alters the "metabolomic" profile. We harvested hearts from 8-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGRs) and controls (Sprague-Dawley), all with or without Ang II type 1 receptor (valsartan) blockade. We used gas chromatography coupled with time-of-flight mass spectrometry to detect 247 intermediary metabolites. We used a partial least-squares discriminate analysis and identified 112 metabolites that differed significantly after corrections (false discovery rate q <0.05). We found great differences in the use of fatty acids as an energy source, namely, decreased levels of octanoic, oleic, and linoleic acids in dTGR (all P<0.01). The increase in cardiac hypoxanthine levels in dTGRs suggested an increase in purine degradation, whereas other changes supported an increased ketogenic amino acid tyrosine level, causing energy production failure. The metabolomic profile of valsartan-treated dTGRs more closely resembled Sprague-Dawley rats than untreated dTGRs. Mitochondrial respiratory chain activity of cytochrome C oxidase was decreased in dTGRs, whereas complex I and complex II were unaltered. Mitochondria from dTGR hearts showed morphological alterations suggesting increased mitochondrial fusion. Cardiac expression of the redox-sensitive and the cardioprotective metabolic sensor sirtuin 1 was increased in dTGRs. Interestingly, valsartan changed the level of 33 metabolites and induced mitochondrial biogenesis in Sprague-Dawley rats. Thus, distinct patterns of cardiac substrate use in Ang II-induced cardiac hypertrophy are associated with mitochondrial dysfunction. The finding underscores the importance of Ang II in the regulation of mitochondrial biogenesis and cardiac metabolomics, even in healthy hearts.

  3. Immunopathological features of rat Staphylococcus aureus arthritis.

    PubMed Central

    Bremell, T; Lange, S; Holmdahl, R; Rydén, C; Hansson, G K; Tarkowski, A

    1994-01-01

    Staphylococcus aureus is the most common bacterial species found in nongonococcal bacterial arthritis in humans. We present the first description, to our knowledge, of an outbreak of spontaneous staphylococcal arthritis in a rat colony. In a group of 10 rats, 9 displayed arthritis. Clinically, the most obvious findings were arthritis of one or both hindpaws and malaise. Bacteriophage typing showed the common phage type 85 in isolates recovered from the joints, blood, and bedding of rats and from the nose and cheeks of one person from the staff of the animal facility. The S. aureus strain proved to produce staphylococcal enterotoxin A and exhibited strong binding to collagen types I and II and bone sialoprotein, which are potentially important virulence factors. When the recovered S. aureus strain was injected intravenously into healthy rats, severe septic arthritis was induced in almost all of the animals. The arthritic lesions were characterized by infiltration of phagocytic cells and T lymphocytes into the synovium. Many of the synovial cells strongly expressed major histocompatibility complex class II molecules. Increased levels of interleukin 6 in serum as well as a prominent polyclonal B-cell activation were noted throughout the disease course. Pretreatment of S. aureus-injected rats in vivo with an antibody to the alpha beta T-cell receptor significantly decreased the severity of the arthritis. Our results indicate that alpha beta + T lymphocytes contribute to an erosive and persistent course of S. aureus arthritis. Images PMID:8188356

  4. Synthesis of the novel PARP-1 inhibitor AG-690/11026014 and its protective effects on angiotensin II-induced mouse cardiac remodeling.

    PubMed

    Feng, Guo-Shuai; Zhu, Cui-Ge; Li, Zhuo-Ming; Wang, Pan-Xia; Huang, Yi; Liu, Min; He, Ping; Lou, Lan-Lan; Chen, Shao-Rui; Liu, Pei-Qing

    2017-02-27

    We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg(-1)·d(-1), ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and β-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac

  5. Rheumatoid arthritis.

    PubMed

    Scott, David L; Wolfe, Frederick; Huizinga, Tom W J

    2010-09-25

    Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50% of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0% of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal.

  6. Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms

    PubMed Central

    Zhou, Yi; Wu, Wenxue; Lindholt, Jes S.; Sukhova, Galina K.; Libby, Peter; Yu, Xueqing; Shi, Guo-Ping

    2015-01-01

    Aims Regulatory T cells (Tregs) protect mice from angiotensin II (Ang-II)-induced abdominal aortic aneurysms (AAA). This study tested whether AAA patients are Treg-insufficient and the Treg molecular mechanisms that control AAA pathogenesis. Methods and results ELISA determined the Foxp3 concentration in blood cell lysates from 485 AAA patients and 204 age- and sex-matched controls. AAA patients exhibited lower blood cell Foxp3 expression than controls (P < 0.0001). Pearson's correlation test demonstrated a significant but negative correlation between Foxp3 and AAA annual expansion rate before (r = –0.147, P = 0.007) and after (r = –0.153, P = 0.006) adjustment for AAA risk factors. AAA in apolipoprotein E-deficient (Apoe–/–) mice that received different doses of Ang-II exhibited a negative correlation of lesion Foxp3+ Treg numbers with AAA size (r = –0.883, P < 0.0001). Adoptive transfer of Tregs from wild-type (WT) and IL10-deficient (Il10–/–) mice increased AAA lesion Treg content, but only WT mice Tregs reduced AAA size, AAA incidence, blood pressure, lesion macrophage and CD4+ and CD8+ T-cell accumulation, and angiogenesis with concurrent increase of lesion collagen content. Both AAA lesion immunostaining and plasma ELISA demonstrated that adoptive transfer of WT Tregs, but not Il10–/– Tregs, reduced the expression of MCP-1. In vitro cell culture and aortic ring assay demonstrated that only Tregs from WT mice, but not those from Il10–/– mice, reduced macrophage MCP-1 secretion, macrophage and vascular cell protease expression and activity, and aortic ring microvessel formation. Conclusion This study supports a protective role of Tregs in human and experimental AAA by releasing IL10 to suppress inflammatory cell chemotaxis, arterial wall remodelling, and angiogenesis. PMID:25824145

  7. Angiotensin II Induced Cardiac Dysfunction on a Chip

    PubMed Central

    Horton, Renita E.; Yadid, Moran; McCain, Megan L.; Sheehy, Sean P.; Pasqualini, Francesco S.; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics. PMID:26808388

  8. Angiotensin II Induced Cardiac Dysfunction on a Chip.

    PubMed

    Horton, Renita E; Yadid, Moran; McCain, Megan L; Sheehy, Sean P; Pasqualini, Francesco S; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.

  9. Effects of Libby amphibole exposure on two models of arthritis in the Lewis rat

    EPA Science Inventory

    Epidemiological data suggest that occupational exposure to the amphibole-containing venniculite in Libby, MT was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen induced arthriti...

  10. Effects of Libby amphibole exposure on two models of arthritis in the Lewis rat

    EPA Science Inventory

    Epidemiological data suggest that occupational exposure to the amphibole-containing venniculite in Libby, MT was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen induced arthriti...

  11. Grammatical Arthritis.

    ERIC Educational Resources Information Center

    Bush, Don

    1994-01-01

    Discusses grammatical arthritis (an internal buildup of rules that hinders writing flexibility); four new "rules" (concerning "data is,""none are,""hopefully," and the restrictive "which"); attitudes toward English grammar; how to be a helpful editor; and where to learn about grammar. (SR)

  12. Fungal arthritis

    MedlinePlus

    ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Fungal Infections Infectious Arthritis Browse the Encyclopedia A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare ... for online health information and services. Learn more about A.D. ...

  13. Grammatical Arthritis.

    ERIC Educational Resources Information Center

    Bush, Don

    1994-01-01

    Discusses grammatical arthritis (an internal buildup of rules that hinders writing flexibility); four new "rules" (concerning "data is,""none are,""hopefully," and the restrictive "which"); attitudes toward English grammar; how to be a helpful editor; and where to learn about grammar. (SR)

  14. Inhibition of inflammatory arthritis using fullerene nanomaterials.

    PubMed

    Dellinger, Anthony L; Cunin, Pierre; Lee, David; Kung, Andrew L; Brooks, D Bradford; Zhou, Zhiguo; Nigrovic, Peter A; Kepley, Christopher L

    2015-01-01

    Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.

  15. Inhibition of Inflammatory Arthritis Using Fullerene Nanomaterials

    PubMed Central

    Dellinger, Anthony L.; Cunin, Pierre; Lee, David; Kung, Andrew L.; Brooks, D. Bradford; Zhou, Zhiguo; Nigrovic, Peter A.; Kepley, Christopher L.

    2015-01-01

    Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis. PMID:25879437

  16. The Collagen Family

    PubMed Central

    Ricard-Blum, Sylvie

    2011-01-01

    Collagens are the most abundant proteins in mammals. The collagen family comprises 28 members that contain at least one triple-helical domain. Collagens are deposited in the extracellular matrix where most of them form supramolecular assemblies. Four collagens are type II membrane proteins that also exist in a soluble form released from the cell surface by shedding. Collagens play structural roles and contribute to mechanical properties, organization, and shape of tissues. They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation. Some collagens have a restricted tissue distribution and hence specific biological functions. PMID:21421911

  17. Arthritis in America

    MedlinePlus

    ... Digital Press Kit Read the MMWR Science Clips Arthritis in America Time to Take Action! Language: English ( ... by about 40% by being physically active. Problem Arthritis is common and a growing health threat. Arthritis ...

  18. Arthritis of the Wrist

    MedlinePlus

    ... is caused by just two types: osteoarthritis and rheumatoid arthritis. Osteoarthritis Osteoarthritis (OA) is a progressive condition that ... other, it results in pain, stiffness, and weakness. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic disease that ...

  19. What Is Rheumatoid Arthritis?

    MedlinePlus

    ... Arthritis PDF Version Size: 57 KB Audio Version Time: 10:20 Size: 9.7 MB November 2014 What Is Rheumatoid Arthritis? Fast Facts: An Easy-to-Read Series of Publications for the Public Rheumatoid arthritis is ...

  20. Juvenile Idiopathic Arthritis

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Juvenile Idiopathic Arthritis (JIA) KidsHealth > For Teens > Juvenile Idiopathic ... can affect people under age 17. What Is Juvenile Idiopathic Arthritis? Arthritis doesn't affect young people ...

  1. Juvenile Idiopathic Arthritis

    MedlinePlus

    ... rule out other conditions or infections, such as Lyme disease , that may cause similar symptoms or occur along ... ESR) Bones, Muscles, and Joints Evaluate Your Child's Lyme Disease Risk Word! Arthritis Arthritis Lupus Juvenile Idiopathic Arthritis ( ...

  2. Arthritis: Frequently Asked Questions

    MedlinePlus

    ... FAQs Five Key Public Health Messages Arthritis Types Fibromyalgia Gout Osteoarthritis Rheumatoid Arthritis (RA) Management Risk Factors ... the Unites States is osteoarthritis followed by gout, fibromyalgia, and rheumatoid arthritis. Top of Page What are ...

  3. Forms of Arthritis

    MedlinePlus

    ... stiffness, inflammation, swelling and, sometimes, destruction of joints. Gout — a form of arthritis that occurs when uric ... the joints. Some 2.1 million Americans have gout. Lupus — a form of arthritis, like rheumatoid arthritis, ...

  4. [Collagen diseases with gastrointestinal manifestations].