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William O'Brien, Brian M Fissel, Yukiko Maeda, Jing Yan, Xianpeng Ge, Ellen M Gravallese, Antonios O Aliprantis, Julia F Charles
OBJECTIVE: Pro-inflammatory molecules promote osteoclast-mediated bone erosion by upregulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as TNFα plus IL-6, induce RANKL-independent osteoclastogenesis. This study sought to better understand TNFα/IL-6 induced osteoclast formation, and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis. METHODS: Myeloid precursors from wild-type (WT) mice, or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12 or Fcrg, were treated with either RANKL, or TNFα plus IL-6...
August 26, 2016: Arthritis & Rheumatology
Aránzazu Mediero, Tuere Wilder, Bhama Ramkhelawon, Kathryn J Moore, Bruce N Cronstein
Rheumatoid arthritis is an autoimmune disease that is characterized by chronic inflammation and destruction of joints. Netrin-1, a chemorepulsant, laminin-like matrix protein, promotes inflammation by preventing macrophage egress from inflamed sites and is required for osteoclast differentiation. We asked whether blockade of Netrin-1 or its receptors [Unc5b and DCC (deleted in colorectal carcinoma)] may be useful therapeutic targets for treatment of inflammatory arthritis. Arthritis was induced in 8-wk-old C57Bl/6 mice by intraperitoneal injection of K/BxN serum...
August 8, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Anne D Christensen, Claus Haase, Andrew D Cook, John A Hamilton
The K/BxN serum-transfer arthritis (STA) model is a murine model in which the immunological mechanisms occurring in rheumatoid arthritis (RA) and other arthritides can be studied. To induce K/BxN STA, serum from arthritic transgenic K/BxN mice is transferred to naive mice and manifestations of arthritis occur a few days later. The inflammatory response in the model is driven by autoantibodies against the ubiquitously expressed self-antigen, glucose-6-phosphate isomerase (G6PI), leading to the formation of immune complexes that drive the activation of different innate immune cells such as neutrophils, macrophages, and possibly mast cells...
2016: Frontiers in Immunology
Keisuke Maeshima, Stephanie M Stanford, Deepa Hammaker, Cristiano Sacchetti, Li-Fan Zeng, Rizi Ai, Vida Zhang, David L Boyle, German R Aleman Muench, Gen-Sheng Feng, John W Whitaker, Zhong-Yin Zhang, Wei Wang, Nunzio Bottini, Gary S Firestein
The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS...
May 19, 2016: JCI Insight
Yoshishige Miyabe, Nancy D Kim, Chie Miyabe, Andrew D Luster
Adoptive cell transfer experiments can be used to study the roles of cell trafficking molecules on the migratory behavior of specific immune cell populations in vivo. Chemoattractants and their G protein-coupled seven-transmembrane-spanning receptors regulate migration of cells in vivo, and dysregulated expression of chemoattractants and their receptors is implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints...
2016: Methods in Molecular Biology
Yuichi Maeda, Atsushi Kumanogoh, Kiyoshi Takeda
  Manifestation of rheumatoid arthritis (RA) can be attributed to both genetic and environmental factors. Some researchers have been focusing on intestinal microbiota which is thought to be one of the environmental factors that may enhance the development of RA. The advancement of culture-independent, high throughput microbial DNA sequencing had enabled us to understand the interplay between intestinal microbiota and host immune systems. In this study, we have reviewed the previous findings in animal and human studies with respect to the role of intestinal microbiota in RA...
2016: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
Anita T Shaw, Yukiko Maeda, Ellen M Gravallese
BACKGROUND: Interleukin-17A (IL-17A) plays a pathogenic role in several rheumatic diseases including spondyloarthritis and, paradoxically, has been described to both promote and protect from bone formation. We therefore examined the effects of IL-17A on osteoblast differentiation in vitro and on periosteal bone formation in an in vivo model of inflammatory arthritis. METHODS: K/BxN serum transfer arthritis was induced in IL-17A-deficient and wild-type mice. Clinical and histologic inflammation was assessed and periosteal bone formation was quantitated...
2016: Arthritis Research & Therapy
Fei Teng, Christina N Klinger, Krysta M Felix, C Pierce Bradley, Eric Wu, Nhan L Tran, Yoshinori Umesaki, Hsin-Jung Joyce Wu
Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer's patch (PP) Tfh cells were essential for gut commensal segmented filamentous bacteria (SFB)-induced systemic arthritis despite the production of auto-antibodies predominantly occurring in systemic lymphoid tissues, not PPs...
April 19, 2016: Immunity
Corinna Wehmeyer, Svetlana Frank, Denise Beckmann, Martin Böttcher, Christoph Cromme, Ulrich König, Michelle Fennen, Annelena Held, Peter Paruzel, Christine Hartmann, Athanasios Stratis, Adelheid Korb-Pap, Thomas Kamradt, Ina Kramer, Wim van den Berg, Michaela Kneissel, Thomas Pap, Berno Dankbar
Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost(-/-)) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)-dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)-like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction...
March 16, 2016: Science Translational Medicine
Ingrid Elisia, Hisae Nakamura, Vivian Lam, Elyse Hofs, Rachel Cederberg, Jessica Cait, Michael R Hughes, Leora Lee, William Jia, Hans H Adomat, Emma S Guns, Kelly M McNagny, Ismael Samudio, Gerald Krystal
Dimethyl sulfoxide (DMSO) is currently used as an alternative treatment for various inflammatory conditions as well as for cancer. Despite its widespread use, there is a paucity of data regarding its safety and efficacy as well as its mechanism of action in human cells. Herein, we demonstrate that DMSO has ex-vivo anti-inflammatory activity using Escherichia coli- (E. coli) and herpes simplex virus-1 (HSV-1)-stimulated whole human blood. Specifically, we found that between 0.5%-2%, DMSO significantly suppressed the expression of many pro-inflammatory cytokines/chemokines and prostaglandin E2 (PGE2)...
2016: PloS One
M M Matzelle, A T Shaw, R Baum, Y Maeda, J Li, S Karmakar, C A Manning, N C Walsh, V Rosen, E M Gravallese
OBJECTIVES: Inflammation in diseases such as rheumatoid arthritis (RA) stimulates osteoclast-mediated articular bone erosion and inhibits osteoblast-mediated bone formation, leading to a net loss of bone. Pro-inflammatory cytokines and antagonists of the Wnt signalling pathway have been implicated in the inhibition of osteoblast differentiation and activity in RA, contributing to the erosive process and impairing erosion healing. Importantly, osteoblast differentiation and function are also regulated by the osteogenic bone morphogenetic protein (BMP) signalling pathway, which is antagonized by BMP3...
October 2016: Scandinavian Journal of Rheumatology
Lindsay E Nyhoff, Bridgette L Barron, Elizabeth M Johnson, Rachel H Bonami, Damian Maseda, Benjamin A Fensterheim, Wei Han, Timothy S Blackwell, Leslie J Crofford, Peggy L Kendall
OBJECTIVE: Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis. METHODS: BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity...
August 2016: Arthritis & Rheumatology
Bálint Botz, Ágnes Kemény, Susanne M Brunner, Felix Locker, Janka Csepregi, Attila Mócsai, Erika Pintér, Jason J McDougall, Barbara Kofler, Zsuzsanna Helyes
Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells...
June 2016: Journal of Molecular Neuroscience: MN
Yoshishige Miyabe, Nancy D Kim, Chie Miyabe, Andrew D Luster
Chemokines regulate the migration of cells in vivo and dysregulated expression of chemokines and their receptors are implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints. The K/BxN serum transfer mouse model of inflammatory arthritis shares many similar features with RA. In this autoantibody-induced model of arthritis, neutrophils are the critical immune cells necessary for the development of joint inflammation and damage...
2016: Methods in Enzymology
Ghada Alsaleh, Ramzi Nehmar, Stephan Blüml, Cédric Schleiss, Eleonore Ostermann, Jean-Philippe Dillenseger, Amira Sayeh, Philippe Choquet, Doulaye Dembele, Antoine Francois, Jean-Hugues Salmon, Nicodème Paul, Gernot Schabbauer, Guillaume Bierry, Alain Meyer, Jacques-Eric Gottenberg, Gabrielle Haas, Sebastien Pfeffer, Laurent Vallat, Jean Sibilia, Seiamak Bahram, Philippe Georgel
OBJECTIVE: While the regulatory role of individual microRNAs (miRNAs) in rheumatoid arthritis (RA) is well established, the role of DICER1 in the pathogenesis of the disease has not yet been investigated. The purpose of this study was to analyze the expression of factors involved in miRNA biogenesis in fibroblast-like synoviocytes (FLS) from RA patients and to monitor the arthritis triggered by K/BxN serum transfer in mice deficient in the Dicer gene (Dicer(d/d) ). METHODS: The expression of genes and precursor miRNAs was quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR)...
August 2016: Arthritis & Rheumatology
Jennifer L Auger, Hannah M Cowan, Brianna J Engelson, Sakeen W Kashem, Immo Prinz, Bryce A Binstadt
OBJECTIVE: Th17 cells and interleukin-17 (IL-17) cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies in mouse models of inflammatory arthritis have demonstrated a key role for the proinflammatory cytokine IL-17A and its receptor, the IL-17 receptor (IL-17R) A/C heterodimer. The aim of this study was to use a rigorous genetic approach to evaluate the contribution of Th17 cells and IL-17 in the autoantibody-dependent KRN T cell receptor-transgenic mouse model of arthritis...
August 2016: Arthritis & Rheumatology
Anne D Christensen, Claus Haase, Andrew D Cook, John A Hamilton
Neutrophils are an abundant cell type in many chronic inflammatory diseases such as rheumatoid arthritis (RA); however, their contribution to the pathology of RA has not been widely studied. A key cytokine involved in neutrophil development and function is granulocyte-colony stimulating factor (G-CSF). In this study we used the K/BxN serum-transfer arthritis (STA) model, mimicking the effector phase of RA, to investigate the importance of G-CSF in arthritis development and its relation to neutrophils. Here, we show for the first time in this model that G-CSF levels are increased both in the serum and in inflamed paws of arthritic mice and importantly that G-CSF blockade leads to a profound reduction in arthritis severity, as well as reduced numbers of neutrophils in blood...
May 2016: European Journal of Immunology
Ricard Garcia-Carbonell, Ajit S Divakaruni, Alessia Lodi, Ildefonso Vicente-Suarez, Arindam Saha, Hilde Cheroutre, Gerry R Boss, Stefano Tiziani, Anne N Murphy, Monica Guma
OBJECTIVE: Up-regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage. METHODS: Synovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA)...
July 2016: Arthritis & Rheumatology
Katharine E Block, Zhong Zheng, Alexander L Dent, Barbara L Kee, Haochu Huang
The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Th17 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yun Hyun Huh, Gyuseok Lee, Keun-Bae Lee, Jeong-Tae Koh, Jang-Soo Chun, Je-Hwang Ryu
INTRODUCTION: Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. METHODS: Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-α transgenic mice were used as experimental RA models...
2015: Arthritis Research & Therapy
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