RESUMEN
BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause bone erosion due to increased osteoclastogenesis. Neutrophils involvement in osteoclastogenesis remains uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis. EXPERIMENTAL APPROACH: The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro-CT in antigen-induced arthritis (AIA)-induced WT mice treated with DNase or in Padi4-deficient mice (Padi4flox/flox LysMCRE ). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from Tlr4-/- and Tlr9-/- mice were cultured with NETs. KEY RESULTS: Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL-induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions in vitro. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis. CONCLUSIONS AND IMPLICATIONS: Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.
Asunto(s)
Artritis Reumatoide , Trampas Extracelulares , Humanos , Animales , Ratones , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacología , Osteogénesis , Trampas Extracelulares/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 9/metabolismo , Artritis Reumatoide/metabolismo , Osteoclastos/metabolismo , Desoxirribonucleasas/metabolismo , Ligando RANK/metabolismoRESUMEN
Lifestyle modifications in preclinical Rheumatoid Arthritis (RA) could delay the ongoing pathogenic immune processes and potentially prevent its onset. Physical exercise (PE) benefits RA patients; however, its impact in reducing the risk of developing RA has scarcely been studied. The objective was to describe the effects of low-intensity PE applied at the disease's preclinical phase on the joints of DBA/1 mice with collagen-induced arthritis (CIA). Twelve mice with CIA were randomly distributed into two groups: the CIA-Ex group, which undertook treadmill PE, and the CIA-NoEx, which was not exercised. The effects of PE were evaluated through clinical, histological, transcriptomics, and immunodetection analyses in the mice's hind paws. The CIA-Ex group showed lower joint inflammation and damage and a decreased expression of RA-related genes (Tnf Il2, Il10, Il12a, IL23a, and Tgfb1) and signaling pathways (Cytokines, Chemokines, JAK-STAT, MAPK, NF-kappa B, TNF, and TGF-beta). TNF-α expression was decreased by PE in the inflamed joints. Low-intensity PE in pre-arthritic CIA reduced the severity through joint down-expression of proinflammatory genes and proteins. Knowledge on the underlying mechanisms of PE in preclinical arthritis and its impact on reducing the risk of developing RA is still needed.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Ratones , Animales , Modelos Animales de Enfermedad , Ratones Endogámicos DBA , Artritis Reumatoide/metabolismo , Inflamación , Citocinas/metabolismo , Ejercicio FísicoRESUMEN
Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN's multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology.
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Artritis Reumatoide , Osteoartritis , Osteopontina , Animales , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Osteoartritis/metabolismo , Osteoartritis/patología , Osteopontina/metabolismo , Membrana Sinovial/metabolismo , HumanosRESUMEN
Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of gut microbiota's bacteria; (2) to evaluate the relationship between the differences in microbial abundance with the serum levels of intestinal fatty-acid binding protein 2 (IFABP2), cytokines, and the response phenotype to csDMARDs therapy in RA. A cross-sectional study was conducted on 23 women diagnosed with RA. The abundance of bacteria in gut microbiota was determined with qPCR. The ELISA technique determined serum levels of IFABP2, TNF-α, IL-10, and IL-17A. We found that the accumulated dose of methotrexate or prednisone is negatively associated with the abundance of Lactobacillus but positively associated with the abundance of Bacteroides fragilis. The Lactobacillus/Porphyromonas gingivalis ratio was associated with the Disease Activity Score-28 for RA with Erythrocyte Sedimentation Rate (DAS28-ESR) (r = 0.778, p = 0.030) and with the levels of IL-17A (r = 0.785, p = 0.027) in the group treated with csDMARD. Moreover, a relation between the serum levels of IFABP2 and TNF-α (r = 0.593, p = 0.035) was observed in the group treated with csDMARD. The serum levels of IFABP2 were higher in patients with secondary non-response to csDMARDs therapy. In conclusion, our results suggest that the ratios of gut microbiota's bacteria and intestinal permeability seems to establish the preamble for therapeutic secondary non-response in RA.
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Antirreumáticos , Artritis Reumatoide , Microbioma Gastrointestinal , Lactobacillus , Femenino , Humanos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Estudios Transversales , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiología , Interleucina-17 , Proyectos Piloto , Porphyromonas gingivalis , Factor de Necrosis Tumoral alfa/uso terapéutico , Intestinos/microbiología , Intestinos/fisiopatología , Permeabilidad de la Membrana CelularRESUMEN
Chronic inflammatory diseases are triggered by causal stimuli that might occur long before the appearance of the symptoms. Increasing evidence suggests that these stimuli are necessary but not always sufficient to induce the diseases. The murine model of type II collagen emulsified in Freund's incomplete adjuvant (collagen-induced arthritis) to induce rheumatoid arthritis (RA) follows this pattern as some animals do not develop the chronically inflamed phenotype. Considering that in the immune-pineal axis (IPA) theory adrenal-pineal cross-talk adjusts early phases of inflammatory processes, we investigated whether differences in IPA activation could explain why some animals are resistant (RES) while others develop RA. We observed a similar increase in 6-sulfatoxymelatonin (aMT6s) excretion from day 3 to 13 in both RES and RA animals, followed by a significant decrease in RA animals. This pattern of aMT6s excretion positively correlated with plasma corticosterone (CORT) in RES animals. Additionally, RA animals presented a lower aMT6s/CORT ratio than saline-injected or RES animals. Plasmatic levels of tumour necrosis factor were similar in both groups, but interleukin (IL)-1ß and monocyte chemotactic protein 1 (MCP-1) levels were lower in RES compared to RA animals. IL-2 and IL-4 were decreased in RES animals compared to saline-injected animals. The aMT6s/CORT ratio inversely correlated with the paw thickness and the inflammatory score (levels of IL-1ß, MCP-1, IL-2 and IL-4 combined). Thus, adrenocortical-pineal positive interaction is an early defence mechanism for avoiding inflammatory chronification. KEY POINTS: Immune-pineal axis imbalance is observed in early-phase rheumatoid arthritis development. Only resistant animals present a positive association between adrenal and pineal hormones. The 6-sulfatoxymelatonin/corticosterone ratio is decreased in animals that develop rheumatoid arthritis. The inflammatory score combining the levels of nocturnal interleukin (IL)-1ß, monocyte chemotactic protein 1, IL-2 and IL-4 presents a very strong positive correlation with the size of inflammatory lesion. The 6-sulfatoxymelatonin/corticosterone ratio presents a strong negative correlation with the inflammatory score and paw oedema size.
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Artritis Experimental , Artritis Reumatoide , Ratas , Ratones , Animales , Quimiocina CCL2 , Corticosterona , Interleucina-4/efectos adversos , Interleucina-2 , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Citocinas/metabolismoRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately 1% of the worldwide population. In recent decades, oxidative stress (OS) has been shown to be involved in the progression of this disease through DNA, lipid and protein damage, resulting in synovial inflammation. There are many causes of OS; metabolism is involved in the production of reactive oxygen species (ROS) but pollution, diet and microbiota imbalances could lead to the overproduction of these ROS. A decade of research focused on understanding how OS is promoted by known RA risk factors is described herein. The use of antioxidants represents an integrative treatment for patients with rheumatoid arthritis, given the evidence of the damage caused by oxidative stress in this disease. Understanding the different factors that contribute to the development and progression of RA, such as OS, will pave the way not only for better pharmacological treatments but also for recommendations for dietary and health behaviours that will benefit patients with this disease.
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Artritis Reumatoide , Estrés Oxidativo , Antioxidantes/farmacología , Artritis Reumatoide/metabolismo , Humanos , Lípidos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Tumor necrosis factor (TNF)-α is a pleiotropic cytokine implicated in the etiology of several autoimmune diseases, including rheumatoid arthritis (RA). TNF-α regulates diverse effector functions through the activation of TNF-α receptor (TNFR)1 and TNFR2. Although the detrimental role of this cytokine has been addressed in distinct disease settings, the effects of TNF-α on cytokine production by isolated CD4+ T helper type 1 (Th1) and Th17 cells, two T cell subpopulations that contribute to the pathogenesis of RA, have not been completely elucidated. Here, we show that TNF-α promotes a reduction and expansion in the frequency of both T cell subsets producing IFN-γ and IL-17, respectively. Selective blockade of TNFR1 or TNFR2 on Th1 and Th17 cells revealed that TNFR2 mediates the decrease in IFN-γ production, while signaling through both receptors augments IL-17 production. We also demonstrate that Th1, but not Th17 cells from RA patients present lower levels of TNFR1 compared to healthy controls, whereas TNFR2 expression on both T cell types is similar between patients and controls. Since TNF-α receptors levels in RA patients are not significantly changed by the therapeutic blockade of TNF-α, we propose that targeting TNFR2 may represent an alternative strategy to normalize the levels of key cytokines that contribute to RA pathogenesis.
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Artritis Reumatoide , Receptores Tipo II del Factor de Necrosis Tumoral , Receptores Tipo I de Factores de Necrosis Tumoral , Células TH1 , Células Th17 , Artritis Reumatoide/metabolismo , Citocinas/metabolismo , Humanos , Interleucina-17 , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Gold salts have been used to treat rheumatoid arthritis (RA) since the 1940s, and, with advances in nanotechnology, the use of nanogold provides multiple options for anti-inflammatory therapies. This paper presents the synthesis and characterization of silica-gold nanostructures (SGNs) and their therapeutic effect in collagen-induced arthritis (CIA) in DBA/1 mice. At the end of the treatment, the synovial membranes, kidneys, livers, and spleens were dissected and analyzed by inductively coupled plasma mass spectroscopy (ICP) showing less than 0.0001 and 0.1% of the administered doses of Au and Si, respectively. Remains of the SGNs were visually identified in the synovial membrane by scanning electron microscopy (SEM), and the bone density of the hind paws was observed by computerized tomography (CT) indicating a reduction of porosity in the CIA-experimental group. The DNA microarray analysis carried out with RNA obtained from the hind paws showed 2628 differentially expressed genes (DEGs) by SGNs. The bioinformatic analysis showed that DEGs were significantly associated with several inflammatory signalling pathways including chemokines, cytokine-cytokine receptor interaction, PI3K-Akt, TNF, IL-17, NFκß, MAPK, and RA. SGNs downregulated relevant inflammatory genes in the arthritic joints, including Tnf, Ifng, Il6, and Cxcl5; immunohistochemistry (IHC) confirmed the reduction of TNFα, IL-6, NFκß, and VEGF in the joints due to the effect of SGNs. TNFα and IL-6 were also reduced in the serum of DBA/1 mice treated with SGNs.
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Artritis Experimental , Artritis Reumatoide , Nanoestructuras , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Expresión Génica , Oro/uso terapéutico , Inflamación/tratamiento farmacológico , Interleucina-6 , Ratones , Ratones Endogámicos DBA , Fosfatidilinositol 3-Quinasas , Dióxido de Silicio/uso terapéutico , Factor de Necrosis Tumoral alfaRESUMEN
Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations.
Asunto(s)
Artritis Reumatoide , Artritis Reumatoide/metabolismo , Cartílago/metabolismo , Condrocitos/metabolismo , Fibroblastos/metabolismo , Humanos , Articulaciones/metabolismoRESUMEN
Exercise is a treatment in rheumatoid arthritis, but participation in moderate-to-vigorous exercise is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. We compared the acute effects of active breaks in sitting with those of moderate-to-vigorous exercise on cardiometabolic risk markers in patients with rheumatoid arthritis. In a crossover fashion, 15 women with rheumatoid arthritis underwent three 8-h experimental conditions: prolonged sitting (SIT), 30-min bout of moderate-to-vigorous exercise followed by prolonged sitting (EX), and 3-min bouts of light-intensity walking every 30 min of sitting (BR). Postprandial glucose, insulin, c-peptide, triglycerides, cytokines, lipid classes/subclasses (lipidomics), and blood pressure responses were assessed. Muscle biopsies were collected following each session to assess targeted proteins/genes. Glucose [-28% in area under the curve (AUC), P = 0.036], insulin (-28% in AUC, P = 0.016), and c-peptide (-27% in AUC, P = 0.006) postprandial responses were attenuated in BR versus SIT, whereas only c-peptide was lower in EX versus SIT (-20% in AUC, P = 0.002). IL-1ß decreased during BR, but increased during EX and SIT (P = 0.027 and P = 0.085, respectively). IL-1ra was increased during EX versus BR (P = 0.002). TNF-α concentrations decreased during BR versus EX (P = 0.022). EX, but not BR, reduced systolic blood pressure (P = 0.013). Lipidomic analysis showed that 7 of 36 lipid classes/subclasses were significantly different between conditions, with greater changes being observed in EX. No differences were observed for protein/gene expression. Brief active breaks in sitting can offset markers of cardiometabolic disturbance, which may be particularly useful for patients who may find it difficult to adhere to exercise.NEW & NOTEWORTHY Exercise is a treatment in rheumatoid arthritis but is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. Our findings show beneficial, but differential, cardiometabolic effects of active breaks in sitting and exercise in patients with rheumatoid arthritis. Breaks in sitting mainly improved glycemic and inflammatory markers, whereas exercise improved lipidomic and hypotensive responses. Breaks in sitting show promise in offsetting aspects of cardiometabolic disturbance associated with prolonged sitting in rheumatoid arthritis.
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Artritis Reumatoide , Sistema Cardiovascular/fisiopatología , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Conducta Sedentaria , Anciano , Artritis Reumatoide/metabolismo , Artritis Reumatoide/fisiopatología , Artritis Reumatoide/terapia , Glucemia/metabolismo , Factores de Riesgo Cardiometabólico , Estudios Cruzados , Femenino , Humanos , Insulina/metabolismo , Persona de Mediana Edad , Periodo Posprandial , Caminata/fisiologíaRESUMEN
BACKGROUND: In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA. METHODS: A non-systematic search in Pubmed included terms as "rheumatoid arthritis", "renin angiotensin system", "osteopenia", "RANKL", "DKK-1", "MMP", "inflammation", "angiogenesis", "local renin-angiotensin system", "angiotensin converting enzyme", "AT2 receptor", "Ang-(1-7)", "VEGF", "angiotensine receptor blocker", "angiotensin converting enzyme inhibitors", "renin inhibitors". RESULTS: Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results. CONCLUSION: The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.
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Artritis Reumatoide/metabolismo , Artritis Reumatoide/fisiopatología , Osteoartritis/metabolismo , Osteoartritis/fisiopatología , Sistema Renina-Angiotensina , Corticoesteroides/uso terapéutico , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/uso terapéutico , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Humanos , Osteoartritis/tratamiento farmacológico , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Proto-Oncogenes Mas/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease with complex pathogenesis associated with cytokine dysregulation. Macrophage migration inhibitory factor (MIF) plays a role in systemic inflammation and joint destruction in RA and could be associated with the secretion of other immune-modulatory cytokines such as IL-25, IL-31, and IL-33. For the above, our main aim was to evaluate the IL-25, IL-31, and IL-33 secretion from recombinant human MIF (rhMIF)-stimulated peripheral blood mononuclear cells (PBMC) of RA patients. The rhMIF and lipopolysaccharide (LPS) plus rhMIF stimuli promote the secretion of IL-25, IL-31, and IL-33 (p < 0.05) from PBMC of RA patients. The study groups, the different stimuli, and the interaction between both showed a statistically significant effect on the secretion of IL-25 (p < 0.05) and IL-31 (p < 0.01). The study of the effect of the RA patient treatments and their interaction with the effect of stimuli did not show an interaction between them. In conclusion, our study generates new evidence for the role of MIF in the secretion of IL-25, IL-31, and IL-33 and its immunomodulatory effect on RA.
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Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucinas/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Leucocitos Mononucleares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Adulto , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Oxidorreductasas Intramoleculares/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Factores Inhibidores de la Migración de Macrófagos/farmacología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacologíaRESUMEN
OBJECTIVES: This study was aimed at assessing the anti-arthritic effects of hesperidin on the inflammatory markers in serum/plasma, ectoenzymes activity in platelet, reactive oxygen species (ROS), apoptosis and cell cycle in bone marrow cells of a rat model of arthritis. METHODS: Fifty-six adult female Wistar rats (245-274 g) were grouped into eight of seven rats each: control rats given normal saline or 40 mg/kg of hesperidin or 80 mg/kg of hesperidin, 0.2 mg/kg of dexamethasone, arthritic rats given normal saline, or 40 mg/kg of hesperidin or 80 mg/kg of hesperidin, and 0.2 mg/kg of dexamethasone. Myeloperoxidase and nitrate plus nitrite levels were evaluated in the plasma and serum, respectively. The ecto-nucleoside triphosphate diphosphohydrolases, ecto-5'-nucleotidase and ecto-adenosine deaminase activities were assessed in platelets. Subsequently, the cells of the bone marrow were obtained, and the assays for ROS, apoptosis and cell cycle were evaluated using flow cytometry. KEY FINDINGS: The results showed that hesperidin mitigated inflammation, modulated adenosine nucleotides and nucleoside hydrolysing enzymes and levels, minimized ROS intracellularly, attenuated apoptotic process and activated cell cycle arrest in arthritic rat. CONCLUSION: This study suggests that hesperidin could be a natural and promising anti-inflammatory compound for the management of arthritis.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental , Puntos de Control del Ciclo Celular/efectos de los fármacos , Citrus/química , Hesperidina/farmacología , Hidrolasas/metabolismo , Inflamación , 5'-Nucleotidasa/metabolismo , Adenosina Desaminasa/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Apoptosis , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Femenino , Adyuvante de Freund , Hesperidina/uso terapéutico , Inflamación/metabolismo , Inflamación/prevención & control , Proteínas de la Membrana/metabolismo , Nucleósido-Trifosfatasa/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Pirofosfatasas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVES: Neutrophil extracellular traps (NETs) play a role in the pathogenesis of periodontitis and rheumatoid arthritis (RA). However, it remains poorly understood whether NETs participate in the cross-talk between periodontitis and RA. Herein, we investigated the production of NETs in individuals with periodontitis and RA and its association with clinical parameters. The impact of periodontal therapy on RA and NET release was also assessed. METHODS: The concentration of NETs and cytokines was determined in the saliva and plasma of individuals with early RA (n = 24), established RA (n = 64) and individuals without RA (n = 76). The influence of periodontitis on the production of NETs and cytokines was also evaluated. RESULTS: Individuals with early RA had a higher concentration of NETs in saliva and plasma than individuals with established RA or without RA. Periodontitis resulted in an increase in the concentration of NETs of groups of individuals without RA and with early RA. The proportion of individuals with high concentrations of IL-6, IL-10 and GM-CSF was higher among individuals with periodontitis than among individuals without periodontitis. The concentrations of TNF-α, IL-6, IL-17/IL-25 and IL-28A were particularly high in individuals with early RA. Worse periodontal clinical parameters, RA onset and RA activity were significantly associated with circulating NETs. Periodontal therapy was associated with a reduction in the concentration of NETs and inflammatory cytokines and amelioration in periodontitis and RA. CONCLUSION: This study reveals that NETs are a possible link between periodontitis and RA, with periodontal therapy resulting in a dramatic switch in circulating NET levels.
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Artritis Reumatoide/metabolismo , Artritis Reumatoide/terapia , Citocinas/metabolismo , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Periodontitis/metabolismo , Periodontitis/terapia , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that microRNA-132 is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. miRNA-132 thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of miR-132 in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of miR-132 than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
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Artritis Reumatoide/genética , MicroARNs/genética , Osteogénesis/fisiología , Adulto , Anciano , Animales , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Fumar Cigarrillos/efectos adversos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Persona de Mediana Edad , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Humo , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease with strong genetic influence, especially upon immune response components. Several cytokines from the toll-like receptors activation pathway display recognized role for RA establishment. However, few studies have verified the role of key mediators such as MYD88 gene and its genetic variants. In the present study, we aim to evaluate the rs6853 functional single-nucleotide variation (SNV) role in RA etiopathogenesis, clinical severity status, and its impact in MYD88 mRNA levels and IL-lß protein levels. For the association study, a total of 423 RA patients and 346 health individuals, enrolled as control, from Northeast and Southeast Brazil were genotyped using specific Taqman probe. For the gene expression assays, we performed a MYD88 rs6853 genotype-guided monocyte cell culture divided into non-stimulated and lypopolysaccharides (LPS)-stimulated cells from healthy individuals. MYD88 gene expression was measured using primer specifics while IL-1ß levels were evaluated by ELISA. We observed that A allele and AA genotype were associated to an increased risk to RA development (OR = 1.60; 95% CI 1.24-2.08; p = 0.0004/OR = 2.83; 95% CI 1.25-6.41; p = 0.0152). The AA genotype exhibited lower MYD88 mRNA levels than GG genotype in non-stimulated monocyte cell culture (FC - 3.83; p = 0.003). Additionally, we verified an increase of IL-1ß levels when AA genotype non-stimulated monocytes were compared to AA genotype LPS-stimulates (p = 0.021). In summary, MYD88 rs6853 polymorphism associated to RA development in our Brazilian cohort and showed influence upon MYD88 mRNA levels' expression and IL-lß production.
Asunto(s)
Artritis Reumatoide/genética , Leucocitos Mononucleares/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Polimorfismo de Nucleótido Simple , Adulto , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Brasil , Estudios de Casos y Controles , Células Cultivadas , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Interleucina-1beta/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/toxicidad , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/metabolismo , FenotipoRESUMEN
OBJECTIVES: To compare serum levels of RAS components in women with RA versus healthy females and to investigate the association between these molecules and subclinical atherosclerosis. METHODS: A cross-sectional study involving female RA patients without ischemic CVD. Disease activity was assessed using the DAS28 and the CDAI. IMT of the common carotid artery was evaluated by ultrasonography. Serum levels of Ang II, Ang-(1-7), ACE and ACE2 were determined by enzyme immunoassay. RESULTS: Fifty women with RA, mean 48.2 (7.3) years, were compared to 30 healthy women, paired by age. RA patients had higher plasma levels of Ang II (p < .01), Ang-(1-7) (p < .01), and ACE (p < .01) than controls. The ratios of ACE to ACE2 were higher in RA patients, whereas Ang II/Ang-(1-7) ratios were lower in RA patients. The presence of hypertension and the treatment with ACE inhibitors did not significantly modify serum levels of Ang II, Ang-(1-7), ACE and ACE2 in patients with RA. Seven RA patients had altered IMT, and eight patients exhibited atherosclerotic plaque. There was a negative correlation between ACE2 levels and IMT (p = .041). IMT positively correlated with age (p = .022), disease duration (p = .012) and overall Framingham risk score (p = .008). Ang II concentrations positively correlated with DAS28 (p = .034) and CDAI (p = .040). CONCLUSION: Patients with RA had an activation of the RAS, suggesting an association with disease activity and cardiovascular risk. Rheumatological key messages Imbalance of both RAS axes may be associated with cardiovascular risk and disease activity in rheumatoid arthritis. Ultrasonography of the carotid arteries can identify early, subclinical atherosclerotic disease in rheumatoid arthritis patients. Angiotensin-converting enzyme inhibition or angiotensin 1 receptor blockade may be beneficial for rheumatoid arthritis patients.
Asunto(s)
Enzima Convertidora de Angiotensina 2/sangre , Artritis Reumatoide , Aterosclerosis , Grosor Intima-Media Carotídeo , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Artritis Reumatoide/metabolismo , Enfermedades Asintomáticas/epidemiología , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiología , Biomarcadores/sangre , Brasil/epidemiología , Estudios Transversales , Diagnóstico Precoz , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Persona de Mediana Edad , Gravedad del Paciente , Sistema Renina-AngiotensinaRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73+CD39+ and CD73-CD39+ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4+ and CD8+ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4+ T cells, but not in CD8+ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.
Asunto(s)
Apirasa/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Inmunomodulación , Adenosina/metabolismo , Apirasa/genética , Artritis Reumatoide/patología , Artritis Reumatoide/terapia , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Estudios de Casos y Controles , Citocinas/biosíntesis , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Humanos , Activación de Linfocitos , Recuento de Linfocitos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases characterized by chronic inflammation and bone erosion. Electroacupuncture (EA) shows anti-inflammatory and anti-resorptive effects in experimental periodontitis (EP) and in RA. It is important to investigate whether EA shows these effects in periodontal tissues in the presence of these two inflammatory diseases or not. For this, Wistar rats were divided into six groups: control (C); experimental rheumatoid arthritis (RA; bovine type II collagen-induced (CII)); experimental periodontitis (EP); RA/EP (RA + EP); EP/EA (EP treated with EA); RA/EP/EA (RA + EP treated with EA). EP was induced 21 days after RA induction and EA was performed previously and during the EP induction period, every 3 days until the 36th experimental day. The rats were euthanized on day 39. RA was evaluated by edema and the withdrawal threshold of hind paws. The maxillae were removed, and alveolar bone loss (ABL) and bone radiographic density (BRD) were evaluated. Immunohistochemical analyses for interleukins (IL)-6 and -17 and nuclear factor (NF)-κB were performed. Our results showed that EA reduced only the pain intensity in arthritic rats. Histomorphometric, macroscopic, and radiographic analyses did not show differences between the control and EP/EA groups. EA caused a reduction in ABL and BRD only in the presence of EP. EA caused a reduction in IL-6 and -17 in all groups, but NF-κB was only reduced in the arthritic rats with EP. In conclusion, EA reduced the inflammation related to periodontitis in arthritic rats but did not prevent ABL.
Asunto(s)
Pérdida de Hueso Alveolar/terapia , Artritis Experimental/terapia , Artritis Reumatoide/terapia , Electroacupuntura/métodos , Mediadores de Inflamación/antagonistas & inhibidores , Periodontitis/terapia , Pérdida de Hueso Alveolar/diagnóstico por imagen , Pérdida de Hueso Alveolar/metabolismo , Animales , Artritis Experimental/diagnóstico por imagen , Artritis Experimental/metabolismo , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/metabolismo , Inflamación/diagnóstico por imagen , Inflamación/metabolismo , Inflamación/terapia , Mediadores de Inflamación/metabolismo , Periodontitis/diagnóstico por imagen , Periodontitis/metabolismo , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Antibodies against carbamylated proteins/peptide (CarP) have been associated with severity in rheumatoid arthritis (RA) patients. However, their role in risk groups, specific targets and relation with periodontal disease (PD) is uncertain yet. The aim of this study was evaluated the association between the levels of anti-CarP with clinical manifestation, human leukocyte antigen (HLA) alleles, periodontal activity markers, PD diagnosis, PD severity, and presence of Porphyromonas gingivalis (P gingivalis) in relatives of patients with RA. METHODS: One hundred and twenty-four individuals with a family history of RA in first-degree relatives (FDR) and 124 healthy individuals gender- and age-matched, RA activity was assessed. Antibodies against carbamylated protein anti-FCS-Carp and 2 carbamylated peptides of fibrinogen were selected (anti-Ca-Fib2, anti-Ca-Fib3). RESULTS: Anti-FCS-Carp-positive, anti-Ca-Fib2 and anti-Ca-Fib3 were more frequent in FDR than controls (25.0% vs 14.5%, 34.7% vs 15.3% and 33.1% vs 11.3%, respectively). Anti-FCS-CarP were associated with the HLA-DRB1-SE* 1402 allele (P = .035) and highly sensitive C-reactive protein levels (P = .016), the anti-Ca-Fib2 antibodies were associated with the HLA-DRB1-SE* 1501 allele (P = .03), with non-SE* 0901 allele (P = .01), the anti-Ca-Fib3 was associated with positive rheumatoid factor (P = .0012). The FDR condition was associated with the presence of anti-Ca-Fib3 (odds ratio [OR] =4.7; 95% CI = 1.8-11.7; P = .001) and painful joints (OR = 2.2; 95% CI = 1.01-4.68; P = .045); we also detected an important trend toward the presence of P gingivalis (OR = 1.9; 95% CI = 0.9-3.7; P = .062). CONCLUSION: The presence of anti-FCS-Carp, anti-Ca-Fib3 and anti-Ca-Fib2 antibodies may have a role for these antibodies as early biomarkers in the development of RA, probably including additional mechanisms related with other non-SE alleles; the anti-peptide antibodies proposed in the present study may represent a simpler way to identify antibodies directed to a specific target.