RESUMEN
Background: Colorectal cancer is a lethal cancer worldwide. Due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of most patients, innovative immunotherapeutic approaches need to be identified. Methods: Using the TCGA-COAD dataset (n = 514), we identified TNFRSF11B as a prognostic factor of colon cancer. An immunohistochemistry (IHC) dataset (n = 86), 290 single colorectal cancer cells (GSE81861), and 31 paired colon cancer transcriptional datasets were further applied to validate the function of TNFRSF11B, which was confirmed via fluorescence-activated cell sorting (FACS) analysis. Results: A risk score system consisting of eight immune-related genes (IRGs) (FGFR2, ZC3HAV1L, TNFRSF11B, CD79A, IGHV3-11, IGHV3-21, IGKV2D-30, and IGKV6D-21) was constructed to predict the prognosis of colon cancer patients. Only TNFRSF11B was closely correlated with late-stage lymph node metastasis and worse survival outcomes (p = 0.010, p = 0.014, and p = 0.0061). In our IHC dataset, 72.09% (62/86) of the colon cancer patients had TNFRSF11B overexpression with significantly shorter overall survival times (p = 0.072). High TNFRSF11B expression typically had a later TNM stage (p = 0.067), a higher frequency of lymph node (p = 0.029) and lymphovascular (p = 0.007) invasion, and a higher incidence of pneumonia (p = 0.056) than their counterparts. The expression of six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, and YWHAZ) related to pathogenic E. coli infection was simultaneously increased with TNFRSF11B overexpression via gene set enrichment analysis (GSEA). These genes are involved in the regulation of the actin cytoskeleton, shigellosis, bacterial invasion of epithelial cells, and Salmonella infection. Finally, only activated memory CD4+ T cells (p = 0.017) were significantly decreased in the high TNFRSF11B expression group via CIBERSORT comparison, which was confirmed by TIMER2.0 analysis of the TCGA-COAD dataset. We also performed FACS analysis to show that TNFRSF11B decreased the infiltration of central memory CD4+ T cells and effector memory CD4+ T cells in the colorectal cancer microenvironment (all p <0.001). Conclusion: TNFRSF11B acts as a prognostic factor for colon cancer patients and could affect the colon cancer immune response. TNFRSF11B was closely related to lymph node invasion and pathogenic E. coli. infection, which may negatively affect memory-activated CD4+ T cell infiltration in colon cancer.
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Linfocitos T CD4-Positivos/inmunología , Neoplasias del Colon/inmunología , Osteoprotegerina/inmunología , Neoplasias del Colon/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Osteoprotegerina/genética , Microambiente Tumoral/inmunologíaRESUMEN
Normal breast fibroblasts (NBFs) support and maintain the architecture of the organ, and can also suppress tumorigenesis. However, the mechanisms involved are not fully understood. We have shown here that NBFs suppress breast carcinogenesis through secretion of osteoprotegerin (OPG), a soluble decoy receptor for the Receptor Activator of NF-κB ligand (RANKL). Indeed, NBFs and human recombinant OPG (rOPG), suppressed breast cancer cells proliferation and motility through inhibition of the epithelial-to-mesenchymal transition (EMT) process both in vitro and in vivo. Additionally, rOPG inhibited the IL-6/STAT3 and NF-κB pathways as well as the OPG gene, which turned out to be STAT3-regulated. This was confirmed using denosumab, a RANKL-targeted antibody, which also inhibited NF-κB, down-regulated OPG and repressed EMT in breast cancer cells grown in 2D and 3D. Importantly, both rOPG and denosumab targeted cancer stem cells (CSCs). This was mediated through inhibition of the CSC-related pathway ß-catenin. Moreover, rOPG reduced tumor growth and inhibited breast CSC biomarkers in orthotopic humanized breast tumors. Therefore, normal mammary fibroblasts can suppress carcinogenesis through OPG, which constitutes great potential as preventive and/or therapeutic molecule for breast carcinomas.
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Neoplasias de la Mama/tratamiento farmacológico , Osteoprotegerina/genética , Ligando RANK/genética , Proteínas Recombinantes/genética , beta Catenina/genética , Anticuerpos/farmacología , Anticarcinógenos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Denosumab/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/genética , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Osteoprotegerina/inmunología , Osteoprotegerina/farmacología , Ligando RANK/antagonistas & inhibidores , Proteínas Recombinantes/farmacología , Factor de Transcripción STAT3/genéticaRESUMEN
Experimental and clinical studies aimed at investigating the mechanism(s) underlying vascular complications of diabetes indicate that a great number of molecules are involved in the pathogenesis of these complications. Most of these molecules are inflammatory mediators or markers generated by immune or adipose tissue. Some of them, i.e. resistin and sortilin, have been shown to be involved in the cross talk between adipocytes and inflammatory cells. This interaction is an attractive area of research, particularly in type 2 diabetes and obesity. Other proteins, such as adiponectin and visfatin, appear to be more promising as possible vascular markers. In addition, some molecules involved in calcium/phosphorus metabolism, such as klotho and FGF23, have an involvement in the pathogenesis of diabetic vasculopathy, which appears to be dependent on the degree of vascular impairment. Inflammatory markers are a promising tool for treatment decisions while measuring plasma levels of adipokines, sortilin, Klotho and FGF23 in adequately sized longitudinal studies is expected to allow a more precise characterization of diabetic vascular disease and the optimal use of personalized treatment strategies.
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Tejido Adiposo/inmunología , Biomarcadores/análisis , Enfermedades Cardiovasculares/diagnóstico , Sistema Inmunológico/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras del Transporte Vesicular/análisis , Proteínas Adaptadoras del Transporte Vesicular/sangre , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Adipoquinas/análisis , Adipoquinas/sangre , Adipoquinas/inmunología , Tejido Adiposo/fisiopatología , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/inmunología , Enfermedades Cardiovasculares/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Exosomas/inmunología , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/análisis , Glucuronidasa/sangre , Glucuronidasa/inmunología , Proteínas HMGB/análisis , Proteínas HMGB/sangre , Proteínas HMGB/inmunología , Humanos , Sistema Inmunológico/fisiopatología , Interleucina-1/análisis , Interleucina-1/sangre , Interleucina-1/inmunología , Proteínas Klotho , Osteoprotegerina/análisis , Osteoprotegerina/sangre , Osteoprotegerina/inmunología , Prevalencia , Componente Amiloide P Sérico/análisis , Componente Amiloide P Sérico/inmunología , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The present study evaluated the protective effects of pseurotin A against inflammation and the destruction of cartilage in a rat model of rheumatoid arthritis (RA). RA was induced by intradermal injections of Freund's complete adjuvant (1 mg/mL), and the treatment with pseurotin A (50 and 100 mg/kg, p.o.) was administered over 1 week. The effects of pseurotin A were assessed by estimating hind paw volume (HPV) and determining the levels of inflammatory mediators in the serum and synovial fluid of collagen-induced arthritis (CIA)-induced RA rats. Western blot and histopathological assays were performed to assess changes in synovial tissues. Additionally, in vitro analyses of receptor activator of nuclear factor-kappa-Β ligand (RANKL)-stimulated RAW264.7 cells treated with pseurotin A at different concentrations (1, 10, and 100 µg/mL) were conducted to assess the effects of pseurotin A on apoptosis ratio, real-time polymerase chain reaction data, and tartrate-resistant acid phosphatase staining. Compared to the RA group, treatment with pseurotin A significantly decreased HPV and reduced the levels of inflammatory mediators in the synovial fluid and blood. Additionally, pseurotin A ameliorated the protein expressions of osteoprotegerin, nuclear factor of activated T-cells, nuclear factor-kappa beta (NF-κB), IκBα, extracellular signal regulated kinase, and P38 as well as histopathological changes in the synovial tissue of CIA-induced RA rats. The in vitro findings revealed that pseurotin A treatment did not alter the apoptosis ratio in RANKL-stimulated RAW264.7 cells but significantly reduced the mRNA expressions of calcitonin receptor, NF-κB, and matrix metallopeptidase-9. The present findings suggest that pseurotin A ameliorated the differentiation of osteoclasts and the destruction of cartilage in RA rats via regulation of the mitogen-activated protein kinase/RANKL/NF-kB pathway.
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Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Pirrolidinonas/uso terapéutico , Animales , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Experimental/prevención & control , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Cartílago/efectos de los fármacos , Cartílago/patología , Diferenciación Celular/efectos de los fármacos , Citocinas/inmunología , Dinoprostona/inmunología , Modelos Animales de Enfermedad , Articulaciones/efectos de los fármacos , Articulaciones/patología , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/inmunología , Osteoclastos/efectos de los fármacos , Osteoprotegerina/inmunología , Sustancias Protectoras/farmacología , Pirrolidinonas/farmacología , Ligando RANK/inmunología , Células RAW 264.7 , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE: To evaluate the clinical, biochemical, and microbiological reactions to nanocomposite containing amorphous calcium phosphate (ACP) in comparison to a traditional composite restorative material in early childhood caries. MATERIALS AND METHODS: Eighteen teeth were restored with the test material (ACP-containing resin) and 18 teeth were restored with the control material (traditional composite, TC) in fourteen paediatric patients using a split-mouth design. One caries- and restoration-free intact tooth in each patient was selected as the healthy control. Gingival crevicular fluid (GCF) and supragingival plaque samples were collected at baseline before the treatment and also on days 1, 7, 14 and 30 after treatment. Unstimulated whole saliva samples were obtained from each patient at baseline, and 1 and 6 months after restoration. GCF and saliva samples were assayed for IL-17A, IL-17F IL-17A/F, IL-17E, OPG and RANKL levels by ELISA, and plaque composition was assessed using RT-PCR. RESULTS: Clinical evaluation indicated no statistically significant differences between the two restorative materials according to the FDI criteria surface lustre, material retention and marginal adaptation properties. Pro-inflammatory IL-17 levels decreased statistically significantly at 6 months compared to baseline and 1-month values (p < 0.05). The baseline pro-inflammatory IL-17 cytokine levels in GCF samples around the carious teeth were higher than those obtained around the healthy teeth (p < 0.05), but similar in GCF from the ACP-test and TC teeth. Microbiological findings were similar in the ACP and T groups. CONCLUSION: It may be suggested that both ACP-containing and traditional resin composites show similar antimicrobial and biochemical effects in early childhood caries.
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Fosfatos de Calcio/uso terapéutico , Resinas Compuestas/uso terapéutico , Caries Dental/terapia , Placa Dental/microbiología , Líquido del Surco Gingival/inmunología , Saliva/inmunología , Niño , Preescolar , Caries Dental/inmunología , Caries Dental/microbiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Fusobacterium nucleatum/genética , Humanos , Interleucina-17/inmunología , Masculino , Osteoprotegerina/inmunología , Ligando RANK/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Streptococcus mutans/genética , Streptococcus sanguis/genéticaRESUMEN
Periodontitis, an inflammatory disease of the gingival tissue, triggered by microbial-derived elements, such as lipopolysaccharide (LPS), collapses the periodontal tissues and resorbs the alveolar bone. This study evaluated the inhibitory effects of standardized Boesenbergia pandurata extract (BPE) and panduratin A (PAN) on periodontitis-induced inflammation and alveolar bone loss. Sprague-Dawley rats with LPS-induced periodontitis were orally administered BPE (50 and 200 mg/kg/day) and PAN (20 mg/kg/day) for 8 days. Histological analysis revealed that BPE- and PAN-administered groups showed decreased cell infiltration and alveolar bone resorption. Furthermore, the BPE and PAN significantly alleviated the mRNA and protein expression levels of nuclear factor kappa B (NF-κB), interleukin-1ß, matrix metalloproteinase (MMP)-2, and MMP-8. BPE and PAN also inhibited the expression of nuclear factor of activated T cells, cytoplasmic 1, c-Fos, and ostoclastogenesis-related enzymes, including cathepsin K and tartrate-resistant acid phosphatase (ALP). BPE and PAN not only upregulated the osteoblastogenesis-associated markers, such as collagen type I (COL1A1) and ALP, but also increased the ratio of osteoprotegerin to receptor activator of NF-κB ligand. Collectively, BPE and PAN efficiently prevent destruction of periodontal tissues and stimulating the loss of alveolar bone tissues, strongly indicative of their potential as natural antiperiodontitis agents.
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Pérdida de Hueso Alveolar/tratamiento farmacológico , Chalconas/administración & dosificación , Enfermedades Periodontales/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Zingiberaceae/química , Pérdida de Hueso Alveolar/inducido químicamente , Pérdida de Hueso Alveolar/inmunología , Animales , Chalconas/química , Colágeno Tipo I/genética , Colágeno Tipo I/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Lipopolisacáridos/efectos adversos , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Osteoprotegerina/genética , Osteoprotegerina/inmunología , Enfermedades Periodontales/inducido químicamente , Enfermedades Periodontales/inmunología , Extractos Vegetales/química , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Our study focused on the RANKL (receptor activator of nuclear factor-κB ligand)/RANK/OPG (osteoprotegerin) axis and selected proinflammatory/immunoregulatory upstream mediators in the peripheral blood (PBL) and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. METHODS: PBL and CSF were collected from healthy controls (n = 35) and MS patients at the clinical onset of the disease (n = 33). In addition, PBL samples were obtained from relapse-remitting (RR)-MS patients (n = 30). Patients were assessed by means of the expanded disability status scale (EDSS) and routine laboratory parameters. Soluble (s)RANKL and OPG were measured in the CSF and plasma; gene expression was detected for RANKL, RANK, OPG, and selected cytokines/chemokines (interleukin [IL]-4, IL-10, IL-17, CCL2, and CXCL12) in PBL mononuclear cells. RESULTS: The OPG level in the CSF was lower in MS patients at clinical onset than in controls. Moreover, the sRANKL/OPG ratio was higher in the CSF of MS patients at clinical onset and in the plasma of RR-MS patients than in controls. Gene expression of RANKL/RANK/OPG in PBL mononuclear cells was higher only in RR-MS patients. IL-4, CCL2, and CXCL12 were positively correlated and IL-10 was negatively correlated with RANKL/RANK expression. OPG was negatively correlated with EDSS and alkaline phosphatase level. CONCLUSION: Our study revealed that changes of RANKL/RANK/OPG axis are associated with MS, particularly the decreased OPG level in the CSF at disease onset. Therefore, these factors may serve as disease biomarkers and molecular targets of novel therapeutic approaches.
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Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Osteoprotegerina/líquido cefalorraquídeo , Ligando RANK/líquido cefalorraquídeo , Receptor Activador del Factor Nuclear kappa-B/líquido cefalorraquídeo , Adulto , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Osteoprotegerina/inmunología , Ligando RANK/inmunología , Receptor Activador del Factor Nuclear kappa-B/inmunologíaRESUMEN
This study was undertaken to generate a novel dual targeting fusion protein (DTF), targeting tumor necrosis factor α (TNF-α) and interleukin 17A (IL-17A), and determine its anti-arthritis properties in vitro and in vivo. DTF consisted of an anti-IL-17A single chain variable fragment, a soluble TNF receptor 1, and an Fc fragment. Both clinical and histopathological evaluations suggest that DTF and etanercept can ameliorate collagen induced arthritis. However, the arthritis severity score of DTF-treated mice was lower than that of etanercept-treated mice. In addition, DTF was more potent than etanercept in decreasing the ratio of RANKL/OPG in the serum and rebalancing the population ratio of Treg/Th17 cells in the spleens. In vitro, IL-17A and TNF-α had synergistic effects in inducing the expression of inflammatory cytokines in fibroblast-like synoviocyte from RA patients (RA-FLS), human leukemia (THP-1), and rheumatoid synovial fibroblast (MH7A). IL-17A and TNF-α also had synergistic effects in inducing proliferation and migration of MH7A cells. However, we observed that DTF was more efficient than etanercept in suppressing these synergistic effects. Our results demonstrate that DTF is highly efficient in the treatment of arthritis and has the potential to overcome the limited therapeutic responses obtained with single cytokine neutralization.
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Artritis Experimental/tratamiento farmacológico , Citocinas/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/inmunología , Células CHO , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cricetulus , Etanercept/uso terapéutico , Femenino , Humanos , Articulaciones/efectos de los fármacos , Articulaciones/patología , Ratones Endogámicos C57BL , Osteoprotegerina/inmunología , Sinoviocitos/efectos de los fármacos , Sinoviocitos/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunologíaRESUMEN
Psoriatic arthritis (PsA) is an inflammatory rheumatic disorder that occurs in patients with psoriasis and predominantly affects musculoskeletal structures, skin, and nails. The etiology of PsA is not well understood but evidence supports an interplay of genetic, immunologic, and environmental factors which promote pathological bone remodeling and joint damage in PsA. Localized and systemic bone loss due to increased activity of osteoclasts is well established in PsA based on animal models and translational studies. In contrast, the mechanisms responsible for pathological bone remodeling in PsA remain enigmatic although new candidate molecules and pathways have been identified. Recent reports have revealed novel findings related to bone erosion and pathologic bone formation in PsA. Many associated risk factors and contributing molecular mechanisms have also been identified. In this review, we discuss new developments in the field, point out unresolved questions regarding the pathogenetic origins of the wide array of bone phenotypes in PsA, and discuss new directions for investigation.
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Artritis Psoriásica/tratamiento farmacológico , Remodelación Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Huesos/efectos de los fármacos , Animales , Artritis Psoriásica/inmunología , Remodelación Ósea/inmunología , Resorción Ósea/inmunología , Huesos/inmunología , Humanos , Osteoclastos/efectos de los fármacos , Osteoclastos/inmunología , Osteoprotegerina/inmunologíaRESUMEN
Multiple cytokines produced by immune cells induce remodeling and aid in maintaining bone homeostasis through differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we investigate bone remodeling controlled by the tumor necrosis factor (TNF) superfamily cytokine LIGHT. LIGHT-deficient mice (Tnfsf14-/- ) exhibit spine deformity and reduced femoral cancellous bone mass associated with an increase in the osteoclast number and a slight decrease of osteoblasts compared with WT mice. The effect of LIGHT in bone cells can be direct or indirect, mediated by both the low expression of the anti-osteoclastogenic osteoprotegerin (OPG) in B and T cells and reduced levels of the pro-osteoblastogenic Wnt10b in CD8+ T cells in Tnfsf14-/- mice. LIGHT stimulation increases OPG levels in B, CD8+ T, and osteoblastic cells, as well as Wnt10b expression in CD8+ T cells. The high bone mass in Light and T- and B-cell-deficient mice (Rag- /Tnfsf14- ) supports the cooperative role of the immune system in bone homeostasis. These results implicate LIGHT as a potential target in bone disease. © 2017 American Society for Bone and Mineral Research.
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Remodelación Ósea/inmunología , Hueso Esponjoso/inmunología , Fémur/inmunología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/deficiencia , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Remodelación Ósea/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Hueso Esponjoso/patología , Fémur/fisiología , Ratones , Ratones Noqueados , Osteoblastos/inmunología , Osteoclastos/inmunología , Osteoclastos/patología , Osteoprotegerina/genética , Osteoprotegerina/inmunología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Proteínas Wnt/genética , Proteínas Wnt/inmunologíaRESUMEN
Osteoporosis is a recognised complication of axial spondyloarthritis (axSpA) and is thought to be due to functional impairment and the osteoclast-activating effects of proinflammatory cytokines. The development of autoantibodies to OPG (OPG-Ab) has been associated with severe osteoporosis and increased bone resorption in rheumatoid arthritis. In this study, we screened for the presence of OPG-Ab in axSpA and reviewed their clinical significance. We studied 134 patients, recruited from two centres in the United Kingdom. Their mean age was 47.5 years and 75% were male. Concentrations of OPG-Ab were related to bone mineral density (BMD) and fracture history using linear and logistic regression models adjusting for age, gender, disease duration and activity, body mass index and bisphosphonate use. We detected OPG-Ab in 11/134 patients (8.2%). Femoral neck and total hip BMD were significantly reduced in OPG-Ab positive patients (0.827 vs. 0.967 g/cm2, p = 0.008 and 0.868 vs. 1.028 g/cm2, p = 0.002, respectively). Regression analysis showed that the presence of OPG-Ab was independently associated with total hip osteopenia (ORadj 24.2; 95% CI 2.57, 228) and history of fractures (ORadj 10.5; 95% CI 2.07, 53.3). OPG-Ab concentration was associated with total hip BMD in g/cm2 (ß = -1.15; 95% CI -0.25, -0.04). There were no associations between OPG-Ab concentration and bone turnover markers, but free sRANKL concentrations were lower in OPG-Ab-positive patients (median 0.04 vs. 0.11 pmol/L, p = 0.050). We conclude that OPG-Ab are associated with hip BMD and fractures in axSpA suggesting that they may contribute to the pathogenesis of bone loss in some patients with this condition.
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Autoanticuerpos/sangre , Densidad Ósea/inmunología , Fracturas Óseas/inmunología , Osteoprotegerina/inmunología , Espondiloartritis/inmunología , Autoantígenos/inmunología , Estudios Transversales , Femenino , Cadera , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/inmunología , Espondiloartritis/complicacionesRESUMEN
PURPOSE OF REVIEW: This review summarizes studies into the permissive role of T cells in the bone catabolic effects of hyperparathyroidism and parathyroid hormone (PTH). RECENT FINDINGS: Work in animals combined with recent translational studies in humans now highlight the potent amplificatory action of T cells on PTH-induced bone resorption. Mechanistic animal studies reveal a complex pathway by which PTH exploits natural self-renewal functions of CD4+ T cells, to drive TNFα production that promotes formation of IL-17A secreting Th17 T cells. TNFα and IL-17 further amplify osteoblastic receptor activator of NF-κB ligand (RANKL) production and down-modulate osteoprotegerin (OPG), establishing conditions propitious for osteoclastic bone resorption. These findings are consistent with, and add to, the traditional view of PTH-induced bone loss involving only osteoblast-lineage cells. T cells potently amplify traditional pathways and provide permissive costimulatory signals to bone marrow stromal cells, facilitating the development of an increased RANKL/OPG ratio favourable to bone resorption and bone loss.
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Resorción Ósea/inmunología , Hiperparatiroidismo/inmunología , Hormona Paratiroidea/inmunología , Linfocitos T/inmunología , Resorción Ósea/metabolismo , Linfocitos T CD4-Positivos/inmunología , Humanos , Hiperparatiroidismo/metabolismo , Interleucina-17/inmunología , Osteoclastos , Osteoprotegerina/inmunología , Enfermedades de las Paratiroides/inmunología , Enfermedades de las Paratiroides/metabolismo , Hormona Paratiroidea/metabolismo , Ligando RANK/inmunología , Células Th17/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
We studied associations of osteocalcin, osteoprotegerin, and calcitonin with markers of inflammation in atherosclerotic plaques in coronary arteries and assessed the influence of these biomolecules on calcification of atherosclerotic plaques. The initial stage of calcification of atherosclerotic plaques is characterized by activation of inflammatory processes, which is seen from increased levels of proinflammatory biomarkers (IL-6, IL 8, TNF-α, and IL-1ß). Progressive calcification of atherosclerotic plaques is accompanied by insignificant accumulation of calcitonin and osteoprotegerin. The exception is osteocalcin, its concentration significantly increased during calcification. The results suggest that severe vascular calcification can be regarded as non-specific marker of atherosclerosis. Instability of atherosclerotic plaques is associated with higher level of calcification.
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Aterosclerosis/diagnóstico , Calcitonina/genética , Osteocalcina/genética , Osteoprotegerina/genética , Placa Aterosclerótica/diagnóstico , Calcificación Vascular/diagnóstico , Anciano , Aterosclerosis/complicaciones , Aterosclerosis/genética , Aterosclerosis/cirugía , Biomarcadores/metabolismo , Calcitonina/inmunología , Vasos Coronarios/inmunología , Vasos Coronarios/patología , Vasos Coronarios/cirugía , Endarterectomía , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , Osteocalcina/inmunología , Osteoprotegerina/inmunología , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/genética , Placa Aterosclerótica/cirugía , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Túnica Íntima/inmunología , Túnica Íntima/patología , Túnica Íntima/cirugía , Calcificación Vascular/complicaciones , Calcificación Vascular/genética , Calcificación Vascular/cirugíaRESUMEN
Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S. aureus regulates osteoclastogenesis to obtain better understanding of the complex mechanisms of S. aureus induced bone destruction in vivo.
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Resorción Ósea/inmunología , Osteogénesis/inmunología , Hueso Parietal/inmunología , Ligando RANK/genética , Infecciones Estafilocócicas/inmunología , Receptor Toll-Like 2/genética , Animales , Animales Recién Nacidos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/microbiología , Resorción Ósea/microbiología , Resorción Ósea/patología , Regulación del Desarrollo de la Expresión Génica , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/inmunología , Osteoblastos/microbiología , Osteoclastos/inmunología , Osteoclastos/microbiología , Osteogénesis/genética , Osteoprotegerina/genética , Osteoprotegerina/inmunología , Hueso Parietal/crecimiento & desarrollo , Hueso Parietal/microbiología , Cultivo Primario de Células , Prostaglandinas/biosíntesis , Ligando RANK/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/inmunologíaRESUMEN
INTRODUCTION: This study assessed the immune-inflammatory profile and the expression of bone resorption activators receptor activator of nuclear factor kappa B ligand (RANKL) and inhibitor osteoprotegerin (OPG) in apical periodontitis (n = 20) that persisted after root canal retreatment. METHODS: Immunohistochemistry was used to characterize lymphocyte populations (CD3+, CD45RO+, CD8+, and FoxP3+ cells), macrophages (CD68+), RANKL+ and OPG+ cells in persistent apical periodontitis (PAP) and primary periapical lesions (PPLs). By using quantitative real-time polymerase chain reaction, the mRNA expression of RANKL and OPG in PAP and periodontal ligament from healthy teeth was comparatively analyzed. The data were analyzed by Mann-Whitney, Pearson χ2, and Wilcoxon tests (5% level). RESULTS: PAP showed an elevated number of FoxP3+ cells compared with PPL (P < .001). The number of CD68+ cells was reduced in the PAP samples compared with the PPLs (P < .001). Similar number of other lymphocyte populations was observed in PAP and PPLs (P > .05 for all comparisons). No differences in the RANKL, OPG, and immune-inflammatory cells were demonstrated when comparing PAP microscopically classified as cyst with those classified as granulomas (P > .05 for all comparisons). The assessment of mRNA expression revealed higher levels of RANKL and OPG in PAP compared with the periodontal ligament from healthy teeth (control) samples (P < .001). Also, a greater expression of RANKL in comparison with OPG was observed in PAP (P < .001). CONCLUSIONS: These findings indicate that PAP consists of biologically active lesions that demonstrate potential of bone resorption (higher expression of RANKL) and is characterized by an immune-inflammatory cell profile that suggests a suppressive and regulatory environment (higher number of FoxP3+ cells and lower number of macrophages) favorable to more chronic clinical behavior.
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Osteoprotegerina/biosíntesis , Periodontitis Periapical/metabolismo , Ligando RANK/biosíntesis , Tratamiento del Conducto Radicular , Adulto , Cavidad Pulpar/inmunología , Cavidad Pulpar/metabolismo , Femenino , Humanos , Linfocitos/inmunología , Linfocitos/patología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Osteoprotegerina/inmunología , Osteoprotegerina/metabolismo , Periodontitis Periapical/inmunología , Periodontitis Periapical/patología , Ligando RANK/inmunología , Ligando RANK/metabolismo , Retratamiento , Insuficiencia del TratamientoRESUMEN
Osteoporosis is a major cause of fractures and associated morbidity in the aged population. The pathogenesis of osteoporosis is multifactorial; whereas traditional pathophysiological concepts emphasize endocrine mechanisms, it has been recognized that also components of the immune system have a significant impact on bone. Since 2000, when the term 'osteoimmunology' was coined, novel insights into the role of inflammatory cytokines by influencing the fine-tuned balance between bone resorption and bone formation have helped to explain the occurrence of osteoporosis in conjunction with chronic inflammatory reactions. Moreover, the phenomenon of a low-grade, chronic, systemic inflammatory state associated with aging has been defined as 'inflamm-aging' by Claudio Franceschi and has been linked to age-related diseases such as osteoporosis. Given the tight anatomical and physiological coexistence of B cells and the bone-forming units in the bone marrow, a role of B cells in osteoimmunological interactions has long been suspected. Recent findings of B cells as active regulators of the RANK/RANKL/OPG axis, of altered RANKL/OPG production by B cells in HIV-associated bone loss or of a modulated expression of genes linked to B-cell biology in response to estrogen deficiency support this assumption. Furthermore, oxidative stress and the generation of advanced glycation end products have emerged as links between inflammation and bone destruction.
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Linfocitos B/inmunología , Osteoporosis/inmunología , Osteoprotegerina/inmunología , Ligando RANK/inmunología , Receptor Activador del Factor Nuclear kappa-B/inmunología , Citidina Desaminasa/inmunología , Productos Finales de Glicación Avanzada/inmunología , Humanos , Inflamación/inmunología , Estrés Oxidativo/inmunologíaRESUMEN
Osteoarticular brucellosis is the most common localization of human active disease. Osteocytes are the most abundant cells of bone. They secrete factors that regulate the differentiation of both osteoblasts and osteoclasts during bone remodeling. The aim of this study is to determine if Brucella abortus infection modifies osteocyte function. Our results indicate that B. abortus infection induced matrix metalloproteinase 2 (MMP-2), receptor activator for NF-κB ligand (RANKL), proinflammatory cytokines, and keratinocyte chemoattractant (KC) secretion by osteocytes. In addition, supernatants from B. abortus-infected osteocytes induced bone marrow-derived monocytes (BMM) to undergo osteoclastogenesis. Using neutralizing antibodies against tumor necrosis factor alpha (TNF-α) or osteoprotegerin (OPG), RANKL's decoy receptor, we determined that TNF-α and RANKL are involved in osteoclastogenesis induced by supernatants from B. abortus-infected osteocytes. Connexin 43 (Cx43) and the integrins E11/gp38, integrin-α, integrin-ß, and CD44 are involved in cell-cell interactions necessary for osteocyte survival. B. abortus infection inhibited the expression of Cx43 but did not modify the expression of integrins. Yet the expression of both Cx43 and integrins was inhibited by supernatants from B. abortus-infected macrophages. B. abortus infection was not capable of inducing osteocyte apoptosis. However, supernatants from B. abortus-infected macrophages induced osteocyte apoptosis in a dose-dependent manner. Taken together, our results indicate that B. abortus infection could alter osteocyte function, contributing to bone damage.
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Brucella abortus/patogenicidad , Conexina 43/biosíntesis , Integrinas/biosíntesis , Osteocitos/metabolismo , Ligando RANK/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis , Brucelosis/microbiología , Brucelosis/patología , Diferenciación Celular , Línea Celular , Quimiocina CXCL1/metabolismo , Macrófagos/microbiología , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Osteoclastos/citología , Osteocitos/microbiología , Osteoprotegerina/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
In the thymus, medullary thymic epithelial cells (mTEC) regulate T cell tolerance via negative selection and Foxp3(+) regulatory T cell (Treg) development, and alterations in the mTEC compartment can lead to tolerance breakdown and autoimmunity. Both the receptor activator for NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis and expression of the transcriptional regulator Aire are involved in the regulation of thymus medullary microenvironments. However, their impact on the mechanisms controlling mTEC homeostasis is poorly understood, as are the processes that enable the thymus medulla to support the balanced production of mTEC-dependent Foxp3(+) Treg. In this study, we have investigated the control of mTEC homeostasis and examined how this process impacts the efficacy of Foxp3(+) Treg development. Using newly generated RANK Venus reporter mice, we identify distinct RANK(+) subsets that reside within both the mTEC(hi) and mTEC(lo) compartments and that represent direct targets of OPG-mediated control. Moreover, by mapping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting mechanisms are able to control the thymus medulla by operating on multiple mTEC targets. Finally, we show that whereas the increase in mTEC availability in OPG-deficient (Tnfrsf11b(-/-)) mice impacts the intrathymic Foxp3(+) Treg pool by enhancing peripheral Treg recirculation back to the thymus, it does not alter the number of de novo Rag2pGFP(+)Foxp3(+) Treg that are generated. Collectively, our study defines patterns of RANK expression within the thymus medulla, and it shows that mTEC homeostasis is not a rate-limiting step in intrathymic Foxp3(+) Treg production.
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Linfopoyesis/inmunología , Osteoprotegerina/genética , Ligando RANK/inmunología , Linfocitos T Reguladores/inmunología , Timo/metabolismo , Animales , Autoinmunidad/inmunología , Células Cultivadas , Proteínas de Unión al ADN/genética , Células Epiteliales , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Tolerancia Inmunológica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/inmunología , Técnicas de Cultivo de Órganos , Osteoprotegerina/biosíntesis , Osteoprotegerina/inmunología , Ligando RANK/biosíntesis , Transducción de Señal/inmunología , Linfocitos T Reguladores/citología , Timo/citología , Timo/inmunología , Factores de Transcripción/biosíntesis , Proteína AIRERESUMEN
Autoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. A direct enzyme-linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. Raised titres of antibodies to OPG were found in 7/71 (9.8 %) patients with coeliac disease, compared with 1/72 (1.4 %) non-coeliac osteoporosis clinic control patients (p < 0.05). Our results suggest that a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z-score of the hip in coeliac patients on univariate (p < 0.05) and multivariate analysis including age, sex height and weight as covariates (p < 0.01). Polyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z-scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies.