RESUMEN
AIM: To study the association of bone mineral density (BMD) with serum biochemical and immunological markers in postmenopausal women with rheumatoid arthritis (RA). MATERIALS AND METHODS: The study included 173 women with RA (age 61.0 [56.0; 66.0] years). A survey, dual-energy X-ray absorptiometry to measure the BMD of the lumbar spine (LI-LIV), femoral neck (FN) and total hip (TH), routine blood chemistry, measurement of C-reactive protein (CRP), rheumatoid factor, cyclic citrullinated peptide antibodies (CCPA), parathyroid hormone (PTH), vitamin D3, myostatin, follistatin, interleukin-6 (IL-6), IL-6 receptors, insulin-like growth factor 1, adiponectin, leptin, fibroblast growth factor 23, and tumor necrosis factor SF12 were performed. RESULTS: PTH (ß=-0.22, -0.35 and -0.30 for LI-LIV, FN and TH, respectively), CRP (ß=-0.18, 0.23 and -0.22 for LI-LIV, FN and TH, respectively) and leptin (ß=0.35, 0.32 and 0.42 for LI-LIV, FN and TH, respectively) were shown a significant association with BMD in all sites of measurement. It was independent of age, body mass index and postmenopause duration. Associations were also found between adiponectin and BMD of LI-LIV and TH (ß=-0.36 and -0.28, respectively), CCPA and BMD of FN and TH (ß=-0.21, -0.24, respectively) and IL-6 and BMD of FN (ß=0.37). CONCLUSION: The study of biochemical and immunological markers in women with RA demonstrated that CRP, CCPA, PTH, IL-6, adiponectin, and leptin influenced BMD.
Asunto(s)
Artritis Reumatoide , Biomarcadores , Densidad Ósea , Humanos , Femenino , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Densidad Ósea/fisiología , Persona de Mediana Edad , Biomarcadores/sangre , Absorciometría de Fotón/métodos , Anciano , Posmenopausia/sangre , Posmenopausia/inmunología , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Adiponectina/sangre , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/fisiopatología , Osteoporosis Posmenopáusica/etiología , Leptina/sangreRESUMEN
Postmenopausal osteoporosis (PMOP) is a common metabolic inflammatory disease. In conditions of estrogen deficiency, chronic activation of the immune system leads to a hypo-inflammatory phenotype and alterations in its cytokine and immune cell profile, although immune cells play an important role in the pathology of osteoporosis, studies on this have been rare. Therefore, it is important to investigate the role of immune cell-related genes in PMOP. PMOP-related datasets were downloaded from the Gene Expression Omnibus database. Immune cells scores between high bone mineral density (BMD) and low BMD samples were assessed based on the single sample gene set enrichment analysis method. Subsequently, weighted gene co-expression network analysis was performed to identify modules highly associated with immune cells and obtain module genes. Differential analysis between high BMD and low BMD was also performed to obtain differentially expressed genes. Module genes are intersected with differentially expressed genes to obtain candidate genes, and functional enrichment analysis was performed. Machine learning methods were used to filter out the signature genes. The receiver operating characteristic (ROC) curves of the signature genes and the nomogram were plotted to determine whether the signature genes can be used as a molecular marker. Gene set enrichment analysis was also performed to explore the potential mechanism of the signature genes. Finally, RNA expression of signature genes was validated in blood samples from PMOP patients and normal control by real-time quantitative polymerase chain reaction. Our study of PMOP patients identified differences in immune cells (activated dendritic cell, CD56 bright natural killer cell, Central memory CD4 T cell, Effector memory CD4 T cell, Mast cell, Natural killer T cell, T follicular helper cell, Type 1 T-helper cell, and Type 17 T-helper cell) between high and low BMD patients. We obtained a total of 73 candidate genes based on modular genes and differential genes, and obtained 5 signature genes by least absolute shrinkage and selection operator and random forest model screening. ROC, principal component analysis, and t-distributed stochastic neighbor embedding down scaling analysis revealed that the 5 signature genes had good discriminatory ability between high and low BMD samples. A logistic regression model was constructed based on 5 signature genes, and both ROC and column line plots indicated that the model accuracy and applicability were good. Five signature genes were found to be associated with proteasome, mitochondria, and lysosome by gene set enrichment analysis. The real-time quantitative polymerase chain reaction results showed that the expression of the signature genes was significantly different between the 2 groups. HIST1H2AG, PYGM, NCKAP1, POMP, and LYPLA1 might play key roles in PMOP and be served as the biomarkers of PMOP.
Asunto(s)
Biomarcadores , Densidad Ósea , Osteoporosis Posmenopáusica , Humanos , Femenino , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/inmunología , Densidad Ósea/genética , Biomarcadores/sangre , Persona de Mediana Edad , Perfilación de la Expresión Génica/métodos , Curva ROC , Anciano , Aprendizaje AutomáticoRESUMEN
Osteoporosis is one of the chronic and often neglected bone diseases in aging postmenopausal women that affect the quality of life. Studies on ovariectomized mice models indicated the reciprocal role of Th17 cells and Treg cells in the aetiology of osteoporosis. While Th17 cells promote osteoclastogenesis, Treg cells exhibit anti-osteoclastogenic activity. This exploratory study aimed to determine the difference in the frequency of these T-cell subtypes in pre-and postmenopausal women and to examine their association with BMD. In our study, the frequency of Treg cells, analyzed by flow cytometry, did not differ between pre-and postmenopausal women. However, plasma levels of IL-10 along with IL-10+CD4+T cells were higher in post- compared to premenopausal women. The frequency of Th17 cells was higher in postmenopausal women irrespective of their BMD, however, only postmenopausal women with low BMD had elevated IL-17 levels and their T-scores were associated with Th17 frequency. Collectively, the results suggest that estrogen insufficiency in postmenopausal women may lead to increased Th17 cell frequency and elevated IL-17 levels which are associated with low BMD. This study highlights, Th17 cells and IL-17 as key players in the pathogenesis of osteoporosis and they can be the potential targets for immunotherapy in the treatment of osteoporosis.
Asunto(s)
Enfermedades Óseas Metabólicas/sangre , Enfermedades Óseas Metabólicas/inmunología , Interleucina-17/sangre , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/inmunología , Posmenopausia/sangre , Posmenopausia/inmunología , Células Th17/inmunología , Adulto , Anciano , Biomarcadores/sangre , Densidad Ósea/inmunología , Enfermedades Óseas Metabólicas/etiología , Linfocitos T CD4-Positivos/inmunología , Estudios de Cohortes , Citocinas/sangre , Estrógenos/deficiencia , Femenino , Humanos , Interleucina-10/sangre , Subunidad alfa del Receptor de Interleucina-2/sangre , Persona de Mediana Edad , Osteoporosis Posmenopáusica/etiología , Linfocitos T Reguladores/inmunologíaRESUMEN
Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause - the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.
Asunto(s)
Remodelación Ósea , Huesos/metabolismo , Estrógenos/deficiencia , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Osteoporosis Posmenopáusica/metabolismo , Linfocitos T/metabolismo , Anabolizantes/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/patología , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/patología , Transducción de Señal , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Increasing evidence in recent years has suggested that regulatory B cells (Bregs) are one of the crucial modulators in various inflammatory disease conditions. However, no study to date has investigated the significance of Bregs in modulating osteoclastogenesis. To the best of our knowledge, in the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and observed that Bregs suppress RANKL-induced osteoclastogenesis in a dose-dependent manner. We further elucidated the mechanism behind the observed suppression of osteoclasts differentiation via Bregs. Our results clearly suggested that the observed anti-osteoclastogenic property of Bregs is mediated via the production of IL-10 cytokine. Next, we explored whether Bregs have any role in mediating inflammatory bone loss under post-menopausal osteoporotic conditions in ovx mice. Remarkably, our in vivo data clearly suggest that the frequencies of both CD19+IL-10+ Bregs and CD19+CD1dhiCD5+IL-10+ "B10" Bregs were significantly reduced in case of osteoporotic mice model. Moreover, we also found a significant reduction in serum IL-10 cytokine levels in osteoporotic mice, thereby further supporting our observations. Taken together, the present study for the first time establishes the direct role of regulatory B cells in modulating osteoclastogenesis in vitro. Further, our in vivo data suggest that modulations in the percentage of Bregs population along with its reduced potential to produce IL-10 might further exacerbate the observed bone loss in ovx mice.
Asunto(s)
Linfocitos B Reguladores/inmunología , Osteoporosis Posmenopáusica/inmunología , Animales , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-10/sangre , Interleucina-10/inmunología , Ratones Endogámicos C57BL , Osteoclastos/inmunología , Osteogénesis , Osteoporosis Posmenopáusica/sangre , Ovariectomía , Bazo/citologíaRESUMEN
BACKGROUND Postmenopausal osteoporosis, a common disease among elderly women, is linked to estrogen deficiency, mechanical loading, and genotype. Circular RNAs (circRNAs) are formed through reverse splicing of the splice donor at the 3' end and the splice accepter at the 5' end in pre-mRNA and have been shown to be involved in the development of multiple diseases. Based on their high sequence conservation and stability, circRNAs may be useful biomarkers in different diseases. However, the roles of circRNAs in postmenopausal osteoporosis remain incompletely understood. MATERIAL AND METHODS Fifty-three postmenopausal women were assigned to either the postmenopausal osteoporosis group (n=28) or the control group (n=25). Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the differential expression of circRNAs between the 2 groups. Receiver-operating characteristic (ROC) curve analysis was conducted to evaluate the clinical diagnostic value of circRNA. Prediction of the binding sites between circRNA and miRNAs was conducted using miRanda and RNAhybrid. The function of the circRNA in osteoclastogenesis was determined by circRNA overexpression followed by tartrate-resistant acid phosphatase staining and RT-qPCR analysis. RESULTS Among 4 circRNAs previously identified by RNA-sequencing analysis as differentially expressed in patients with postmenopausal osteoporosis, only hsa_circ_0021739 showed a significant difference in expression between the groups and was downregulated in patients with postmenopausal osteoporosis. The hsa_circ_0021739 expression level was determined to be correlated with the lumbar vertebra, femur, and forearm T-scores. Overexpression of hsa_circ_0021739 decreased the level of hsa-miR-502-5p and inhibited the differentiation of osteoclasts. CONCLUSIONS The circRNA hsa_circ_0021739 is a potential blood biomarker for postmenopausal osteoporosis. In addition, hsa-miR-502-5p is a likely target of hsa_circ_0021739, which acts to regulate the differentiation of osteoclasts.
Asunto(s)
Leucocitos Mononucleares/inmunología , MicroARNs/genética , Osteoclastos/fisiología , Osteoporosis Posmenopáusica/genética , ARN Circular/genética , Anciano , Biomarcadores , Diferenciación Celular , Células Cultivadas , Regulación hacia Abajo , Femenino , Humanos , Osteoporosis Posmenopáusica/inmunología , Curva ROC , TranscriptomaRESUMEN
Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.
Asunto(s)
Movimiento Celular/inmunología , Intestinos , Osteoporosis Posmenopáusica , Ovariectomía , Células Th17/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Quimiocina CCL20/genética , Quimiocina CCL20/inmunología , Femenino , Humanos , Intestinos/inmunología , Intestinos/microbiología , Ratones , Ratones Noqueados , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/microbiología , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The complex crosstalk between the immune and the skeletal systems plays an indispensable role in the maintenance of skeletal homeostasis. Various cytokines are involved, including interleukin (IL)-17A. A variety of immune and inflammatory cells produces IL-17A, especially Th17 cells, a subtype of CD4+ T cells. IL-17A orchestrates diverse inflammatory and immune processes. IL-17A induces direct and indirect effects on osteoclasts. The dual role of IL-17A on osteoclasts partly depends on its concentrations and interactions with other factors. Interestingly, IL-17A exerts a dual role in osteoblasts in vitro. IL-17A is a bone-destroying cytokine in numerous immune-mediated bone diseases including postmenopausal osteoporosis (PMOP), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). This review will summarize and discuss the pathophysiological roles of IL-17A on the skeletal system and its potential strategies for application in immune-mediated bone diseases.
Asunto(s)
Artritis Psoriásica/inmunología , Artritis Reumatoide/inmunología , Interleucina-17/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporosis Posmenopáusica/inmunología , Espondiloartritis/inmunología , Artritis Psoriásica/genética , Artritis Reumatoide/genética , Citocinas/metabolismo , Humanos , Osteoporosis Posmenopáusica/genética , Transducción de Señal/inmunología , Espondiloartritis/genética , Células Th17/inmunologíaRESUMEN
Osteoimmunology is a new subject which focuses on the communication between the immune and the skeletal systems. Both the immune system and bone communicate with each other. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play important roles in immune responses and bone metabolism. TNF-α and IL-6 enhance macrophage activation and antigen presentation, as well as regulating immunity through different mechanisms. A variety of groups have reported that TNF-α suppresses osteoblasts activity at some stages of differentiation and stimulates osteoclast proliferation and differentiation. In contrast, IL-6 mediates the actions of osteoblasts and osteoclasts through sophisticated mechanisms, which reflect dual effects. Both TNF-α and IL-6 can mediate the activity of osteocytes. Furthermore, both TNF-α and IL-6 are important pathogenic factors related to immune-mediated bone diseases including rheumatoid arthritis and postmenopausal osteoporosis. This review will discuss the contradictory findings concerning TNF-α and IL-6 in osteoimmunology and their potential for clinical application.
Asunto(s)
Huesos/inmunología , Huesos/metabolismo , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Humanos , Osteoblastos/inmunología , Osteoblastos/metabolismo , Osteoclastos/inmunología , Osteoclastos/metabolismo , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/metabolismoRESUMEN
BACKGROUND: Postmenopausal osteoporosis (PMOP) is a bone metabolism disorder involving systematic inflammation activation. Blood routine examination is easily available in clinical practice and contains abundant information reflecting the systematic inflammation level. Thus, it is attractive to achieve early diagnosis of PMOP and predict osteoporotic fracture risk just based on the biomarkers in blood routine examination. METHODS: A multi-centric prospective cohort study was designed and enrolled postmenopausal women from two independent institutions. All participants underwent the dual-energy X-ray absorptiometry (DEXA) scanning for diagnosing PMOP. Blood routine examination was conducted, and the key inflammatory biomarkers such as neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were calculated. PMOP patients were followed up to observe osteoporotic fracture and identify the related risk predictors. RESULTS: A total of 92 participants out of 238 enrolled postmenopausal women were diagnosed with PMOP, with a prevalence of 38.66%. The main risk factors identified for PMOP included older age (OR = 2.06, 95% CI = 1.14-3.72), longer menopause duration (OR = 3.14, 95% CI = 2.06-4.79), higher NLR (OR = 2.11, 95% CI = 1.37-3.25), and higher SII (OR = 3.02, 95% CI = 1.98-4.61). Besides age and menopause duration, SII ≥834.89 was newly identified as a prominent risk factor for discriminating osteoporotic fracture risk in PMOP patients (HR = 3.66, 95% CI = 1.249-10.71). CONCLUSION: As an easy and economical biomarker calculated from blood routine examination, SII not only acts as a good risk predictor for PMOP diagnosis but also well discriminates the osteoporotic fracture risk, which deserves further investigation and application in clinical practice.
Asunto(s)
Biomarcadores/metabolismo , Inflamación/inmunología , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/patología , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Anciano , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Osteoporosis Posmenopáusica/diagnóstico , Factores de RiesgoRESUMEN
BACKGROUND: Oestrogen-deficiency induced by menopause is associated with reduced bone density and primary osteoporosis, resulting in an increased risk of fracture. While the exact etiology of menopause-induced primary osteoporotic bone loss is not fully known, members of the tumour necrosis factor super family (TNFSF) are known to play a role. Recent studies have revealed that the TNFSF members death receptor 3 (DR3) and one of its ligands, TNF-like protein 1A (TL1A) have a key role in secondary osteoporosis; enhancing CD14+ peripheral blood mononuclear cell (PBMC) osteoclast formation and bone resorption. Whether DR3 and TL1A contribute towards bone loss in menopause-induced primary osteoporosis however, remains unknown. METHODS: To investigate this we performed flow cytometry analysis of DR3 expression on CD14+ PBMCs isolated from pre- and early post-menopausal females and late post-menopausal osteoporotic patients. Serum levels of TL1A, CCL3 and total MMP-9 were measured by ELISA. In vitro osteoclast differentiation assays were performed to determine CD14+ monocyte osteoclastogenic potential. In addition, splenic CD4+ T cell DR3 expression was investigated 1 week and 8 weeks post-surgery, using the murine ovariectomy model. RESULTS: In contrast to pre-menopausal females, CD14+ monocytes isolated from post-menopausal females were unable to induce DR3 expression. Serum TL1A levels were decreased approx. 2-fold in early post-menopausal females compared to pre-menopausal controls and post-menopausal osteoporotic females; no difference was observed between pre-menopausal and late post-menopausal osteoporotic females. Analysis of in vitro CD14+ monocyte osteoclastogenic potential revealed no significant difference between the post-menopausal and post-menopausal osteoporotic cohorts. Interestingly, in the murine ovariectomy model splenic CD4+ T cell DR3 expression was significantly increased at 1 week but not 8 weeks post-surgery when compared to the sham control. CONCLUSION: Our results reveals for the first time that loss of oestrogen has a significant effect on DR3; decreasing expression on CD14+ monocytes and increasing expression on CD4+ T cells. These data suggest that while oestrogen-deficiency induced changes in DR3 expression do not affect late post-menopausal bone loss they could potentially have an indirect role in early menopausal bone loss through the modulation of T cell activity.
Asunto(s)
Estrógenos/deficiencia , Osteoporosis Posmenopáusica/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adulto , Anciano , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Receptores de Lipopolisacáridos/metabolismo , Menopausia/sangre , Menopausia/fisiología , Ratones , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/inmunología , Ovariectomía , Adulto JovenRESUMEN
Milk contains various bioactive components with osteoanabolic properties. This study investigates the comparative effect of the whey-derived antioxidative (YVEEL) and angiotensin-converting enzyme inhibitory (YLLF) bioactive peptides on bone remodelling in ovariectomised (OVX) osteoporotic rat model. OVX animals were administered with antioxidative (AO) (500 µg kg-1 day-1) and angiotensin-converting enzyme inhibitory (ACE inhibitory) (50 µg kg-1 day-1) peptides for eight weeks. Trabecular microarchitectural parameters of femoral and tibiae bone were determined using micro-CT scan. Bone formation, resorption, turnover markers (ALP, RANKL, OCN) and inflammatory cytokines (TNF-α, TGF-ß, IFN-γ) were determined by ELISA. Both AO and ACE inhibitory peptides inhibited the increase in bone turnover and inflammatory cytokines while increased the bone formation markers. The altered morphometric parameters of femoral and tibiae bones due to OVX were strikingly attenuated by the peptide administration. The results indicated that AO peptide exerts more osteoprotective potential than ACE inhibitory peptide by suppressing inflammatory status and enhancing bone formation markers.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Suplementos Dietéticos , Oligopéptidos/uso terapéutico , Osteoporosis Posmenopáusica/prevención & control , Fragmentos de Péptidos/uso terapéutico , Proteína de Suero de Leche/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antiinflamatorios no Esteroideos , Antioxidantes/química , Antioxidantes/uso terapéutico , Biomarcadores/sangre , Conservadores de la Densidad Ósea/química , Remodelación Ósea , Huesos/diagnóstico por imagen , Huesos/inmunología , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/inmunología , Femenino , Humanos , Mediadores de Inflamación/sangre , Oligopéptidos/química , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/diagnóstico por imagen , Osteoporosis Posmenopáusica/inmunología , Ovariectomía/efectos adversos , Fragmentos de Péptidos/química , Distribución Aleatoria , Ratas Wistar , Tomografía Computarizada por Rayos X , Proteína de Suero de Leche/químicaRESUMEN
OBJECTIVES: Postmenopausal osteoporosis is one of most commonly occurring skeletal diseases leading to bone loss and fragility. Probiotics have been associated with various immunomodulatory properties and thus can be exploited to enhance bone health. In the present study, we report, to our knowledge for the first time, that oral administration of Bacillus clausii (BC) in postmenopausal osteoporotic (OVX) mice model enhances bone health. METHODS: BC was selected as probiotic of choice due to its established immunomodulatory properties. BC skews the Treg-Th17 cell balance in vivo by inhibiting osteoclastogenic Th17 cells and promoting antiosteoclastogenic Treg cell development in postmenopausal osteoporotic mice. Mice were divided into three groups (sham, OVX, and OVX + BC), and BC was administered orally in drinking water for 6 wk post-ovariectomy. At the end of experiment, mice were sacrificed and bones were analyzed for various parameters, along with lymphoid tissues for Treg-Th17 cells and serum cytokines. RESULTS: We observed that BC administration enhanced bone health. This effect of BC administration was found due to skewing of Treg-Th17 cell balance (enhanced Treg and decreased Th17 cells) in vivo. BC administration reduced levels of proinflammatory cytokines (interleukin [IL]-6, IL-17, IFN-γ and tumor necrosis factor-α) and increased levels of anti-inflammatory cytokine (IL-10). CONCLUSIONS: The present study strongly supports and establishes the osteoprotective potential of BC leading to enhanced bone health in postmenopausal osteoporotic mice model.
Asunto(s)
Bacillus clausii , Osteoporosis Posmenopáusica/terapia , Probióticos/uso terapéutico , Linfocitos T Reguladores/microbiología , Células Th17/microbiología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Osteogénesis/inmunología , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/microbiologíaRESUMEN
Osteomicrobiology refers to the role of microbiota in bone health and the mechanisms by which the microbiota regulates post-natal skeletal development, bone aging, and pathologic bone loss. Here, we review recent reports linking gut microbiota to changes in bone phenotype. A pro-inflammatory cytokine milieu drives bone resorption in conditions such as sex steroid hormone deficiency. The response of the immune system to activation by the microbiome results in increased circulating osteoclastogenic cytokines in a T cell-dependent mechanism. Additionally, gut microbiota affect bone homeostasis through nutrient absorption, mediation of the IGF-1 pathway, and short chain fatty acid and metabolic products. Manipulation of microbiota through prebiotics or probiotics reduces inflammatory cytokine production, leading to changes in bone density. One mechanism of probiotic action is through upregulating tight junction proteins, increasing the strength of the gut epithelial layer, and leading to less antigen presentation and less activation of intestinal immune cells. Thus, prebiotics or probiotics may represent a future therapeutic avenue for ameliorating the risk of postmenopausal bone loss in humans.
Asunto(s)
Huesos/inmunología , Intestinos/inmunología , Microbiota/inmunología , Osteoporosis Posmenopáusica/inmunología , Animales , Humanos , Sistema Inmunológico/inmunología , PrebióticosRESUMEN
Rheumatoid arthritis (RA) is characterized, among other factors, by systemic bone loss, reaching ~50% prevalence of osteoporosis in postmenopausal women. This is roughly a doubled prevalence in comparison with age-matched non-RA women. Postmenopausal RA women are more likely to be sero-positive for the anti-citrullinated peptide antibody (ACPA). Our extensive review of recent scientific literature enabled us to propose several mechanisms as responsible for the accelerated bone loss in ACPA(+) RA postmenopausal women. Menopause-associated estrogen deficiency plays a major role in these pathological mechanisms, as follows.
Asunto(s)
Artritis Reumatoide/complicaciones , Resorción Ósea/inmunología , Estrógenos/deficiencia , Osteoporosis Posmenopáusica/epidemiología , Osteoporosis Posmenopáusica/inmunología , Anticuerpos Antiproteína Citrulinada/inmunología , Artritis Reumatoide/inmunología , Femenino , Humanos , Prevalencia , Células Th17/inmunologíaRESUMEN
This study represented a translational study that first compared gene expression of B cells of BM from ovariectomized and control mice, and then analyzed some of the differentially expressed genes in women. Results showed novel genetic associations with bone phenotypes and points to the CD80 gene as relevant in postmenopausal bone loss. INTRODUCTION: Osteoporosis is a multifactorial disease with a strong genetic component. However, to date, research into osteoporosis has only been able to explain a small part of its heritability. Moreover, several components of the immune system are involved in the regulation of bone metabolism. Among them, B cells occupy a prominent place. METHODS: The study consisted of two stages. In the first, gene expression in bone marrow B cells is compared between ovariectomized and SHAM control mice using microarrays. In the second, we studied the association of polymorphisms in some differentially expressed genes (DEG) in a cohort of postmenopausal women. RESULTS: The present study has found 2791 DEG (false discovery rate (FDR) <5%), of which 1569 genes were upregulated (56.2%) and 1122 genes (43.8%) were downregulated. Among the most altered pathways were inflammation, interleukin signaling, B cell activation, TGF-beta signaling, oxidative stress response, and Wnt-signaling. Sixteen DEG were validated by MALDI-TOF mass spectrometry or qPCR. The translational stage of the study genotyped nine single nucleotide polymorphisms (SNPs) of DEG or related and detected association with bone mineral density (BMD) (nominal P values), while adjusting for confounders, for SNPs in the CD80, CD86, and HDAC5 genes. In the logistic regression analysis adjusted for confounders, in addition to the SNPs in the aforementioned genes, the SNPs in the MMP9 and SOX4 genes were associated with an increased risk of osteoporosis. Finally, two SNPs (in the CD80 and SOX6 genes) were associated with an increased risk of bone fragility fracture (FF). However, after Bonferroni correction for multiple testing, only the association between CD80 with BMD and risk of osteoporosis remained significant. CONCLUSION: These results show that the use of animal models is an appropriate method for identifying genes associated with human bone phenotypes.
Asunto(s)
Antígeno B7-1/genética , Osteoporosis Posmenopáusica/genética , Adulto , Anciano , Animales , Antropometría/métodos , Linfocitos B/metabolismo , Densidad Ósea/genética , Densidad Ósea/inmunología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Osteoporosis Posmenopáusica/inmunología , Ovariectomía , Fenotipo , Polimorfismo de Nucleótido Simple , Investigación Biomédica Traslacional/métodosRESUMEN
A growing understanding of the bone remodeling process suggests that inflammation significantly contributes to the pathogenesis of osteoporosis. T cells and various cytokines contribute majorly to the estrogen deficiency-induced bone loss. Recent studies have identified the IL-12 cytokine family as consisting of pro-inflammatory IL-12 and IL-23 and the anti-inflammatory IL-27 and IL-35 cytokines. IL-27 exerts protective effects in autoimmune diseases like experimental autoimmune encephalomyelitis; however, its role in the pathogenesis of osteoporosis remains to be determined. In this report, we study the effect of IL-27 supplementation on ovariectomized estrogen-deficient mice on various immune and skeletal parameters. IL-27 treatment in ovariectomized mice suppressed Th17 cell differentiation by inhibiting transcription factor RORγt. Supplementation of IL-27 activates Egr-2 to induce IL-10 producing Tr1 cells. IL-27 treatment prevented the loss of trabecular micro-architecture and preserved cortical bone parameters. IL-27 also inhibited osteoblast apoptosis through increased Egr-2 expression, which induces anti-apoptotic factors like MCL-1. IL-27 suppressed osteoclastogenesis in an Egr-2-dependent manner that up-regulates Id2, the repressor of the receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis. Additionally, these results were corroborated in female osteoporotic subjects where we found decreased serum IL-27 levels along with reduced Egr-2 expression. Our study forms a strong basis for using humanized IL-27 toward the treatment of post-menopausal osteoporosis.
Asunto(s)
Antiinflamatorios/uso terapéutico , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Interleucina-27/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/inmunología , Antiinflamatorios/metabolismo , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/metabolismo , Huesos/patología , Células Cultivadas , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Estrógenos/genética , Femenino , Eliminación de Gen , Humanos , Interleucina-10/inmunología , Interleucina-27/genética , Interleucina-27/inmunología , Ratones , Ratones Endogámicos BALB C , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/inmunología , Osteoclastos/patología , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/patología , ARN Mensajero/genética , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/patologíaRESUMEN
BACKGROUND: Increased reactive oxygen species and estrogen deficiency contribute to the pathophysiology of postmenopausal osteoporosis. Reactive oxygen species contribute to bone degradation and is necessary for RANKL-induced osteoclast differentiation. In postmenopausal bone loss, reactive oxygen species can also activate immune cells to further enhance bone resorption. Here, we investigated the role of reactive oxygen species in ovariectomy-induced osteoporosis in mice deficient in Ncf1, a subunit for the NADPH oxidase 2 and a well-known regulator of the immune system. METHODS: B10.Q wild-type (WT) mice and mice with a spontaneous point mutation in the Ncf1-gene (Ncf1*/*) were ovariectomized (ovx) or sham-operated. After 4 weeks, osteoclasts were generated ex vivo, and bone mineral density was measured using peripheral quantitative computed tomography. Lymphocyte populations, macrophages, pre-osteoclasts and intracellular reactive oxygen species were analyzed by flow cytometry. RESULTS: After ovx, Ncf1*/*-mice formed fewer osteoclasts ex vivo compared to WT mice. However, trabecular bone mineral density decreased similarly in both genotypes after ovx. Ncf1*/*-mice had a larger population of pre-osteoclasts, whereas lymphocytes were activated to the same extent in both genotypes. CONCLUSION: Ncf1*/*-mice develop fewer osteoclasts after ovx than WT mice. However, irrespective of genotype, bone mineral density decreases after ovx, indicating that a compensatory mechanism retains bone degradation after ovx.
Asunto(s)
Densidad Ósea , Resorción Ósea/inmunología , Estrógenos/metabolismo , NADPH Oxidasas/metabolismo , Osteoclastos/metabolismo , Osteoporosis Posmenopáusica/metabolismo , Especies Reactivas de Oxígeno/inmunología , Animales , Resorción Ósea/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Genotipo , Humanos , Activación de Linfocitos , Macrófagos/inmunología , Ratones , NADPH Oxidasas/genética , Osteoclastos/inmunología , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/inmunología , Ovariectomía , Mutación Puntual , Especies Reactivas de Oxígeno/metabolismoRESUMEN
IL-18BP is a natural antagonist of pro-inflammatory IL-18 cytokine linked to autoimmune disorders like rheumatoid arthritis. However, its role in post menopausal osteoporosis is still unknown. In this study, we investigated the role of IL-18BP on murine osteoblasts, its effect on osteoblasts-CD4+ T cells and osteoblasts-CD11b+ macrophage co-culture. mIL-18BPd enhances osteoblast differentiation and inhibits the activation of NLRP3 inflammasome and caspase-1 which process IL-18 to its active form. Using estrogen deficient mice, we also determined the effect of mIL-18BP on various immune and skeletal parameters. Ovariectomized mice treated with mIL-18BPd exhibited decrease in Th17/Treg ratio and pro-inflammatory cytokines. mIL-18BPd treatment restored trabecular microarchitecture, preserved cortical bone parameters likely attributed to an increased number of bone lining cells and reduced osteoclastogenesis. Importantly, these results were corroborated in female osteoporotic subjects where decreased serum IL-18BP levels and enhanced serum IL-18 levels were observed. Our study forms a strong basis for using humanized IL-18BP towards the treatment of postmenopausal osteoporosis.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Osteoporosis Posmenopáusica/metabolismo , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Proteína Morfogenética Ósea 2/genética , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamasomas/metabolismo , Mediadores de Inflamación , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Interleucina-18/metabolismo , Leucocitos Mononucleares , Linfopoyesis/genética , Linfopoyesis/inmunología , Ratones , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/inmunología , Osteoporosis Posmenopáusica/patología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/metabolismoRESUMEN
INTRODUCTION: Postmenopausal women with rheumatoid arthritis (RA) have increased risk of developing osteoporosis due to chronic inflammation and estrogen deprivation. Collagen antibody-induced arthritis (CAIA), an experimental polyarthritis model representing the effector phase of arthritis, is mainly mediated by the innate immune system. Compared to the widely used collagen-induced arthritis model, CAIA is conveniently short and can be used in C57BL/6 mice, enabling studies with knock-out mice. However, the impact on bone of the CAIA model in C57BL/6 mice has not previously been studied. Therefore, the aim of this study was to determine if CAIA can be used to study postmenopausal arthritis-induced osteoporosis. METHODS: CAIA was induced by administration of collagen-type II antibodies and lipopolysaccharide to ovariectomized female C57BL/6J mice. Control mice received lipopolysaccharide, but no antibodies. Nine days later, femurs were collected for high-resolution micro-CT and histomorphometry. Serum was used to assess cartilage breakdown and levels of complement. Frequencies of immune cell subsets from bone marrow and lymph nodes were analyzed by flow cytometery. RESULTS: Trabecular bone mass was decreased and associated with increased number of osteoclasts per bone surface in the CAIA model. Also, the frequency of interleukin-17(+) cells in lymph nodes was increased in CAIA. CONCLUSION: The present study show that CAIA, a short reproducible arthritis model that is compatible with C57BL/6 mice, is associated with increased number of osteoclasts and trabecular bone loss.