RESUMO
Background: There are complex interactions between osteoporosis and the immune system, and it has become possible to explore their causal relationship based on Mendelian randomization methods. Methods: Utilizing openly accessible genetic data and employing Mendelian randomization analysis, we investigated the potential causal connection between 731 immune cell traits and the risk of developing osteoporosis. Results: Ten immune cell phenotypes were osteoporosis protective factors and three immune cell phenotypes were osteoporosis risk factors. Specifically, the odds ratio (OR) of IgD+ CD24+ %B cell (B cell panel) risk on Osteoporosis was estimated to be 0.9986 (95% CI = 0.9978~0.9996, P<0.01). The OR of CD24+ CD27+ %B cell (B cell panel) risk on Osteoporosis was estimated to be 0.9991 (95% CI = 0.9984~0.9998, P = 0.021). The OR of CD33- HLA DR+AC (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9996 (95% CI = 0.9993~0.9999, P = 0.038). The OR of EM CD8br %CD8br (Maturation stages of T cell panel) risk on Osteoporosis was estimated to be 1.0004 (95% CI = 1.0000~1.0008, P = 0.045). The OR of CD25 on IgD+ (B cell panel) risk on Osteoporosis was estimated to be 0.9995 (95% CI = 0.9991~0.9999, P = 0.024). The OR of CD25 on CD39+ activated Treg+ (Treg panel) risk on Osteoporosis was estimated to be 1.001 (95% CI = 1.0001~1.0019, P = 0.038). The OR of CCR2 on CD62L+ myeloid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9992 (95% CI = 0.9984~0.9999, P = 0.048). The OR of CCR2 on CD62L+ plasmacytoid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9993 (95% CI = 0.9987~0.9999, P = 0.035). The OR of CD45 on CD33dim HLA DR+ CD11b- (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9988 (95% CI = 0.9977~0.9998, P = 0.031). The OR of CD45 on Mo MDSC (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9992 (95% CI = 0.9985~0.9998, P = 0.017). The OR of SSC-A on B cell (TBNK panel) risk on Osteoporosis was estimated to be 0.9986 (95% CI = 0.9972~0.9999, P = 0.042). The OR of CD11c on CD62L+ myeloid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9987 (95% CI = 0.9978~0.9996, P<0.01). The OR of HLA DR on DC (cDC panel) risk on Osteoporosis was estimated to be 1.0007 (95% CI = 1.0002~1.0011, P<0.01). No causal effect of osteoporosis on immune cells was observed. Conclusions: Our study identified 13 unreported immune phenotypes that are causally related to osteoporosis, providing a theoretical basis for the bone immunology doctrine.
Assuntos
Imunofenotipagem , Análise da Randomização Mendeliana , Osteoporose , Humanos , Osteoporose/genética , Osteoporose/epidemiologia , Osteoporose/imunologia , Fatores de Risco , Predisposição Genética para Doença , Linfócitos B/imunologiaRESUMO
OBJECTIVE: Osteoporosis (OP) is a disease characterized by decreased bone mass, deteriorated microstructure, and increased fragility and fracture risk. The diagnosis and prevention of OP and its complications have become major public health challenges. Therefore, exploring the complex ecological connections between the immune and skeletal systems may provide new insights for clinical prevention and treatment strategies. METHODS: First, we performed single-cell RNA sequencing on human lumbar lamina tissue and conducted clustering and subgroup analysis of quality-controlled single-cell transcriptome data to identify target subgroups. Subsequently, enrichment analysis and pseudotime analysis were performed. In addition, we conducted in-depth studies on the gene regulatory network between different cell subgroups and the communication between bone immune cells. RESULTS: In this study, we identified several cell subgroups that may be involved in the progression of OP. For example, the CCL4+ NKT and CXCL8+ neutrophils subgroups promote OP progression by mediating an inflammatory environment that disrupts bone homeostasis, and the MNDA+ Mac subgroup promotes osteoclast differentiation to promote OP. Moreover, the TNFAIP6+ Obl, NR4A2+ B and HMGN2+ erythrocyte subgroups promoted the balance of bone metabolism and suppressed OP. In the cell communication network, Obl closely interacts with immune cell subgroups through the CXCR4-CXCL12, CTGF-ITGB2, and TNFSF14-TNFRSF14 axes. CONCLUSION: Our research revealed specific subgroups and intercellular interactions that play crucial roles in the pathogenesis of OP, providing potential new insights for more precise therapeutic interventions for OP.
Assuntos
Osteoporose , Análise de Célula Única , Humanos , Osteoporose/imunologia , Osteoporose/genética , Análise de Sequência de RNA , Sistema Imunitário/imunologia , Transcriptoma , Feminino , Osso e Ossos/metabolismo , Osso e Ossos/imunologia , Osso e Ossos/patologia , Redes Reguladoras de Genes , Osteoclastos/imunologia , Comunicação Celular , MasculinoRESUMO
Osteoporosis, characterized by compromised bone density and microarchitecture, represents a significant global health challenge, particularly in aging populations. This comprehensive review delves into the intricate signaling pathways implicated in the pathogenesis of osteoporosis, providing valuable insights into the pivotal role of signal transduction in maintaining bone homeostasis. The exploration encompasses cellular signaling pathways such as Wnt, Notch, JAK/STAT, NF-κB, and TGF-ß, all of which play crucial roles in bone remodeling. The dysregulation of these pathways is a contributing factor to osteoporosis, necessitating a profound understanding of their complexities to unveil the molecular mechanisms underlying bone loss. The review highlights the pathological significance of disrupted signaling in osteoporosis, emphasizing how these deviations impact the functionality of osteoblasts and osteoclasts, ultimately resulting in heightened bone resorption and compromised bone formation. A nuanced analysis of the intricate crosstalk between these pathways is provided to underscore their relevance in the pathophysiology of osteoporosis. Furthermore, the study addresses some of the most crucial long non-coding RNAs (lncRNAs) associated with osteoporosis, adding an additional layer of academic depth to the exploration of immune system involvement in various types of osteoporosis. Finally, we propose that SKP1 can serve as a potential biomarker in osteoporosis.
Assuntos
Osteoporose , Transdução de Sinais , Osteoporose/imunologia , Osteoporose/genética , Osteoporose/metabolismo , Humanos , Animais , Remodelação Óssea , Osteoclastos/metabolismo , Osteoclastos/imunologia , Osteoblastos/metabolismo , Osteoblastos/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Osteoporosis represents a systemic imbalance in bone metabolism, augmenting the susceptibility to fractures among patients and emerging as a notable mortality determinant in the elderly population. It has evolved into a worldwide concern impacting the physical well-being of the elderly, imposing a substantial burden on both human society and the economy. Presently, the precise pathogenesis of osteoporosis remains inadequately characterized and necessitates further exploration. The advancement of osteoporosis is typically linked to the initiation of an inflammatory response. Cells in an inflammatory environment can cause inflammatory death including pyroptosis. Pyroptosis is a recently identified form of programmed cell death with inflammatory properties, mediated by the caspase and gasdermin families. It is regarded as the most inflammatory form of cell death in contemporary medical research. Under the influence of diverse cytokines, macrophages, and other immune cells may undergo pyroptosis, releasing inflammatory factors, such as IL-1ß and IL-18. Numerous lines of evidence highlight the pivotal role of pyroptosis in the pathogenesis of inflammatory diseases, including cancer, intestinal disorders, hepatic conditions, and cutaneous ailments. Osteoporosis progression is frequently associated with inflammation; hence, pyroptosis may also play a role in the pathogenesis of osteoporosis to a certain extent, making it a potential target for treatment. This paper has provided a comprehensive summary of pertinent research concerning pyroptosis and its impact on osteoporosis. The notion proposing that pyroptosis mediates osteoporosis via the inflammatory immune microenvironment is advanced, and we subsequently investigate potential targets for treating osteoporosis through the modulation of pyroptosis.
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Inflamação , Osteoporose , Piroptose , Humanos , Piroptose/imunologia , Osteoporose/imunologia , Osteoporose/metabolismo , Osteoporose/etiologia , Animais , Inflamação/imunologia , Microambiente Celular/imunologiaRESUMO
As the world population ages, osteoporosis, the most common disease of bone metabolism, affects more than 200 million people worldwide. The etiology is an imbalance in bone remodeling process resulting in more significant bone resorption than bone remodeling. With the advent of the osteoimmunology field, the immune system's role in skeletal pathologies is gradually being discovered. The cytokine interferon-gamma (IFN-γ), a member of the interferon family, is an important factor in the etiology and treatment of osteoporosis because it mediates bone remodeling. This review starts with bone remodeling process and includes the cellular and key signaling pathways of bone remodeling. The effects of IFN-γ on osteoblasts, osteoclasts, and bone mass are discussed separately, while the overall effects of IFN-γ on primary and secondary osteoporosis are summarized. The net effect of IFN-γ on bone appears to be highly dependent on the environment, dose, concentration, and stage of cellular differentiation. This review focuses on the mechanisms of bone remodeling and bone immunology, with a comprehensive discussion of the relationship between IFN-γ and osteoporosis. Finding the paradoxical balance of IFN-γ in bone immunology and exploring the potential of its clinical application provide new ideas for the clinical treatment of osteoporosis and drug development.
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Remodelação Óssea , Interferon gama , Osteoporose , Humanos , Remodelação Óssea/efeitos dos fármacos , Osteoporose/imunologia , Osteoporose/etiologia , Interferon gama/metabolismo , Interferon gama/imunologia , Animais , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteoblastos/imunologia , Osteoblastos/metabolismo , Transdução de Sinais , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Osso e Ossos/patologiaRESUMO
Disulfidptosis, a newly recognized cell death triggered by disulfide stress, has garnered attention for its potential role in osteoporosis (OP) pathogenesis. Although sulfide-related proteins are reported to regulate the balance of bone metabolism in OP, the precise involvement of disulfidptosis regulators remains elusive. Herein, leveraging the GSE56815 dataset, we conducted an analysis to delineate disulfidptosis-associated diagnostic clusters and immune landscapes in OP. Subsequently, vertebral bone tissues obtained from OP patients and controls were subjected to RNA sequencing (RNA-seq) for the validation of key disulfidptosis gene expression. Our analysis unveiled seven significant disulfidptosis regulators, including FLNA, ACTB, PRDX1, SLC7A11, NUBPL, OXSM, and RAC1, distinguishing OP samples from controls. Furthermore, employing a random forest model, we identified four diagnostic disulfidptosis regulators including FLNA, SLC7A11, NUBPL, and RAC1 potentially predictive of OP risk. A nomogram model integrating these four regulators was constructed and validated using the GSE35956 dataset, demonstrating promising utility in clinical decision-making, as affirmed by decision curve analysis. Subsequent consensus clustering analysis stratified OP samples into two different disulfidptosis subgroups (clusters A and B) using significant disulfidptosis regulators, with cluster B exhibiting higher disulfidptosis scores and implicating monocyte immunity, closely linked to osteoclastogenesis. Notably, RNA-seq analysis corroborated the expression patterns of two disulfidptosis modulators, PRDX1 and OXSM, consistent with bioinformatics predictions. Collectively, our study sheds light on disulfidptosis patterns, offering potential markers and immunotherapeutic avenues for future OP management.
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Osteoporose , Análise de Sequência de RNA , Proteínas rac1 de Ligação ao GTP , Humanos , Osteoporose/genética , Osteoporose/imunologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Filaminas/genética , Feminino , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Nomogramas , Masculino , PeroxirredoxinasRESUMO
A retrospective analysis was conducted using data from the NHANES. Bone mineral density (BMD) was compared in different thyroid-specific autoantibodies groups. Strengths of associations were calculated by using binary logistic regression models. Higher titers of thyroid-specific autoantibodies (TgAb and/or TPOAb) may lead to decreased BMD. Higher prevalence of TgAb and TPOAb significantly associated with fractures in females but not in males. PURPOSE: Hashimoto's thyroiditis is characterized by elevated thyroid-specific autoantibodies. It is currently believed that osteoporosis is not only a disease with abnormal mineral metabolism but also with immune abnormalities. This study investigated the relationship between thyroid-specific autoantibodies and osteoporosis, including the bone mineral density (BMD) values and fractures. METHODS: A retrospective analysis was conducted using data from the National Health and Nutrition Examination Survey (2007-2010). BMD was compared in different thyroid-specific autoantibodies groups. The associations between thyroid-specific autoantibodies and fractures were explored. Strengths of associations were calculated by binary logistic regression models. Candidate variables for binary logistic regression model were selected after screened in univariate analysis (variables with P < 0.05). RESULTS: A total of 3865 study participants were included in this analysis; 224 participants were TgAb positive and 356 were TPOAb positive. A total of 392 participants reported hip, spine or wrist fractures. Participants with higher prevalence of TgAb or TPOAb had lower BMD. In females, significant cigarettes use, higher prevalence of TgAb and TPOAb, and the BMD of the total femur and femoral neck were significantly associated with fractures. Higher prevalence of TPOAb was particularly associated with a higher possibility of hip or spine fractures. In males, significant cigarettes use, 25OHD3, the BMD values of the total femur, femoral neck and total spine were significantly associated with fractures. CONCLUSION: Higher prevalence of thyroid-specific autoantibodies may lead to decreased BMD. In females, higher prevalence of TgAb and TPOAb significantly associated with fractures and TPOAb especially relating to the fractures of hip and spine. Males patients with vitamin D deficiency or insufficiency associated a higher possibility of fractures.
Assuntos
Autoanticorpos , Densidade Óssea , Inquéritos Nutricionais , Fraturas por Osteoporose , Humanos , Feminino , Autoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , Densidade Óssea/fisiologia , Estudos Retrospectivos , Fraturas por Osteoporose/imunologia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/fisiopatologia , Fraturas por Osteoporose/sangue , Idoso , Adulto , Prevalência , Estados Unidos/epidemiologia , Iodeto Peroxidase/imunologia , Osteoporose/imunologia , Osteoporose/epidemiologia , Osteoporose/fisiopatologia , Fatores SexuaisRESUMO
BACKGROUND AND PURPOSE: Osteoporosis (OP) is a frequent clinical problem for the elderly. Traditional Chinese Medicine (TCM) has achieved beneficial results in the treatment of OP. Ziyuglycoside II (ZGS II) is a major active compound of Sanguisorba officinalis L. that has shown anti-inflammation and antioxidation properties, but little information concerning its anti-OP potential is available. Our research aims to investigate the mechanism of ZGS II in ameliorating bone loss by inflammatory responses and regulation of gut microbiota and short chain fatty acids (SCFAs) in ovariectomized (OVX) mice. METHODS: We predicted the mode of ZGS II action on OP through network pharmacology and molecular docking, and an OVX mouse model was employed to validate its anti-OP efficacy. Then we analyzed its impact on bone microstructure, the levels of inflammatory cytokines and pain mediators in serum, inflammation in colon, intestinal barrier, gut microbiota composition and SCFAs in feces. RESULTS: Network pharmacology identified 55 intersecting targets of ZGS II related to OP. Of these, we predicted IGF1 may be the core target, which was successfully docked with ZGS II and showed excellent binding ability. Our in vivo results showed that ZGS II alleviated bone loss in OVX mice, attenuated systemic inflammation, enhanced intestinal barrier, reduced the pain threshold, modulated the abundance of gut microbiota involving norank_f__Muribaculaceae and Dubosiella, and increased the content of acetic acid and propanoic acid in SCFAs. CONCLUSIONS: Our data indicated that ZGS II attenuated bone loss in OVX mice by relieving inflammation and regulating gut microbiota and SCFAs.
Assuntos
Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Simulação de Acoplamento Molecular , Osteoporose , Ovariectomia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Feminino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Saponinas/farmacologia , Saponinas/uso terapêutico , Humanos , Citocinas/metabolismo , Farmacologia em Rede , Inflamação/tratamento farmacológicoRESUMO
NOD-like receptor family CARD domain containing 3 (NLRC3) is the intracellular protein belonging to NLR (NOD-like receptor) family. NLRC3 can negatively regulate inflammatory signal transduction pathways within the adaptive and innate immunocytes. However, studies need to elucidate the biological role of NLRC3 in bone remodeling. Herein, our study proved that NLRC3 prevents bone loss by inhibiting TNFα+ Th17 cell responses. In osteoporosis, NLRC3 attenuated TNFα+ Th17 cell accumulation in the bone marrow. However, osteoporosis (OP) development was aggravated without affecting bone marrow macrophage (BMM) osteoclastogenesis in NLRC3-deficient ovariectomized (OVX) mice. In this study, we transferred the wild-type and NLRC3-/- CD4+ cells into Rag1-/- mice. Consequently, we evidenced the effects of NLRC3 in CD4+ T cells on inhibiting the accumulation of TNFα + Th17 cells, thus restricting bone loss in the OVX mice. Simultaneously, NLRC3-/- CD4+ T cells promoted the recruitment of osteoclast precursors and inflammatory monocytes into the OVX mouse bone marrow. Mechanism-wise, NLRC3 reduced the secretion of TNFα + Th17 cells of RANKL, MIP1α, and MCP1, depending on the T cells. In addition, NLRC3 negatively regulated the Th17 osteoclastogenesis promoting functions via limiting the NF-κB activation. Collectively, this study appreciated the effect of NLRC3 on modulating bone mass via adaptive immunity depending on CD4+ cells. According to findings of this study, NLRC3 may be the candidate anti-OP therapeutic target. KEY MESSAGES: NLRC3 negatively regulated the Th17 osteoclastogenesis promoting functions via limiting the NF-κB activation. NLRC3 may be the candidate anti-OP therapeutic target.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Osteoclastos , Osteogênese , Osteoporose , Células Th17 , Fator de Necrose Tumoral alfa , Animais , Feminino , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteoporose/genética , Osteoporose/imunologia , Osteoporose/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: The purpose of this study was to analyze the relationship between thyroid autoimmunity and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM), and to further explore the influence of thyroid autoimmunity on diabetic osteoporosis. METHODS: A total of 601 T2DM patients were included and divided into two groups according to thyroid autoantibodies, namely thyroid autoimmunity positive group (TPOAb+ or TGAb + ) and thyroid autoimmunity negative group (TPOAb- and TGAb-). Clinical data were collected and BMD was determined by dual-energy X-ray absorptiometry (DXA). SPSS26.0 software was used to data analysis. Model regression was used to analyze the influencing factors of BMD, and ROC curve was used to analyze the optimal cut-off point of thyroid peroxidase antibody (TPOAb) for screening osteoporosis. RESULTS: TPOAb and thyroglobulin antibody (TGAb) were negatively correlated with BMD and T-score (LS, FN and WB) (P < 0.01), and TGAb was negatively correlated with 25(OH)D (P < 0.05). Multiple linear regression analysis showed that TPOAb was an independent influence factor on LS, FN and WB BMD. ROC curve analysis showed that the optimal threshold of TPOAb for predicting osteoporosis was 12.35. CONCLUSIONS: In T2DM patients, TPOAb and TGAb levels are negatively correlated with LS, FN and WB BMD, and TPOAb is an independent influencing factor for diabetic osteoporosis, and TPOAb has a certain predictive value for the occurrence and development of diabetic osteoporosis clinically.
Assuntos
Autoanticorpos , Densidade Óssea , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/complicações , Estudos Transversais , Feminino , Masculino , Pessoa de Meia-Idade , Autoanticorpos/sangue , Idoso , Adulto , Autoimunidade , Osteoporose/etiologia , Osteoporose/imunologia , Absorciometria de Fóton , Iodeto Peroxidase/imunologia , Glândula Tireoide/imunologia , Glândula Tireoide/diagnóstico por imagemRESUMO
Mesenchymal stem cell (MSC) exosomes promote tissue regeneration and repair, and thus might be used to treat many diseases; however, the influence of microenvironmental conditions on exosomes remains unclear. The present study aimed to analyze the effect of osteogenic induction on the functions of human umbilical cord MSC (HucMSC)-derived exosomes. Exosomes from standardized stem cell culture (Exo1) and osteogenic differentiation-exosomes (Exo2) were co-cultured with osteoblasts, separately. Cell counting kit-8 assays, alkaline phosphatase and alizarin red staining were used to observe the exosomes' effects on osteoblast proliferation and differentiation. The levels of osteogenic differentiation-related proteins were analyzed using western blotting. Estrogen-deficient osteoporosis model mice were established, and treated with the two exosome preparations. Micro-computed tomography and hematoxylin and eosin staining were performed after 6 weeks. MicroRNAs in Exo1 and Exo2 were sequenced and analyzed using bioinformatic analyses. Compared with Exo1 group, Exo2 had a stronger osteogenic differentiation promoting effect, but a weaker proliferation promoting effect. In ovariectomy-induced osteoporosis mice, both Exo1 and Exo2 improved the tibial density and reversed osteoporosis in vivo. High-throughput microRNA sequencing identified 221 differentially expressed microRNAs in HucMSC-derived exosomes upon osteogenic induction as compared with the untreated control group. Importantly, we found that 41 of these microRNAs are potentially critical for MSC-secreted exosomes during osteogenic induction. Mechanistically, exosomal miRNAs derived from osteogenic induced-HucMSCs are involved in bone development and differentiation, such as osteoclast differentiation and the MAPK signaling pathway. The expression of hsa-mir-2110 and hsa-mir-328-3p gradually increased with prolonged osteogenic differentiation and regulated target genes associated with bone differentiation, suggesting that they are probably the most important osteogenesis regulatory microRNAs in exosomes. In conclusion, we examined the contribution of osteogenic induction to the function of exosomes secreted by HucMSCs following osteogenic differentiation in vitro and in vivo, and reveal the underlying molecular mechanisms of exosome action during osteoporosis.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese/imunologia , Osteoporose/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Camundongos , Transdução de Sinais , Microambiente TumoralRESUMO
Osteoporosis, characterized by bone loss and microstructure damage, occurs when osteoclast activity outstrips osteoblast activity. Natural compounds with inhibitory effect on osteoclast differentiation and function have been evidenced to protect from osteoporosis. After multiple compounds screening, 12-deoxyphorbol 13-acetate (DPA) was found to decline RANKL-induced osteoclastogenesis dose-dependently by attenuating activities of NFATc1 and c-Fos, followed by decreasing the level of osteoclast function-associated genes and proteins including Acp5, V-ATPase-d2 and CTSK. Mechanistically, we found that DPA suppressing RANKL-induced downstream signaling pathways, including MAPK signaling pathway and calcium oscillations. Furthermore, the in vivo efficacy of DPA was further confirmed in an OVX-induced osteoporosis mice model. Collectively, the results in our presentation reveal that DPA might be a promising compound to manage osteoporosis.
Assuntos
Fatores de Transcrição NFATC/antagonistas & inibidores , Osteoporose/tratamento farmacológico , Ésteres de Forbol/farmacologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Osteoporose/imunologia , Ésteres de Forbol/uso terapêutico , Células RAW 264.7RESUMO
Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another 'fil rouge' between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.
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Plaquetas/imunologia , COVID-19/complicações , Osteoporose/imunologia , Trombose/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/metabolismo , Plaquetas/metabolismo , Remodelação Óssea/imunologia , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/imunologia , Retroalimentação Fisiológica , Humanos , Osteoporose/sangue , Ativação Plaquetária/imunologia , Contagem de Plaquetas , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Trombose/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicaçõesRESUMO
Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.
Assuntos
Imunidade Inata , Osteoporose/imunologia , Remodelação Óssea , Osso e Ossos/citologia , Osso e Ossos/imunologia , Linfócitos/imunologiaRESUMO
Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular dysfunction in EAO on bone status. Male mice were immunized with testicular homogenate in adjuvant to induce EAO (n = 5). Age-matched mice were treated with adjuvant alone (adjuvant, n = 6) or remained untreated (control, n = 7). Fifty days after the first immunization specimens were harvested. Real-time reverse transcription-PCR indicated decreased bone metabolism by alkaline phosphatase and Cathepsin K as well as remodeling of cell-contacts by Connexin-43. Micro computed tomography demonstrated a loss of bone mass and mineralization. These findings were supported by histomorphometric results. Additionally, biomechanical properties of femora in a three-point bending test were significantly altered. In summary, the present study illustrates the induction of osteoporosis in the investigated mouse model. However, results suggest that the major effects on bone status were mainly caused by the complete Freund's adjuvant rather than the autoimmune-orchitis itself. Therefore, the benefit of the EAO model to transfer laboratory findings regarding bone metabolism in context with orchitis into a clinical application is limited.
Assuntos
Doenças Autoimunes/complicações , Osso e Ossos/metabolismo , Orquite/complicações , Osteoporose/imunologia , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Orquite/metabolismo , Orquite/patologia , Orquite/fisiopatologia , Osteoporose/diagnóstico por imagem , Microtomografia por Raio-XRESUMO
Objectives: To investigate the association of anti-citrullinated protein antibodies (ACPA) with changes in systemic bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) after two years of treat-to-target. Methods: BMD was measured at the lumbar spine (LS) and femoral neck (FN) in 100 patients with recent onset RA at baseline and after 24 months of treatment aimed at low disease activity (LDA) according to the 28-joints disease activity score (DAS28 <3.2). Multivariable regression analyses were performed to determine independent associations between autoantibodies and other disease and treatment-related parameters with BMD loss. Results: After 24 months, the majority of the patients were at least in LDA (78%), with slightly more ACPA-positive subjects achieving the target. The BMD had significantly decreased at both the LS (mean [SD] percent loss -1.8 [6.2], p=0.03) and the FN (-2.4 [7.3], p=0.03) in ACPA-positive but not in ACPA-negative patients. Consequently, the proportion of patients with reduced BMD (Z score ≤-1) after 24 months was significantly higher among ACPA-positive patients at both the spine (39.5% vs 19.3%, p=0.05) and the hip (37.2% vs 12.2%, p=0.007). The association between ACPA and BMD loss was independent of other variables including age, gender, disease activity, cumulative dose of glucocorticoids and duration of therapy with bisphosphonates at the LS but not the FN. Conclusions: ACPA are associated with ongoing BMD loss at the spine despite suppression of inflammation and adoption of prophylactic measures. ACPA-positive RA patients should be therefore strictly monitored for the development of osteoporosis.
Assuntos
Anticorpos Antiproteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Densidade Óssea/imunologia , Autoanticorpos/imunologia , Feminino , Glucocorticoides/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/imunologiaRESUMO
Available therapies aimed at treating age-related osteoporosis are still insufficient. Therefore, designing reliable in vitro model for the analysis of molecular mechanisms underlying senile osteoporosis is highly required. We have isolated and characterized progenitor cells isolated from bone marrow (BMSCs) of osteoporotic mice strain SAM/P6 (BMSCSAM/P6 ). The cytophysiology of BMSCSAM/P6 was for the first time compared with BMSCs isolated from healthy BALB/c mice (BMSCBALB/c ). Characterization of the cells included evaluation of their multipotency, morphology and determination of specific phenotype. Viability of BMSCs cultures was determined in reference to apoptosis profile, metabolic activity, oxidative stress, mitochondrial membrane potential and caspase activation. Additionally, expression of relevant biomarkers was determined with RT-qPCR. Obtained results indicated that BMSCSAM/P6 and BMSCBALB/c show the typical phenotype of mesenchymal stromal cells (CD44+, CD73+, CD90+) and do not express CD45. Further, BMSCSAM/P6 were characterized by deteriorated multipotency, decreased metabolic activity and increased apoptosis occurrence, accompanied by elevated oxidative stress and mitochondria depolarisation. The transcriptome analyses showed that BMSCSAM/P6 are distinguished by lowered expression of molecules crucial for proper osteogenesis, including Coll-1, Opg and Opn. However, the expression of Trap, DANCR1 and miR-124-3p was significantly up-regulated. Obtained results show that BMSCSAM/P6 present features of progenitor cells with disturbed metabolism and could serve as appropriate model for in vitro investigation of age-dependent osteoporosis.
Assuntos
Diferenciação Celular/genética , Células-Tronco Mesenquimais/imunologia , Osteogênese/genética , Osteoporose/genética , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Animais , Diferenciação Celular/imunologia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteogênese/imunologia , Osteoporose/imunologia , Osteoporose/patologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Antígenos Thy-1/genética , Antígenos Thy-1/imunologiaRESUMO
Heme oxygenase-1 (HO-1) exerts a protective effect against cell damage and induces the activity of many enzymes involved in the treatment of many human diseases, including osteoporosis. The increasing prevalence of osteoporosis and the limitations of the current treatments available led to a continuous occurrence of bone loss and osteoporotic fractures, highlighting the need of a better understanding of the mechanism and function of HO-1. Many factors cause osteoporosis, including lack of estrogen, aging, and iron overload, and they either cause the increase in inflammatory factors or the increase in reactive oxygen species to break bone reconstruction balance. Therefore, regulating the production of inflammatory factors and reactive oxygen species may become a strategy for the treatment of osteoporosis. Solid evidence showed that the overexpression of HO-1 compensates high oxidation levels by increasing intracellular antioxidant levels and reduces inflammation by suppressing pro-inflammatory factors. Some extracts can target HO-1 and ameliorate osteoporosis. However, no systematic report is available on therapies targeting HO-1 to combat osteoporosis. Therefore, this review summarizes the biological characteristics of HO-1, and the relationship between inflammatory response and reactive oxygen species production regulated by HO-1 and osteoporosis. The understanding of the role of HO-1 in osteoporosis may provide ideas for a potential clinical treatment and new drugs targeting HO-1.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Osteoporose/tratamento farmacológico , Animais , Conservadores da Densidade Óssea/uso terapêutico , Modelos Animais de Doenças , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Osteoporose/imunologia , Osteoporose/patologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Estrogen receptors alpha (ERα), a member of the nuclear receptor protein family, was found to play an important role in maintaining bone mass. Its downstream signaling proteins such as ERK and NF-κB were reported to be involved in development of osteoporosis, which meant that targeting ERα might be an effective strategy for searching for new drugs to prevent bone loss. In this study, we demonstrate that isobavachalcone (ISO), as one of bioactive compounds isolated from Psoralea corylifoliaLinn, has high affinity with ERα. The effects of ISO are investigated on receptor activator of NF-κB ligand (RANKL)-induced osteocalstogenesis. It is reported that ISO inhibits the RANKL-mediated increase of osteoclast-related genes MMP9, cathepsink and TRAR in RAW264.7 cells. Moreover, in vitro experiment shows that ISO exhibits an inhibitory effect on ERK and NF-κB signaling pathway, and suppresses RANKL-induced expression of osteoclast-related transcription factors NFATc1 and c-Fos. However, the impact of ISO in these molecules is eliminated by the application of ERα antagonist AZD9496.We further verified pharmacological effects of ISO in ovariectomized osteoporotic mice, and ISO significantly prevented bone loss and decreased M1 polarization of macrophages from marrow and spleen. Collectively, our data suggest that ISO prevents osteoporosis via suppressing activation of ERK and NF-κB signaling pathways as well as M1 polarization of macrophages.