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1.
Biochem Pharmacol ; 208: 115402, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592706

RESUMO

Osteoarthritis (OA) is a common joint illness that negatively impacts people's lives. The main active ingredient of cassia seed or rhubarb is chrysophanol. It has various pharmacological effects including anticancer, anti-diabetes and blood lipid regulation. Previous evidence suggests that chrysophanol has anti-inflammatory properties in various diseases, but its effect on OA has not been investigated yet. In this study, chrysophanol inhibited IL-1ß -induced expression of ADAMTS-4, MMP13, COX-2 and iNOS. Meanwhile, it can inhibit aggrecan and collagen degradation in osteoarthritic chondrocytes induced by IL-1ß.Further studies depicted that SIRT6 silencing eliminated the chrysophanol effect on IL-1ß. The results demonstrated that chrysophanol could stimulate SIRT6 activation and, more importantly, increase SIRT6 levels. We also discovered that chrysophanol might impede the NF-κB pathway of OA mice's chondrocytes induced by IL-1ß, which could be because it depends on SIRT6 activation to some extent. It had also been previously covered that chrysophanol could produce a marked effect on Nrf2/NF-κB axis [1]. Therefore, we can infer that chrysophanol may benefit chondrocytes by regulating the SIRT6/NF-κB and Nrf2/NF-κB signaling axis.We examined the anti-inflammatory mechanism and the impact of chrysophanol on mice in vitro and in vivo. In summary, we declare that chrysophanol diminishes the inflammatory reaction of OA in mice in vitro by regulating SIRT6/NF-κB and Nrf2/NF-κB signaling pathway and protects articular cartilage from degradation in vivo. We can infer that chrysophanol could be an efficient therapy for OA.


Assuntos
Osteoartrite , Sirtuínas , Camundongos , Animais , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo , Interleucina-1beta/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Sirtuínas/farmacologia , Condrócitos , Células Cultivadas
2.
Aging (Albany NY) ; 15(1): 193-212, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36641761

RESUMO

Osteoarthritis (OA) is one of the most common diseases in the orthopedic clinic, characterized by progressive cartilage degradation. RNA-binding proteins (RBPs) are capable of binding to RNAs at transcription and translation levels, playing an important role in the pathogenesis of OA. This study aims to investigate the diagnosis values of RBP-related genes in OA. The RBPs were collected from previous studies, and the GSE114007 dataset (control = 18, OA = 20) was downloaded from the Gene Expression Omnibus (GEO) as the training cohort. Through various bioinformatical and machine learning methods, including genomic difference detection, protein-protein interaction network analyses, Lasso regression, univariate logistic regression, Boruta algorithm, and SVM-RFE, RNMT and RBM24 were identified and then included into the random forest (RF) diagnosis model. GSE117999 dataset (control = 10, OA = 10) and clinical samples collected from local hospital (control = 10, OA = 11) were used for external validation. The RF model was a promising tool to diagnose OA in the training dataset (area under curve [AUC] = 1.000, 95% confidence interval [CI] = 1.000-1.000), the GSE117999 cohort (AUC = 0.900, 95% CI = 0.769-1.000), and local samples (AUC = 0.759, 95% CI = 0.568-0.951). Besides, qPCR and Western Blotting experiments showed that RNMT (P < 0.05) and RBM24 (P < 0.01) were both down-regulated in CHON-001 cells with IL-1ß treatment. In all, an RF model to diagnose OA based on RNMT and RBM24 in cartilage tissue was constructed, providing a promising clinical tool and possible cut-in points in molecular mechanism clarification.


Assuntos
Condrócitos , Osteoartrite , Humanos , Condrócitos/metabolismo , Cartilagem/metabolismo , Osteoartrite/metabolismo , Articulação do Joelho , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
4.
JAMA Netw Open ; 6(1): e2250674, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36662529

RESUMO

Importance: The degree to which health and economic outcomes of musculoskeletal disorders are attributable to high body mass index (BMI) has not been quantified on a global scale. Objective: To estimate global health and economic outcomes associated with musculoskeletal disorders-low back pain (LBP), gout, and osteoarthritis attributable to high BMI in 2019. Design, Setting, and Participants: This cross-sectional study used data of 192 countries and territories from the Global Burden of Diseases, Injuries, and Risk Factors Study, World Health Organization Global Health Expenditure, World Bank, and International Labour Organization databases. Data analyses were conducted from February 24 to June 16, 2022. Main Outcomes and Measures: Prevalence, years lived with disability (YLDs), health care costs, and productivity losses due to morbidity from LBP, gout, and osteoarthritis attributable to high BMI by region and country. Prevalence and YLDs were calculated with the population attributable fraction approach. The economic burden, including health care costs and productivity losses due to morbidity, was also quantified. Health care costs borne by the public, private, and out-of-pocket sectors were estimated based on their corresponding payment shares. Productivity losses were estimated based on the output per worker. A sensitivity analysis was conducted to arrive at the base, minimum, and maximum estimates (ie, uncertainty interval [UI]) by using the mean, lower, and upper bounds of all input variables. Results: High BMI was estimated to be responsible for 36.3 million (UI, 18.4-61.0 million), 16.9 million (UI, 7.5-32.5 million), and 73.0 million (UI, 32.4-131.1 million) prevalent cases of LBP, gout, and osteoarthritis, respectively, which accounted for 7.3 million (UI, 3.0-15.0 million) YLDs across 192 countries and territories in 2019. Globally, the YLDs of musculoskeletal disorders attributable to high BMI accounted for 1.0% of all-cause YLDs in the working-age population aged 15 to 84 years. The global total costs of musculoskeletal disorders attributable to high BMI reached $180.7 billion (UI, $83.8-$333.1 billion), including $60.5 billion (UI, $30.7-$100.5 billion) in health care costs and $120.2 billion (UI, $53.1-$232.7 billion) in productivity losses. In terms of the global health care costs, 58.9% ($35.6 billion; UI, $17.8-$59.6 billion) was borne by the public sector, 24.0% ($14.5 billion; UI, $7.8-$23.2 billion) by the private sector, and 17.1% ($10.3 billion; UI, $5.1-$17.6 billion) by the out-of-pocket sector. On average, the total costs accounted for 0.2% of global gross domestic product. Great inequalities in the disease and economic burden existed across regions and countries. Nearly 80% of global health care (82.4%) and morbidity-related costs (82.9%) were paid by high-income countries, whereas more than 60% (61.4%) of global YLDs occurred in middle-income countries. Conclusions and Relevance: In this cross-sectional study of 192 countries and territories, a substantial amount of the health and economic impact of musculoskeletal disorders was attributable to high BMI. Developing effective policies and active participation from health professionals to prevent excessive weight gain are needed. More available estimates are also needed to facilitate a global analysis.


Assuntos
Gota , Osteoartrite , Humanos , Índice de Massa Corporal , Carga Global da Doença , Estudos Transversais , Custos de Cuidados de Saúde , Osteoartrite/epidemiologia
5.
Biomolecules ; 13(1)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36671508

RESUMO

Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1ß, and identified miR-146a-5p as the most responsive miRNA to IL-1ß. miR-146a-5p was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of miR-146a-5p antagonized IL-1ß-mediated inflammatory responses and IL-1ß-induced catabolism in vitro, and silencing of miR-146a in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1ß were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative miR-146a-5p gene targets and following prediction of protein-protein interactions suggest a functional role of miR-146a-5p in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of miR-146a-5p in OA pathogenesis and implicate modulation of miR-146a-5p in articular chondrocytes as a potential therapeutic strategy to alleviate OA.


Assuntos
Cartilagem Articular , MicroRNAs , Osteoartrite , Humanos , Camundongos , Animais , Osteoartrite/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Condrócitos , Inflamação/metabolismo , Cartilagem Articular/patologia , Apoptose
6.
Biomolecules ; 13(1)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36671512

RESUMO

Osteoarthritis (OA) is the one of most common joint diseases worldwide. Cuproptosis, which had been discovered lately, is a novel form of cell death induced by copper. Our purpose is to study the relationship between cuproptosis-related genes (CRGs) and inflammatory microenvironments in patients with OA and identify characteristic cuproptosis-related biomarkers. First, the combinatory analysis of OA transcriptome data from five datasets identified differentially expressed CRGs associated with OA. Then, we applied single-sample gene set enrichment analysis (ssGSEA) to evaluate immune-cell infiltration and immune-function levels in OA patients and normal controls, respectively. Hub CRGs for OA were mined based on the random forest (RF) model, and a nomogram prediction model was constructed based on them. In total, four differentially expressed CRGs were identified through bioinformatics analysis and confirmed by RT-qPCR. FDX1 and LIPT1 were expressed at a high level in OA, while DBT and DLST were expressed higher in the normal group. In total, 10 CRGs were found to be significantly correlated with immune landscape. Four hub CRGs were subsequently obtained by the RF analysis as potential biomarkers for OA. We constructed an OA predictive model based on these four CRGs (DBT, DLST, FDX1, and LIPT1).


Assuntos
Osteoartrite , Humanos , Osteoartrite/genética , Inflamação/genética , Morte Celular , Biologia Computacional , Cobre
7.
Cells ; 12(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36672165

RESUMO

Melanoma inhibitory activity/cartilage-derived retinoicacid-sensitive protein (MIA/CD-RAP) is a protein expressed and secreted by chondrocytes and cartilaginous tissues. MIA/CD-RAP-deficient mice develop milder osteoarthritis than wildtype mice. In this study, we investigated MIA/CD-RAP downstream targets to explain this reduced disease development. As a possible mediator, we could detect matrix metalloproteinase 13 (MMP13), and the influence of MIA/CD-RAP on MMP13 regulation was analyzed in vitro using SW1353 chondrosarcoma cells and primary chondrocytes. The femoral head cartilage of WT and MIA/CD-RAP -/- mice were cultured ex vivo to further investigate MMP13 activity. Finally, osteoarthritis was surgically induced via DMM in C57BL/6 mice, and the animals were treated with an MIA/CD-RAP inhibitory peptide by subcutaneously implanted pellets. MMP13 was regulated by MIA/CD-RAP in SW1353 cells, and MIA/CD-RAP -/- murine chondrocytes showed less expression of MMP13. Further, IL-1ß-treated MIA/CD-RAP -/- chondrocytes displayed less MMP13 expression and activity. Additionally, MIA/CD-RAP-deficient ex vivo cultured cartilage explants showed less MMP13 activity as well as reduced cartilage degradation. The mice treated with the MIA/CD-RAP inhibitory peptide showed less osteoarthritis development. Our findings revealed MIA/CD-RAP as a new regulator of MMP13 and highlighted its role as a potential new target for osteoarthritis therapy.


Assuntos
Cartilagem , Osteoartrite , Camundongos , Animais , Metaloproteinase 13 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Cartilagem/metabolismo , Condrócitos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo
8.
Sci Rep ; 13(1): 1124, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670151

RESUMO

Osteoarthritis (OA) is the most prevalent joint disorder with increasing worldwide incidence. Mechanistic insights into OA pathophysiology are evolving and there are currently no disease-modifying OA drugs. An increase in protease activity is linked to progressive degradation of the cartilage in OA. Proteases also trigger inflammation through a family of G protein-coupled receptors (GPCRs) called the Proteinase-Activated Receptors (PARs). PAR signaling can trigger pro-inflammatory responses and targeting PARs is proposed as a therapeutic approach in OA. Several enzymes can cleave the PAR N-terminus, but the endogenous protease activators of PARs in OA remain unclear. Here we characterized PAR activating enzymes in knee joint synovial fluids from OA patients and healthy donors using genetically encoded PAR biosensor expressing cells. Calcium signaling assays were performed to examine receptor activation. The class and type of enzymes cleaving the PARs was further characterized using protease inhibitors and fluorogenic substrates. We find that PAR1, PAR2 and PAR4 activating enzymes are present in knee joint synovial fluids from healthy controls and OA patients. Compared to healthy controls, PAR1 activating enzymes are elevated in OA synovial fluids while PAR4 activating enzyme levels are decreased. Using enzyme class and type selective inhibitors and fluorogenic substrates we find that multiple PAR activating enzymes are present in OA joint fluids and identify serine proteinases (thrombin and trypsin-like) and matrix metalloproteinases as the major classes of PAR activating enzymes in the OA synovial fluids. Synovial fluid driven increase in calcium signaling was significantly reduced in cells treated with PAR1 and PAR2 antagonists, but not in PAR4 antagonist treated cells. OA associated elevation of PAR1 cleavage suggests that targeting this receptor may be beneficial in the treatment of OA.


Assuntos
Osteoartrite , Receptor PAR-1 , Humanos , Receptor PAR-1/metabolismo , Líquido Sinovial/metabolismo , Corantes Fluorescentes , Trombina/metabolismo , Receptor PAR-2/metabolismo
9.
Jt Dis Relat Surg ; 34(1): 166-175, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700279

RESUMO

OBJECTIVES: This study aims to evaluate the efficacy of high-molecular-weight hyaluronic acid (HMWHA) and lactoferrin (LF) injections on temporomandibular joint (TMJ) cartilage and subchondral bone in mono-iodoacetate (MIA)-induced temporomandibular joint osteoarthritis model in rats. MATERIALS AND METHODS: In this in vivo study, a total of 24 rats were divided into three groups as follows: saline group (Group 1), HMWHA group (Group 2), and LF group (Group 3) including eight rats in each group. The intra-articular injections were administered once a week for three weeks after osteoarthritis was induced. All animals were euthanized 28 days after induction of osteoarthritis, and TMJs were harvested for histomorphometric, immunohistochemical, and micro-computed tomography (CT) analysis. RESULTS: There was no significant difference between the HMWHA and LF groups in terms of the histomorphometric and immunohistochemical analysis results (p>0.05). According to the micro-CT analysis, the LF group had the highest mean bone volume fraction (74.9±0.5) and trabecular thickness (0.122±0.002), while the saline group had the lowest mean values (55.0±0.3 and 0.071±0.002, respectively) (p<0.001). There was no significant difference between the HMWHA and LF groups according to the micro-CT analysis (p>0.05). Both groups had better healing effects than the saline group in all analyses. CONCLUSION: Lactoferrin has a healing effect at least as much as HMWHA in MIA-induced TMJ osteoarthritis. We suggest that LF may be evaluated in future clinical studies as a promising agent in the treatment of osteoarthritis.


Assuntos
Ácido Hialurônico , Osteoartrite , Ratos , Animais , Ácido Hialurônico/uso terapêutico , Microtomografia por Raio-X/métodos , Lactoferrina/efeitos adversos , Imuno-Histoquímica , Articulação Temporomandibular/diagnóstico por imagem , Osteoartrite/induzido quimicamente , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Injeções Intra-Articulares
10.
J Agric Food Chem ; 71(3): 1499-1509, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36630614

RESUMO

Osteoarthritis (OA) is a common joint disease, and studies have reported that the endoplasmic reticulum stress (ERS) in chondrocytes caused by the cartilage tissue damage could mediate the activation of Nod-like receptor protein 3 (NLRP3) inflammasomes through inositol-requiring enzyme 1 alpha (IRE1α) and thioredoxin interacting protein (TXNIP). Ginsenoside compound K (CK) has an inhibitory effect on IRE1α activation. However, the role of IRE1α-TXNIP and its interaction with CK are still unclear. In this study, we examined the role and mechanism of action of CK in OA. We found that CK ameliorated OA and ERS in IL-1ß-treated chondrocytes and a monoiodoacetate-induced rat OA model. The effect of CK on inflammation, pyroptosis, and ERS was blocked by the ERS inducer tunicamycin. In conclusion, CK hindered OA progression by inhibiting the ERS-IRE1α-TXNIP-NLRP3 axis. Overall, our data indicate that CK could be useful in the treatment of OA and other chronic inflammatory diseases.


Assuntos
Osteoartrite , Proteínas Serina-Treonina Quinases , Ratos , Animais , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Endorribonucleases/genética , Endorribonucleases/metabolismo , Endorribonucleases/farmacologia , Condrócitos , Apoptose , Estresse do Retículo Endoplasmático , Inflamassomos , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/farmacologia
13.
Curr Opin Rheumatol ; 35(2): 128-134, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36695054

RESUMO

PURPOSE OF REVIEW: The understanding of inflammation in osteoarthritis is rapidly evolving. This review highlights important basic science, mechanistic, and clinical findings since 2020 that underscore the current notion of osteoarthritis as an inflammatory disease. RECENT FINDINGS: There exists a disconnect between clinical radiographic findings and patient symptoms in osteoarthritis. Inflammation, in particular synovitis, has been put forward as a potential explanation for this disconnect. New findings have shed light on the temporal dynamics and activation states of joint-resident or systemically derived immune cell populations, notably macrophages, that participate in the inflammatory response. The intricate crosstalk in which they engage may underpin disparate pain and symptoms in patients, for instance during osteoarthritis flares. The role of biological and environmental factors such as exercise, age, and diet, have been the subject of recent studies for their protective or destructive roles in osteoarthritis inflammation. Despite these advances, no disease-modifying osteoarthritis treatments targeting inflammation have emerged. SUMMARY: Osteoarthritis is a debilitating chronic disease that manifests with widely varying symptomatology. Inflammation is now appreciated as a key pathophysiological process in osteoarthritis, but there remain considerable gaps in our understanding of its role in disease progression and how best to target the inflammatory response for therapeutic interventions.


Assuntos
Osteoartrite , Sinovite , Humanos , Inflamação , Osteoartrite/etiologia , Osteoartrite/terapia , Macrófagos , Dor
14.
PeerJ ; 11: e14563, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36655043

RESUMO

Osteoarthritis (OA) is the most common joint disease in the world, characterized by pain and loss of joint function, which has led to a serious reduction in the quality of patients' lives. In this work, ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QToF/MS) in conjunction with multivariate pattern recognition methods and an univariate statistical analysis scheme were applied to explore the serum metabolic signatures within OA group (n = 31), HC (healthy controls) group (n = 57) and non-OA group (n = 19) for early diagnosis and differential diagnosis of OA. Based on logistic regression analysis and receiver operating characteristic (ROC) curve analysis, seven metabolites, including phosphatidylcholine (18:0/22:6), p-cresol sulfate and so on, were identified as critical metabolites for the diagnosis of OA and HC and yielded an area under the curve (AUC) of 0.978. The other panel of unknown m/z 239.091, phosphatidylcholine (18:0/18:0) and phenylalanine were found to distinguish OA from non-OA and achieved an AUC of 0.888. These potential biomarkers are mainly involved in lipid metabolism, glucose metabolism and amino acid metabolism. It is expected to reveal new insight into OA pathogenesis from changed metabolic pathways.


Assuntos
Metabolômica , Osteoartrite , Humanos , Metabolômica/métodos , Cromatografia Líquida , Biomarcadores , Osteoartrite/diagnóstico , Lecitinas
15.
J Orthop Trauma ; 37(2): e68-e72, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36658698

RESUMO

OBJECTIVES: We report our clinical results following surgical intervention for capitellar fractures in a pediatric population, highlighting approaches, surgical instruments, and possible prognostic factors. DESIGN: Retrospective descriptive case-series study. SETTING: A tertiary referral hospital. PATIENTS: Twelve pediatric patients with capitellar or capitellar-trochlear injuries were treated between 2017 and 2021. INTERVENTION: Open reduction and internal fixation primarily using cannulated headless screws. MAIN OUTCOME MEASUREMENTS: The mean follow-up period was 22 months (range: 10-35 months). Functional outcomes were assessed using the Mayo Elbow Performance Score. Post-traumatic elbow arthrosis was assessed using the Bromberg and Morrey rating system. RESULTS: All fractures healed within 5-7 weeks. The mean Mayo Elbow Performance Score value was 98 (range, 85-100). Three patients developed arthrosis, and one had capitellar osteonecrosis. CONCLUSIONS: Based on our experience, the Kocher approach and fixation of 2-3 retrograde cannulated screws together represent an appropriate surgical technique for isolated capitellar fractures, whereas good functional outcomes are attainable for capitellar-trochlear shear fractures using the transolecranon approach with 3 cannulated screw fixations. Further injuries to the osseoligamentous structures around the elbow joint are suspected to be an unfavorable prognostic factor. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Articulação do Cotovelo , Fraturas do Úmero , Osteoartrite , Humanos , Criança , Estudos Retrospectivos , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/cirurgia , Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Articulação do Cotovelo/cirurgia , Amplitude de Movimento Articular , Resultado do Tratamento
16.
J Orthop Surg Res ; 18(1): 58, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681837

RESUMO

BACKGROUND: Osteoarthritis is a chronic degenerative joint disease, and increasing evidences suggest that the pathogenic mechanism involves immune system and inflammation. AIMS: The aim of current study was to uncover hub genes linked to immune infiltration in osteoarthritis synovial tissue using comprehensive bioinformatics analysis and experimental confirmation. METHODS: Multiple microarray datasets (GSE55457, GSE55235, GSE12021 and GSE1919) for osteoarthritis in Gene Expression Omnibus database were downloaded for analysis. Differentially expressed genes (DEGs) were identified using Limma package in R software, and immune infiltration was evaluated by CIBERSORT algorithm. Then weighted gene co-expression network analysis (WGCNA) was performed to uncover immune infiltration-associated gene modules. Protein-protein interaction (PPI) network was constructed to select the hub genes, and the tissue distribution of these genes was analyzed using BioGPS database. Finally, the expression pattern of these genes was confirmed by RT-qPCR using clinical samples. RESULTS: Totally 181 DEGs between osteoarthritis and normal control were screened. Macrophages, mast cells, memory CD4 T cells and B cells accounted for the majority of immune cell composition in synovial tissue. Osteoarthritis synovial showed high abundance of infiltrating resting mast cells, B cells memory and plasma cells. WGCNA screened 93 DEGs related to osteoarthritis immune infiltration. These genes were involved in TNF signaling pathway, IL-17 signaling pathway, response to steroid hormone, glucocorticoid and corticosteroid. Ten hub genes including MYC, JUN, DUSP1, NFKBIA, VEGFA, ATF3, IL-6, PTGS2, IL1B and SOCS3 were selected by using PPI network. Among them, four genes (MYC, JUN, DUSP1 and NFKBIA) specifically expressed in immune system were identified and clinical samples revealed consistent change of these four genes in synovial tissue retrieved from patients with osteoarthritis. CONCLUSION: A 4-gene-based diagnostic model was developed, which had well predictive performance in osteoarthritis. MYC, JUN, DUSP1 and NFKBIA might be biomarkers and potential therapeutic targets in osteoarthritis.


Assuntos
Osteoartrite , Transcriptoma , Humanos , Transcriptoma/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética
17.
Ann Med ; 55(1): 175-189, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36661308

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with an increased risk of death, but its underlying mechanisms are not fully understood. Circular RNAs (circRNAs) have recently been implicated in various biological processes. The aim of this study was to investigate the key circRNAs related to RA. METHODS: A microarray assay was used to identify the differentially expressed circRNAs (DEcircRNAs) in peripheral blood mononuclear cells (PBMCs) from patients with RA compared to patients with osteoarthritis (OA) and healthy controls. Then, quantitative real-time PCR was applied to verify the DEcircRNAs, and correlations between the levels of DEcircRNAs and laboratory indices were analysed. We also performed extensive bioinformatic analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) pathway and potential circRNA-miRNA-mRNA network analyses to predict the function of these DEcircRNAs. RESULTS: A total of 35,342 and 6146 DEcircRNAs were detected in RA patients compared to controls and OA patients, respectively. Nine out of the DEcircRNAs in RA were validated by real-time PCR. There were correlations between the levels of DEcircRNAs and some of the laboratory indices. GO analyses revealed that these DEcircRNAs in RA were closely related to cellular protein metabolic processes, gene expression, the immune system, cell cycle, posttranslational protein modification and collagen formation. Functional annotation of host genes of these DEcircRNAs was implicated in several significantly enriched pathways, including metabolic pathways, ECM-receptor interaction, the PI3K-Akt signalling pathway, the AMPK signalling pathway, leukocyte transendothelial migration, platelet activation and the cAMP signalling pathway, which might be responsible for the pathophysiology of RA. CONCLUSIONS: The findings of this study may help to elucidate the role of circRNAs in the specific mechanism underlying RA.Key messagesMicroarray assays showed that a total of 35,342 and 6146 DEcircRNAs were detected in RA patients compared to controls and OA patients, respectively.Nine out of the DEcircRNAs in RA were validated by real-time PCR, and the levels of the DEcircRNAs were related to some of the laboratory indices.GO analyses revealed that the DEcircRNAs in RA were closely related to cellular protein metabolic processes, gene expression, the immune system, etc.Functional annotation of host genes of the DEcircRNAs in RA was implicated in several significantly enriched pathways, including metabolic pathways, ECM-receptor interaction, the PI3K-Akt signalling pathway, etc.


Assuntos
Artrite Reumatoide , MicroRNAs , Osteoartrite , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Leucócitos Mononucleares/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Perfilação da Expressão Gênica , MicroRNAs/genética , Artrite Reumatoide/genética , Osteoartrite/genética , Osteoartrite/metabolismo
18.
FASEB J ; 37(2): e22746, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36622202

RESUMO

In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence-like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor-α (ERα) was associated with an increased senescence level in human chondrocytes. Since DNA damage is a common cause of cellular senescence, we aimed to study the relationship among ERα levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ERα, representative markers of DNA damage and senescence in normal and OA cartilage harvested from male and female human donors, as well as from male mice. The influence of DNA damage on ERα levels was studied by treating human chondrocytes with doxorubicin (DOX), which is an often-used DNA-damaging agent. Next, we tested the potential of overexpressing ERα in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ERα and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ERα levels. Overexpression of ERα reduced the levels of DNA damage and senescence in DOX-treated normal chondrocytes and OA chondrocytes. Moreover, DOX-induced the activation of NF-κB pathway, which was partially reversed by overexpressing ERα. Taken together, our results demonstrated the critical role of ERα in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ERα level may represent a new avenue to prevent and treat OA.


Assuntos
Condrócitos , Osteoartrite , Masculino , Humanos , Feminino , Camundongos , Animais , Condrócitos/metabolismo , NF-kappa B/metabolismo , Receptores de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ligantes , Osteoartrite/metabolismo , Senescência Celular/fisiologia , Dano ao DNA
19.
Medicina (Kaunas) ; 59(1)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36676791

RESUMO

Background and objective: Matrix metalloproteinases (MMPs) are the key enzymes in the pathogenesis of cartilage and joint damage and potentially a new biomarker of the early erosive form of rheumatoid arthritis (RA). Firstly, the study aimed to compare the level of MMP-9 in plasma (PL) and synovial fluid (SF) of patients with RA and osteoarthritis (OA). Secondly, the goal was to examine the association of MMP-9 level in PL and SF with early erosive changes in RA, and finally, to determine the association of MMP-9 level with serological parameters of the disease (rheumatoid factor-RF and anti-citrulline protein antibodies-ACPA). Materials and Methods: A total of 156 subjects were involved in this study (84 patients with RA and 72 patients with OA, who were involved as a control group). MMP-9 level was measured in PL and SF of all subjects by the sandwich enzyme-linked immunosorbent assay (ELISA) method. Standard radiographs of the hands and feet were used to detect joint damage and classification into erosive or non-erosive RA. The Larsen score (LS) was used for the quantitative assessment of joint damage, and its annual change (∆ LS) was used to assess the radiographic progression of the disease. Results: MMP-9 level in PL and SF was significantly higher in RA compared to controls (PL: 19.26 ± 7.54 vs. 14.57 ± 3.11 ng/mL, p< 0.01; SF: 16.17 ± 12.25 vs. 0.75 ± 0.53 ng/mL, p < 0.001) as well as in SF of patients with erosive compared to non-erosive RA (18.43 ± 12.87 vs. 9.36 ± 7.72; p < 0.05). Faster radiographic progression was recorded in erosive compared to non-erosive early RA (11.14 ± 4.75 vs. 6.13 ± 2.72; p < 0.01). MMP-9 level in SF, but not in PL, significantly correlates with the radiographic progression in both erosive and non-erosive RA (ρ = 0.38 and ρ = 0.27). We did not find a significant association between RF and MMP-9 level in early RA, but the ACPA level significantly correlates with MMP-9 level in SF (r = 0.48). Conclusion: The level of MMP-9 in plasma and synovial fluid of patients with RA is significantly higher compared to patients with osteoarthritis. The level of MMP-9 in synovial fluid is significantly higher in erosive than non-erosive early RA. It is significantly associated with the radiographic progression of the disease and the level of anti-citrulline protein antibodies.


Assuntos
Artrite Reumatoide , Osteoartrite , Humanos , Líquido Sinovial/química , Líquido Sinovial/metabolismo , Metaloproteinase 9 da Matriz , Osteoartrite/diagnóstico por imagem , Metaloproteinases da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo
20.
Arthroscopy ; 39(2): 358-359, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36604002

RESUMO

When we are looking at the stars, we are in fact looking back in time. This is because it takes years for the light from the stars to reach us. In similar fashion, when we are evaluating data on osteoarthritis after patellofemoral surgery, we need to consider what kind of procedure was performed. Furthermore, it is extremely important to answer the question of whether the patellofemoral instability itself or the surgical procedure is causing the arthritis. Recent evidence suggests that recurrent patellofemoral instability is causing cartilage degeneration and stopping this process via surgical restoration of the anatomy and biomechanics of the patellofemoral joint may significantly reduce the risk of osteoarthritis. Shear loading of the cartilage can be detrimental. An instability event elicits inflammatory markers that are shown to induce arthritis. On the other hand, there is the argument that over-constraint may lead to arthritis owing to an increase in cartilage loading. Another argument is that surgery may not fully restore the patellofemoral anatomy. Appropriate patient selection and continuous evolution of our surgical procedures are key elements toward successful management of patellofemoral instability.


Assuntos
Doenças das Cartilagens , Instabilidade Articular , Osteoartrite , Articulação Patelofemoral , Humanos , Articulação Patelofemoral/cirurgia , Articulação Patelofemoral/anatomia & histologia , Cartilagem , Instabilidade Articular/etiologia , Instabilidade Articular/cirurgia
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