RESUMEN

The role of mitochondria in the pathogenesis of osteoarthritis (OA) is significant. In this study, we aimed to identify diagnostic signature genes associated with OA from a set of mitochondria-related genes (MRGs). First, the gene expression profiles of OA cartilage GSE114007 and GSE57218 were obtained from the Gene Expression Omnibus. And the limma method was used to detect differentially expressed genes (DEGs). Second, the biological functions of the DEGs in OA were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Wayne plots were employed to visualize the differentially expressed mitochondrial genes (MDEGs) in OA. Subsequently, the LASSO and SVM-RFE algorithms were employed to elucidate potential OA signature genes within the set of MDEGs. As a result, GRPEL and MTFP1 were identified as signature genes. Notably, GRPEL1 exhibited low expression levels in OA samples from both experimental and test group datasets, demonstrating high diagnostic efficacy. Furthermore, RT-qPCR analysis confirmed the reduced expression of Grpel1 in an in vitro OA model. Lastly, ssGSEA analysis revealed alterations in the infiltration abundance of several immune cells in OA cartilage tissue, which exhibited correlation with GRPEL1 expression. Altogether, this study has revealed that GRPEL1 functions as a novel and significant diagnostic indicator for OA by employing two machine learning methodologies. Furthermore, these findings provide fresh perspectives on potential targeted therapeutic interventions in the future.

Asunto(s)

Aprendizaje Automático , Osteoartritis , Humanos , Osteoartritis/genética , Osteoartritis/diagnóstico , Osteoartritis/metabolismo , Biomarcadores/metabolismo , Perfilación de la Expresión Génica/métodos , Mitocondrias/genética , Mitocondrias/metabolismo , Algoritmos , Transcriptoma/genética

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. METHODS: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. RESULTS: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. CONCLUSION: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.

Asunto(s)

Estudio de Asociación del Genoma Completo , Proteoma , Sitios de Carácter Cuantitativo , Humanos , Osteoartritis/genética , Osteoartritis/sangre , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/sangre , Predisposición Genética a la Enfermedad/genética , Osteoartritis de la Cadera/genética , Osteoartritis de la Cadera/sangre , Análisis de la Aleatorización Mendeliana , Masculino , Femenino , Terapia Molecular Dirigida/métodos

RESUMEN

Osteoarthritis (OA) is a comprehensive joint disorder. The specific genes that trigger OA and the strategies for its effective management are not fully understood. This study focuses on identifying key genes linked to iron metabolism that could influence both the diagnosis and therapeutic approaches for OA. Analysis of GEO microarray data and iron metabolism genes identified 15 ferroptosis-related DEGs, enriched in hypoxia and HIF-1 pathways. Ten key hub genes (ATM, GCLC, PSEN1, CYBB, ATG7, MAP1LC3B, PLIN2, GRN, APOC1, SIAH2) were identified. Through stepwise regression, we screened 4 out of the above 10 genes, namely, GCLC, GRN, APOC1, and SIAH2, to obtain the optimal model. AUROCs for diagnosis of OA for the four hub genes were 0.81 and 0.80 of training and validation sets, separately. According to immune infiltration results, OA was related to significantly increased memory B cells, M0 macrophages, regulatory T cells, and resting mast cells but decreased activated dendritic cells. The four hub genes showed a close relation to them. It is anticipated that this model will aid in diagnosing osteoarthritis by assessing the expression of specific genes in blood samples. Moreover, studying these hub genes may further elucidate the pathogenesis of osteoarthritis.

Asunto(s)

Biomarcadores , Ferroptosis , Osteoartritis , Ferroptosis/genética , Osteoartritis/genética , Osteoartritis/inmunología , Humanos , Biomarcadores/metabolismo , Perfilación de la Expresión Génica

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative disease. We explored the role and regulatory mechanisms of lncRNA-FAS-AS1 in OA progression. METHODS: We exposed human immortalized chondrocytes to IL-1ß for 24 h to induce an OA cell model. The target molecule levels were assessed using western blot and quantitative real-time PCR (RT-qPCR). Cell viability and apoptosis were measured using CCK-8 and flow cytometry. The m6A modification of FAS-AS1 was determined using MeRIP. We examined the binding relationships between FAS-AS1, Fragile X mental retardation 1 (FMR1), and A disintegrin and metalloproteinase 8 (ADAM8) using RIP and RNA pull-down. The OA animal model was established by separating the medial collateral ligament and medial meniscus. Safranin-O staining and Mankin's scale were employed to evaluate pathological changes within the cartilage. RESULTS: FAS-AS1, METTL14, and ADAM8 were upregulated, and the JAK/STAT3 signaling pathway was activated in OA mice and IL-1ß-induced chondrocytes. FAS-AS1 knockdown inhibited extracellular matrix degradation in IL-1ß-induced chondrocytes; however, ADAM8 overexpression reversed this effect. FAS-AS1 maintained the stability of ADAM8 mRNA by recruiting FMR1. METTL14 knockdown repressed FAS-AS1 expression in an m6A-dependent manner. FAS-AS1 overexpression reversed the inhibitory effects of METTL14 knockdown on JAK/STAT3 signaling and cartilage damage in the OA model both in vitro and in vivo. CONCLUSION: METTL14-mediated FAS-AS1 promotes OA progression through the FMR1/ADAM8/JAK/STAT3 axis.

Asunto(s)

Proteínas ADAM , Condrocitos , Progresión de la Enfermedad , Proteínas de la Membrana , ARN Largo no Codificante , Factor de Transcripción STAT3 , Transducción de Señal , Regulación hacia Arriba , Animales , Humanos , Masculino , Ratones , Proteínas ADAM/metabolismo , Proteínas ADAM/genética , Adenosina/análogos & derivados , Apoptosis , Artritis Experimental/metabolismo , Artritis Experimental/genética , Artritis Experimental/patología , Cartílago Articular/metabolismo , Cartílago Articular/patología , Línea Celular , Condrocitos/metabolismo , Condrocitos/patología , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Metiltransferasas/metabolismo , Metiltransferasas/genética , Ratones Endogámicos C57BL , Osteoartritis/metabolismo , Osteoartritis/genética , Osteoartritis/patología , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética

RESUMEN

Osteoarthritis (OA) is the most common form of arthritic disease, and phenotypic modification of chondrocytes is an important mechanism that contributes to the loss of cartilage homeostasis. This study identified that Fascin actin-bundling protein 1 (FSCN1) plays a pivotal role in regulating chondrocytes phenotype and maintaining cartilage homeostasis. Proteome-wide screening revealed markedly upregulated FSCN1 protein expression in human OA cartilage. FSCN1 accumulation was confirmed in the superficial layer of OA cartilage from humans and mice, primarily in dedifferentiated-like chondrocytes, associated with enhanced actin stress fiber formation and upregulated type I and III collagens. FSCN1-inducible knockout mice exhibited delayed cartilage degeneration following experimental OA surgery. Mechanistically, FSCN1 promoted actin polymerization and disrupted the inhibition of Decorin on TGF-ß1, leading to excessive TGF-ß1 production and ALK1/Smad1/5 signaling activation, thus, accelerated chondrocyte dedifferentiation. Intra-articular injection of FSCN1-overexpressing adeno-associated virus exacerbated OA progression in mice, which was mitigated by an ALK1 inhibitor. Moreover, FSCN1 inhibitor NP-G2-044 effectively reduced extracellular matrix degradation in OA mice, cultured human OA chondrocytes, and cartilage explants by suppressing ALK1/Smad1/5 signaling. These findings suggest that targeting FSCN1 represents a promising therapeutic approach for OA.

Asunto(s)

Proteínas Portadoras , Condrocitos , Proteínas de Microfilamentos , Osteoartritis , Animales , Humanos , Masculino , Ratones , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Cartílago Articular/metabolismo , Cartílago Articular/patología , Condrocitos/metabolismo , Condrocitos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Osteoartritis/patología , Osteoartritis/metabolismo , Osteoartritis/genética , Fenotipo , Receptores Odorantes , Transducción de Señal

RESUMEN

OBJECTIVES: This study aims to explore the mechanisms of dual regulation of osteoarthritis (OA) progression by the involvement of estrogen receptor (ER) in autophagy and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to explore the relationship among associated genes. Western blot assays were used to detect related protein expression of OA in C28I2 and induced OA cellular model. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis were used to detect OA related gene expression in C28I2 and induced OA cellular model. Co-immunoprecipitation (CO-IP) analysis were used to verify the direct interaction between ER and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). RESULTS: The C28I2 cellular model of OA was induced by interleukin-1ß (IL-1ß). The small interfering ribonucleic acid (SiRNA)-mediated knockdown of autophagy-related 16 like 1 (ATG16L1) in C28I2 decreased the expression of MAP1LC3B (LC3B) and NLRP3. Besides, ER-beta (ERß) agonist changed the gene expression of NLRP3 and ATG16L1. Moreover, CO-IP analysis indicated the direct interaction between ER and NLRP3. CONCLUSION: Our study results revealed that ATG16L1, NLRP3, and IL-1ß interacted closely and ERß was involved in OA process by affecting autophagy and inflammatory activation.

Asunto(s)

Proteínas Relacionadas con la Autofagia , Receptor beta de Estrógeno , Proteína con Dominio Pirina 3 de la Familia NLR , Osteoartritis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Humanos , Receptor beta de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Autofagia , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Línea Celular

RESUMEN

OBJECTIVE: Several observational studies have revealed a potential relationship between menstrual reproductive factors (MRF) and osteoarthritis (OA). However, the precise causal relationship remains elusive. This study performed Mendelian randomization (MR) to provide deeper insights into this relationship. METHODS: Utilizing summary statistics of genome-wide association studies (GWAS), we conducted univariate MR to estimate 2 menstrual factors (Age at menarche, AAM; Age at menopause, AMP) and 5 reproductive factors (Age at first live birth, AFB; Age at last live birth, ALB; Number of live births, NLB; Age first had sexual intercourse, AFSI; Age started oral contraceptive pill, ASOC) on OA (overall OA, OOA; knee OA, KOA and hip OA, HOA). The sample size of MRF ranged from 123846 to 406457, and the OA sample size range from 393873 to 484598. Inverse variance weighted (IVW) method was used as the primary MR analysis methods, and MR Egger, weighted median was performed as supplements. Sensitivity analysis was employed to test for heterogeneity and horizontal pleiotropy. Finally, multivariable MR was utilized to adjust for the influence of BMI on OA. RESULTS: After conducting multiple tests (P<0.0023) and adjusting for BMI, MR analysis indicated that a lower AFB will increase the risk of OOA (odds ratio [OR] = 0.97, 95% confidence interval [CI]: 0.95-0.99, P = 3.39×10-4) and KOA (OR = 0.60, 95% CI: 0.47-0.78, P = 1.07×10-4). ALB (OR = 0.61, 95% CI: 0.45-0.84, P = 2.06×10-3) and Age AFSI (OR = 0.66, 95% CI: 0.53-0.82, P = 2.42×10-4) were negatively associated with KOA. In addition, our results showed that earlier AMP adversely affected HOA (OR = 1.12, 95% CI: 1.01-1.23, P = 0.033), and earlier ASOC promote the development of OOA (OR = 0.97, 95% CI: 0.95-1.00, P = 0.032) and KOA (OR = 0.58, 95% CI: 0.40-0.84, P = 4.49×10-3). ALB (OR = 0.98, 95% CI: 0.96-1.00, P = 0.030) and AFSI (OR = 0.98, 95% CI: 0.97-0.99, P = 2.66×10-3) also showed a negative association with OOA but they all did not pass multiple tests. The effects of AAM and NLB on OA were insignificant after BMI correction. CONCLUSION: This research Certificates that Early AFB promotes the development of OOA, meanwhile early AFB, ALB, and AFSI are also risk factors of KOA. Reproductive factors, especially those related to birth, may have the greatest impact on KOA. It provides guidance for promoting women's appropriate age fertility and strengthening perinatal care.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Osteoartritis/genética , Osteoartritis/epidemiología , Factores de Riesgo , Menarquia/genética , Menopausia , Polimorfismo de Nucleótido Simple , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/epidemiología , Osteoartritis de la Rodilla/etiología , Adulto , Persona de Mediana Edad , Menstruación

RESUMEN

Osteoarthritis is the most prevalent whole-joint degenerative disorder, and is characterized by the degradation of articular cartilage and the underlying bone structures. Almost 600 million people are affected by osteoarthritis worldwide. No curative treatments are available, and management strategies focus mostly on pain relief. Here, we provide a comprehensive overview of the available human genetic and functional genomics studies for osteoarthritis to date and delineate how these studies have helped shed light on disease etiopathology. We highlight genetic discoveries from genome-wide association studies and provide a detailed overview of molecular-level investigations in osteoarthritis tissues, including methylation-, transcriptomics-, and proteomics-level analyses. We review how functional genomics data from different molecular levels have helped to prioritize effector genes that can be used as drug targets or drug-repurposing opportunities. Finally, we discuss future directions with the potential to drive a step change in osteoarthritis research.

Asunto(s)

Estudio de Asociación del Genoma Completo , Genómica , Osteoartritis , Humanos , Osteoartritis/genética , Proteómica , Predisposición Genética a la Enfermedad , Metilación de ADN

RESUMEN

This study aimed to characterize PANoptosis-related genes with immunoregulatory features in osteoarthritis (OA) and investigate their potential diagnostic and therapeutic implications. Gene expression data from OA patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis and functional enrichment analysis were conducted to identify PANoptosis-related genes (PRGs) associated with OA pathogenesis. A diagnostic model was developed using LASSO regression, and the diagnostic value of key PRGs was evaluated using Receiver Operating Characteristic Curve (ROC) analysis. The infiltration of immune cells and potential small molecule agents were also examined. A total of 39 differentially expressed PANoptosis-related genes (DE-PRGs) were identified, with functional enrichment analysis revealing their involvement in inflammatory response regulation and immune modulation pathways. Seven key PRGs, including CDKN1A, EZH2, MEG3, NR4A1, PIK3R2, S100A8, and SYVN1, were selected for diagnostic model construction, demonstrating high predictive performance in both training and validation datasets. The correlation between key PRGs and immune cell infiltration was explored. Additionally, molecular docking analysis identified APHA-compound-8 as a potential therapeutic agent targeting key PRGs. This study identified and analyzed PRGs in OA, uncovering their roles in immune regulation. Seven key PRGs were used to construct a diagnostic model with high predictive performance. The identified PRGs' correlation with immune cell infiltration was elucidated, and APHA-compound-8 was highlighted as a potential therapeutic agent. These findings offer novel diagnostic markers and therapeutic targets for OA, warranting further in vivo validation and exploration of clinical applications.

Asunto(s)

Simulación del Acoplamiento Molecular , Osteoartritis , Humanos , Osteoartritis/genética , Osteoartritis/inmunología , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Inmunomodulación/genética

RESUMEN

Osteoarthritis (OA) is a common degenerative disease that affects millions of individuals worldwide. OBJECTIVE: There is no conclusive epidemiological evidence regarding the relationship between OA, depression, and whole-body fat mass. In this study, we conducted a two-step Mendelian randomization analysis to determine the causal relationships between them. DESIGN: The published summary-level data are from genome-wide association studies (GWAS). Our study included 357,957 samples and 10,828,862 SNPs. Finally, the outcome GWAS data for OA came from a GWAS on the genetic architecture of OA using UK Biobank data. This study included 50,508 samples and 15,845,511 SNPs. We used five different modes of analysis, including inverse variance weighted meta-analysis (IVW), MR-Egger regression, weighted median, simple mode, and weighted mode, to explore causal relationships. RESULTS: We found a positive correlation between depression and body fat mass, with depression leading to body fat mass an increase in (IVW result: p = 3.39E-07, OR (95 % CI) =2.16 (1.61, 2.90)). We also found a positive correlation between body fat mass and OA, with body fat mass increasing the risk of OA (IVW result: p = 1.65E-33, OR (95 % CI) = 1.98 (1.77, 2.21). Body fat mass played an important role as a mediator in the causal relationship between depression and OA, with approximately 14 % of the risk of OA caused by depression being mediated by body fat mass. CONCLUSIONS: Our study offers reliable evidence that depression has a detrimental impact on the risk of OA. Future research can support these associations from improving depressed effect, including social, biological, and behavioral factors, to reduce the risk of chronic diseases such as osteoarthritis. And we identified high-risk variation of alleles which associated with OA and depression can be used to predict disease and provide a basis for clinical intervention and treatment of OA.

Asunto(s)

Depresión , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoartritis , Polimorfismo de Nucleótido Simple , Humanos , Osteoartritis/genética , Osteoartritis/epidemiología , Depresión/genética , Depresión/epidemiología , Tejido Adiposo , Predisposición Genética a la Enfermedad/genética

RESUMEN

The (patho)physiological function of the sphingolipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) in articular joints during osteoarthritis (OA) is largely unknown. Therefore, we investigated the influence of these lipids on protein expression by fibroblast-like synoviocytes (FLSs) from OA knees. Cultured human FLSs (n = 7) were treated with 1 of 3 lipid species-C1P, S1P, or SPC-IL-1ß, or with vehicle. The expression of individual proteins was determined by tandem mass tag peptide labeling followed by high-resolution electrospray ionization (ESI) mass spectrometry after liquid chromatographic separation (LC-MS/MS/MS). The mRNA levels of selected proteins were analyzed using RT-PCR. The 3sphingolipids were quantified in the SF of 18 OA patients using LC-MS/MS. A total of 4930 proteins were determined using multiplex MS, of which 136, 9, 1, and 0 were regulated both reproducibly and significantly by IL-1ß, C1P, S1P, and SPC, respectively. In the presence of IL-1ß, all 3 sphingolipids exerted ancillary effects. Only low SF levels of C1P and SPC were found. In conclusion, the 3 lipid species regulated proteins that have not been described in OA. Our results indicate that charged multivesicular body protein 1b, metal cation symporter ZIP14, glutamine-fructose-6-P transaminase, metallothionein-1F and -2A, ferritin, and prosaposin are particularly interesting proteins due to their potential to affect inflammatory, anabolic, catabolic, and apoptotic mechanisms.

Asunto(s)

Ceramidas , Fibroblastos , Lisofosfolípidos , Proteómica , Esfingosina , Sinoviocitos , Humanos , Sinoviocitos/metabolismo , Sinoviocitos/patología , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Proteómica/métodos , Fibroblastos/metabolismo , Ceramidas/metabolismo , Esfingolípidos/metabolismo , Femenino , Células Cultivadas , Masculino , Anciano , Interleucina-1beta/metabolismo , Espectrometría de Masas en Tándem , Persona de Mediana Edad , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/genética , Fosforilcolina/análogos & derivados

RESUMEN

Connexin 43 (Cx43) is crucial for the development and homeostasis of the musculoskeletal system, where it plays multifaceted roles, including intercellular communication, transcriptional regulation and influencing osteogenesis and chondrogenesis. Here, we investigated Cx43 modulation mediated by inflammatory stimuli involved in osteoarthritis, i.e., 10 ng/mL Tumor Necrosis Factor alpha (TNFα) and/or 1 ng/mL Interleukin-1 beta (IL-1ß), in primary chondrocytes (CH) and osteoblasts (OB). Additionally, we explored the impact of synovial fluids from osteoarthritis patients in CH and cartilage explants, providing a more physio-pathological context. The effect of TNFα on Cx43 expression in cartilage explants was also assessed. TNFα downregulated Cx43 levels both in CH and OB (-73% and -32%, respectively), while IL-1ß showed inconclusive effects. The reduction in Cx43 levels was associated with a significant downregulation of the coding gene GJA1 expression in OB only (-65%). The engagement of proteasome in TNFα-induced effects, already known in CH, was also observed in OB. TNFα treatment significantly decreased Cx43 expression also in cartilage explants. Of note, Cx43 expression was halved by synovial fluid in both CH and cartilage explants. This study unveils the regulation of Cx43 in diverse musculoskeletal cell types under various stimuli and in different contexts, providing insights into its modulation in inflammatory joint disorders.

Asunto(s)

Condrocitos , Conexina 43 , Interleucina-1beta , Osteoartritis , Osteoblastos , Factor de Necrosis Tumoral alfa , Humanos , Conexina 43/metabolismo , Conexina 43/genética , Condrocitos/metabolismo , Osteoblastos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Líquido Sinovial/metabolismo , Cartílago Articular/metabolismo , Cartílago Articular/patología , Células Cultivadas , Anciano , Persona de Mediana Edad , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Cartílago/metabolismo , Cartílago/patología , Artropatías/metabolismo , Artropatías/patología , Artropatías/genética

RESUMEN

Osteoarthritis (OA) is a worldwide joint disease, leading to the physical pain, stiffness, and even disability. Lactate dehydrogenase A (LDHA) is known as a lactylation mediator that can regulate histone lactylation of its target genes. However, the role of LDHA-mediated histone H3 lysine 18 lactylation (H3K18la) in OA progression is yet to be clarified. Our study aims at revealing the role and mechanism of LDHA-mediated histone lactylation in the glycolysis of chondrocytes. In this study, we determined at first that the H3K18la level was enhanced in OA. Energy metabolism such as glycolysis is often altered in OA progress. Therefore, we further explored the mechanism mediating glycolysis and thus promoting OA progress. Moreover, glycolysis was enhanced in LPS-induced OA cell model, as evidenced by the increased glucose consumption and lactate production. Furthermore, we silenced LDHA for loss-of-function assays. The results showed that knockdown of LDHA suppressed glycolysis of LPS-induced chondrocytes. In vivo animal study demonstrated that knockout of LDHA recovered cartilage injury of OA mice. Mechanistically, we uncovered that LDHA-mediated H3K18la in TPI1 promoter enhanced the transcription activity of TPI1. Mutation of K69 site was found to ameliorate LPS-induced glycolysis in OA cell model. In conclusion, our study reveals the role of LDHA-mediated H3K18la of TPI1 promoter in OA progress.

Asunto(s)

Condrocitos , Glucólisis , Histonas , Osteoartritis , Osteoartritis/metabolismo , Osteoartritis/genética , Osteoartritis/patología , Animales , Ratones , Histonas/metabolismo , Humanos , Condrocitos/metabolismo , Modelos Animales de Enfermedad , Lactato Deshidrogenasa 5/metabolismo , Masculino , Regulación de la Expresión Génica , Ratones Noqueados , Regiones Promotoras Genéticas , Transcripción Genética

RESUMEN

BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis. AIMS: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis. METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted. RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments. CONCLUSION: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.

Asunto(s)

Fragilidad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Fragilidad/genética , Artritis/genética , Artritis/epidemiología , Osteoartritis/genética , Osteoartritis/epidemiología , Artritis Reumatoide/genética , Artritis Reumatoide/epidemiología , Anciano , Masculino , Femenino , Artritis Psoriásica/genética , Artritis Psoriásica/epidemiología , Predisposición Genética a la Enfermedad , Persona de Mediana Edad

RESUMEN

Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, ß-galactosidase (ß-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.

Asunto(s)

Senescencia Celular , Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Inflamación , Péptidos y Proteínas de Señalización Intracelular , Osteoartritis , Progeria , Animales , Ratones , Osteoartritis/terapia , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoartritis/etiología , Osteoartritis/patología , Senescencia Celular/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/terapia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terapia Genética/métodos , Progeria/genética , Progeria/terapia , Progeria/metabolismo , Dependovirus/genética , Envejecimiento , Cartílago Articular/metabolismo , Cartílago Articular/patología , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Condrocitos/metabolismo , Ratones Noqueados , Factor de Necrosis Tumoral alfa/metabolismo , Humanos

RESUMEN

Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large-scale genome-wide association studies have identified numerous genetic variants linked to OA risk factors, facilitating MR study design. In this review, we systematically identified 52 MR studies meeting specific criteria and evaluated their quality, exploring the impact of lifestyle, nutrition, comorbidities, circulating metabolites, plasma proteins, and other health factors on OA risk. We discuss the results and potential mechanisms of MR findings, addressing conflicting evidence based on existing literature and our prior research. With the ongoing expansion of genome-wide association data, we anticipate MR's role in future OA studies to broaden, particularly in drug development research using targeted MR approaches. We thus aim for this paper to offer valuable insights for researchers and clinicians in related fields.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoartritis , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Osteoartritis/genética , Factores de Riesgo , Predisposición Genética a la Enfermedad , Estilo de Vida

RESUMEN

BACKGROUND: Abdominal aortic aneurysm (AAA) represents one of the most life-threatening cardiovascular diseases and is increasingly becoming a significant global public health concern. The aneurysms-osteoarthritis syndrome (AOS) has gained recognition, as patients with this syndrome often exhibit early-stage osteoarthritis (OA) and have a substantially increased risk of rupture, even with mild dilation of the aneurysm. The aim of this study was to discover potential biomarkers that can predict the occurrence of AAA rupture in patients with OA. METHODS: Two gene expression profile datasets (GSE98278, GSE51588) and two single-cell RNA-seq datasets (GSE164678, GSE152583) were obtained from the GEO database. Functional enrichment analysis, PPI network construction, and machine learning algorithms, including LASSO, Random Forest, and SVM-RFE, were utilized to identify hub genes. In addition, a nomogram and ROC curves were generated to predict the risk of rupture in patients with AAA. Moreover, we analyzed the immune cell infiltration in the AAA tissue microenvironment by CIBERSORT and validated key gene expression in different macrophage subtypes through single-cell analysis. RESULTS: A total of 105 intersecting DEGs that showed consistent changes between rAAA and OA dataset were identified. From these DEGs, four hub genes (PAK1, FCGR1B, LOX and PDPN) were selected by machine learning. High predictive performance was observed for the nomogram based on these hub genes, with an AUC of 0.975 (95 % CI: 0.942-1.000). Abnormal immune cell infiltration was detected in rAAA and correlated significantly with the hub genes. Ruptured AAA cases exhibited higher nomoscore values and lower M2 macrophage infiltration compared to stable AAA. Validation in animal models (PPE+BAPN-induced rAAA) confirmed the significant role of these biomarkers in AAA pathology. CONCLUSION: The present study successfully identified four potential hub genes (PAK1, FCGR1B, LOX and PDPN) and developed a robust predictive nomogram to assess the risk of AAA rupture. The findings also shed light on the connection between hub genes and immune cell components in the microenvironment of rAAA. These findings support future research on key genes in AAA patients with OA, providing insights for novel management strategies for AAA.

Asunto(s)

Aneurisma de la Aorta Abdominal , Osteoartritis , Humanos , Aneurisma de la Aorta Abdominal/genética , Osteoartritis/genética , Rotura de la Aorta/genética , Masculino , Mapas de Interacción de Proteínas/genética , Aprendizaje Automático , Perfilación de la Expresión Génica/métodos , Biomarcadores , Transcriptoma , Curva ROC , Factores de Riesgo , Macrófagos/metabolismo , Proteína-Lisina 6-Oxidasa/genética , Bases de Datos Genéticas

RESUMEN

Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.

Asunto(s)

Artritis Reumatoide , Redes Reguladoras de Genes , Membrana Sinovial , Humanos , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Membrana Sinovial/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Perfilación de la Expresión Génica , Biología Computacional/métodos , Sinoviocitos/metabolismo , Osteoartritis/genética , Osteoartritis/metabolismo , Regulación de la Expresión Génica , Linfocitos B/inmunología , Linfocitos B/metabolismo , Transcriptoma

RESUMEN

Extracellular vesicles secreted by bone marrow mesenchymal stem cells (BM-MSCs) exert therapeutic effects in osteoarthritis (OA). As an important N6-Methyladenosine (m6A) demethylase, it is reported that fat mass and obesity-associated protein (FTO) involves in regulating OA progression. Here, we generated MSCs-derived FTO-overexpressing EVs (FTO-EVs) to investigate whether FTO-EVs could be used for the potential treatment of OA. Our experiments verify that FTO-EVs suppressed cellular senescence, aging, apoptosis, and enhanced cell autophagy in LPS-treated chondrocytes in vitro and monosodium iodoacetate (MIA)-treated mice tissues in vivo. Also, ROS scavenger NAC reversed LPS-induced detrimental effects in chondrocytes. Mechanical experiments illustrated that FTO-EVs induced m6A-demethylation in autophagy-associated genes (Atg5 and Atg7) and pro-apoptosis gene (BNIP3), subsequently inducing the upregulation of Atg5/Atg7 and downregulation of BNIP3 in a YTHDF2-dependent manner, and the effects of FTO-EVs on the expressions of Atg5/Atg7 and BNIP3 were all reversed by upregulating m6A methyltransferase METTL3. Furthermore, FTO-EVs-induced suppressing effects on LPS-treated chondrocytes senescence and aging were abolished by Atg5/Atg7 knockdown and BNIP3 overexpression. In conclusion, this study evidenced that BM-MSCs-derived FTO-EVs suppressed cellular senescence and apoptosis, and triggered protective autophagy to suppress OA development through demethylating m6A modifications, and the engineering FTO-EVs could be potentially used to treat OA in clinic.

Asunto(s)

Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Senescencia Celular , Condrocitos , Vesículas Extracelulares , Células Madre Mesenquimatosas , Metiltransferasas , Osteoartritis , Proteínas de Unión al ARN , Animales , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Vesículas Extracelulares/metabolismo , Osteoartritis/metabolismo , Osteoartritis/terapia , Osteoartritis/patología , Osteoartritis/genética , Ratones , Células Madre Mesenquimatosas/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Condrocitos/metabolismo , Autofagia , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptosis , Envejecimiento/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , ARN/metabolismo , ARN/genética , Metilación de ARN , Proteínas Mitocondriales

RESUMEN

Osteoarthritis (OA) is a prevalent degenerative condition among the elderly on a global scale. Research has demonstrated that hypoxia can promote chondrocyte apoptosis and autophagy leading to OA. Hence, it was vital to screen the hypoxia related biomarkers in OA. We introduced transcriptome data to screen out differentially expressed genes (DEGs) in GSE114007 and GSE57218 (OA samples vs control samples). We performed differential expression analysis in key annotated cell to obtain differentially expressed marker genes at the single-cell level (GSE169454). Venn diagram was executed to identify hypoxia related differentially expressed genes (HR-DEGs) associated with OA. Further, feature genes were obtained through the application of least absolute shrinkage and selection operator (LASSO) regression and the Random Forest (RF) algorithm. Receiver operating characteristic (ROC) and expression level analysis were used to identify hypoxia related biomarkers in OA. We further performed immune infiltration and gene set enrichment analysis (GSEA) based on hypoxia related biomarkers. Finally, we analyzed the expression of biomarkers in single-cell level. We identified 2351 DEGs associated with OA. At the single-cell level, 242 differentially expressed marker genes were obtained. 12 HR-DEGs were retained venn diagram. Subsequently, three hypoxia related biomarkers (ADM, DDIT3 and MAFF) were identified. Moreover, we got 15 significantly different immune cells. Finally, we found a lower expression of ADM, DDIT3 and MAFF in OA group compared to the control group in ECs. Overall, we obtained three hypoxia related biomarkers (ADM, DDIT3 and MAFF) associated with OA, which established a theoretical basis for addressing OA.

Asunto(s)

Biomarcadores , Hipoxia , Osteoartritis , Análisis de la Célula Individual , Transcriptoma , Humanos , Osteoartritis/genética , Osteoartritis/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Análisis de la Célula Individual/métodos , Hipoxia/metabolismo , Hipoxia/genética , Perfilación de la Expresión Génica/métodos