RESUMEN
BACKGROUND: Dysregulation of the OPG/RANK/RANKL signalling pathway is a key step in the occurrence of steroid-induced osteonecrosis of the femoral head (ONFH). This study aims to understand the degree of methylation of the OPG, RANK, and RANKL genes in steroid-related ONFH. METHODS: A case-control study was designed, including 50 patients (25 males and 25 females) and 50 matched controls. The European Molecular Biology Open Software Suite (EMBOSS) was used to predict the existence and location of CpG islands in the OPG, RANK, and RANKL genes. The Agena MassARRAY platform was used to detect the methylation status of the above genes in the blood of subjects. The relationship between the methylation level of CpG sites in each gene and steroid-related ONFH was analysed by the chi-square test, logistic regression analysis, and other statistical methods. RESULTS: In the CpG islands of the OPG, RANK, and RANKL genes in patients with steroid-related ONFH, several CpG sites with high methylation rates and high methylation levels were found. Some hypermethylated CpG sites increase the risk of steroid-related ONFH. In addition, a few hypermethylated CpG sites have predictive value for the early diagnosis of steroid-related ONFH. CONCLUSION: Methylation of certain sites in the OPG/RANK/RANKL signalling pathway increases the risk of steroid-related ONFH. Some hypermethylated CpG sites may be used as early prediction and diagnostic targets for steroid-related ONFH.
Asunto(s)
Metilación de ADN , Necrosis de la Cabeza Femoral , Estudios de Casos y Controles , Femenino , Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/genética , Humanos , Masculino , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Esteroides/efectos adversosRESUMEN
The purpose of this research was to examine if the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. We found that IL1B rs1143630 decreased the SANFH's risk and IL1B rs2853550 increased the risk of steroid-induced ONFH. So, we guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH. INTRODUCTION: Genetic polymorphisms in IL1B gene could be related in the pathogenesis of osteonecrosis. Discusses on the relationship between the IL1B gene and steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is still less in Chinese Han population. So, in this research, we want to examine whether the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. METHODS: A total of 286 steroid-induced ONFH patients and 441 controls were recruited, and seven SNPs (rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623) in IL1B gene were selected; unconditional logistic regression analysis was used to research the influence on the risk of steroid-induced ONFH. Functional annotations of IL1B variants were performed by RegulomeDB and HaploReg. RESULTS: rs1143630 (A>C) in the IL1B gene decreased the risk of steroid-induced ONFH in the allele model (OR = 0.69, 95%CI 0.51-0.93, p = 0.014). Further genetic model analyses found that IL1B rs2853550 AG genotype increased the risk of steroid-induced ONFH compared with the people who are carriers of the IL1B rs2853550 GG genotype (OR = 1.69, 95%CI 1.16-2.46, p = 0.012). In the dominant model, IL1B rs1143630 GG-GT genotype decreased the risk of steroid-induced ONFH (OR = 0.62, 95%CI 0.44-0.87, p = 0.0051). And further haplotype analysis was performed, while the result was not significant. Using RegulomeDB and HaploReg, rs2853550 is likely to affect TF binding, any motif and DNase peak. CONCLUSIONS: We guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH.
Asunto(s)
Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/genética , Glucocorticoides/efectos adversos , Interleucina-1beta/genética , Polimorfismo de Nucleótido Simple , Adulto , Pueblo Asiatico/genética , Estudios de Casos y Controles , China/epidemiología , Femenino , Necrosis de la Cabeza Femoral/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Osteonecrosis of the femoral head (ONFH) caused by steroids is a severe orthopedic disorder resulting from the use of high-dose steroid drugs, characterized by structural changes in the bone, joint dysfunction, and femoral head collapse. CircRNAs and miRNAs have increasingly been suggested to play pivotal roles in osteogenic differentiation and osteogenesis. Significant upregulation of circ_0058792 was observed in patients with steroid-induced ONFH. Bioinformatic analysis showed that circ_0058792 might act as a sponge for miR-181a-5p. This study further investigated the mechanisms underlying the role of circ_0058792 and miR-181a-5p in osteogenic differentiation in methylprednisolone-induced ONFH rats and MC3T3-E1 cells. The results showed a notable decrease in the serum of miR-181a-5p in methylprednisolone-induced ONFH rats. Silencing of circ_0058792 using siRNAs and overexpression of miR-181a-5p significantly increased alkaline phosphatase activity and matrix mineralization capacity. Additionally, markers for osteogenic differentiation were significantly upregulated in miR-181a-5p-transfected cells. However, overexpression of circ_0058792 and the addition of the miR-181a-5p inhibitor reversed this increase. Smad7 was identified to be miR-181a-5p's direct target and circ_0058792 was confirmed to be miR-181a-5p's competing endogenous RNA (ceRNA). Upregulation of miR-181a-5p promotes phosphorylation of Smad2 and Smad3. Furthermore, circ_0058792 and miR-181a-5p had opposing effects on Smad7 expression. Collectively, these findings indicate that circ_0058792 regulates osteogenic differentiation by sponging miR-181a-5p via the TGF-ß/Smad7 pathway. These findings elucidated the functions of circ_0058792 and miR-181a-5p in the regulation of steroid-induced ONFH. Our findings also indicated that circ_0058792 and miR-181a-5p are possible diagnostic markers and therapeutic targets for treating steroid-induced ONFH.
Asunto(s)
Necrosis de la Cabeza Femoral , MicroARNs , ARN Circular , Proteína smad7 , Animales , Diferenciación Celular/genética , Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/genética , Necrosis de la Cabeza Femoral/metabolismo , Humanos , Metilprednisolona/toxicidad , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Osteogénesis/genética , ARN Circular/genética , Ratas , Proteína smad7/genética , Proteína smad7/metabolismo , Esteroides/efectos adversosRESUMEN
BACKGROUND: Gene polymorphism has an important influence on RETN gene expression level, and the increased level of resistin encoded in RETN will lead to metabolic disorder, especially lipid metabolism. Moreover, steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is closely related to lipid metabolism level, so this study is intended to explore the relationship of RETN polymorphisms with susceptibility to steroid-induced ONFH in the Chinese Han population. METHODS: In this case-control study, eight single-nucleotide polymorphisms (SNPs) of RETN were genotyped by the Agena MassARRAY system in 199 steroid-induced ONFH patients and 200 healthy controls. The relationship between RETN polymorphisms and steroid-induced ONFH risk was assessed using genetic models and haplotype analyses. Odds ratio (OR) and 95% confidence intervals (CIs) were obtained by logistic regression adjusted for age. RESULTS: We found significant differences in the distribution of HDL-C, TG/HDL-C, and LDL-C/HDL-C between the patients and the control group (p < 0.05). In allele model and genotype model analysis, rs34861192, rs3219175, rs3745368, and rs1477341 could reduce the risk of steroid-induced ONFH. Further stratified analysis showed that rs3745367 was related to the clinical stage of patients, and rs1477341 was significantly correlated with an increased TG level and a decreased TC/HDL-C level. The linkage analysis showed that two SNPs (rs34861192 and rs3219175) in RETN even significant linkage disequilibrium. CONCLUSIONS: Our results provide the firstly evidence that RETN gene polymorphisms were associated with a reduced risk of steroid-induced ONFH in Chinese Han population.
Asunto(s)
Pueblo Asiatico/genética , Necrosis de la Cabeza Femoral/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Polimorfismo de Nucleótido Simple/genética , Resistina/genética , Adulto , Pueblo Asiatico/etnología , Estudios de Casos y Controles , Femenino , Necrosis de la Cabeza Femoral/etnología , Predisposición Genética a la Enfermedad/etnología , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) in young adults is a challenging disorder that can impairs the quality of life of a patient. The disease also leads to frequent occurrences of collapse of the femoral head and resultant dysfunction of the hip joint. In recent years, some scholars have studied steroid-induced lipid metabolism disorder and achieved the effect of steroid-induced ONFH treatment. This study aims to review the investigations on the hepatic CYP3A (cytochrome P4503A enzyme) genetic polymorphisms in steroid-induced ONFH patients. We then further explore its activity correlation with the development of steroid-induced ONFH in a rabbit model. METHODS: A systematic literature search of articles was conducted in PubMed, Web of Science, Google Scholar, Springerlink, and the Chinese National Knowledge Infrastructure database up to February 2017. Twelve relevant articles were retrieved. The odds ratios, standard mean difference, and 95% confidence intervals were calculated to assess the effect of hepatic CYP3A activity on the rabbit model with steroid-induced ONFH. Fixed-effects and random-effects models were used to analyze the heterogeneity. Begg's funnel plot was used to assess publication bias. RESULTS: High hepatic CYP3A activity significantly decreased the risk for steroid-induced ONFH in the rabbit model (p <. 05). The CYP3A gene may be potentially associated with increased risk of steroid-induced ONFH in the human allele model. CONCLUSION: The study suggests that high hepatic CYP3A activity decreases the risk of steroid-induced ONFH.