RESUMEN
Intervertebral disc degeneration (IDD) is the most common degenerative disease all over the word. Our previous study confirmed that the downregulated circ-GRB10 directly interacts with miR-328-5p, which modulate ERBB2 and leads to the degeneration of intervertebral disc; however, the underpinning mechanism of circ-GRB10 dysregulation remains unclear. We identified that FUS and demonstrated that circ-GBR10 biosynthesis in nucleus pulposus (NP) cells was promoted by FUS, whose expression was controlled by miR-141-3p. In addition, ERBB2 downregulation led to decreased Erk1/2 phosphorylation which enhanced miR-141-3p production in NP cells. In vivo data indicated that circ-GRB10 inhibited IDD in rat model. The present study revealed that miR-141-3p and FUS are key factors that regulate circ-GRB10 synthesis in NP cells. In addition, circ-GBR10 participates in the molecular circuitry that controls human IDD development. These findings provide a basis for further functional, diagnostic and therapeutic studies of circ-GRB10 in IDD.
Asunto(s)
Redes Reguladoras de Genes , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/patología , ARN Circular/metabolismo , Adulto , Animales , Secuencia de Bases , Modelos Animales de Enfermedad , Femenino , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Fosforilación , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Circular/genética , Proteína FUS de Unión a ARN/metabolismo , Ratas Sprague-Dawley , Receptor ErbB-2/metabolismoRESUMEN
Intervertebral disc degeneration (IDD) is an important cause of lower back pain, although the underlying mechanisms remain poorly understood. The present study aimed to examine the role of a circular RNA derived from tissue inhibitor of metallopeptidases 2 (circTIMP2) in degenerative nucleus pulposus (NP) tissues, and to validate its function in cultured human NP cells. Overexpression of miR1855p in NP cells markedly inhibited the enhanced extracellular matrix (ECM) catabolism induced by tumor necrosis factorα (TNFα) and interleukin1ß (IL1ß) treatment. Bioinformatics analysis demonstrated that matrix metalloproteinase 2 (MMP2) was a potential target of miR1855p. MMP2 protein expression levels were increased following treatment with TNFα and IL1ß in NP cells compared with those in untreated cells, and this effect was attenuated by transfection with miR1855p. Compared with normal NP tissues, IDD samples exhibited higher circTIMP2 expression levels. In addition, overexpression of circTIMP2 promoted ECM catabolism and suppressed ECM anabolism. Furthermore, circTIMP2 sequestered miR1855p, which may potentially upregulate the target genes associated with ECM degradation. In conclusion, the results of the present study revealed that circTIMP2 promoted TNFα and IL1ßinduced NP cell imbalance between ECM anabolism and catabolism via miR1855pMMP2 signaling. These findings provide a potential therapeutic option for the treatment of IDD.
Asunto(s)
Metaloproteinasa 2 de la Matriz/metabolismo , Núcleo Pulposo/metabolismo , Adulto , Northern Blotting , Western Blotting , Biología Computacional , Femenino , Humanos , Inmunoprecipitación , Hibridación Fluorescente in Situ , Degeneración del Disco Intervertebral/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Transducción de Señal/fisiologíaRESUMEN
Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, although the underlying mechanisms remain poorly understood. In this study we examined the role of circular RNA FAM169A (circ-FAM169A) in degenerative nucleus pulposus (NP) tissues, and validated its function in cultured human NP cells. Overexpression of circ-FAM169A in NP cells markedly enhanced extracellular matrix (ECM) catabolism and suppressed ECM anabolism in NP cells. Furthermore, circ-FAM169A sequestered miR-583, which could potentially upregulate BTRC, an inducer of the NF-κB signaling pathway. In conclusion, the present study revealed that circ-FAM169A promotes IDD development via miR-583/BTRC signaling. These findings provide a potential therapeutic option for the treatment of IDD.
Asunto(s)
Degeneración del Disco Intervertebral/genética , MicroARNs/metabolismo , ARN Circular/metabolismo , Proteínas con Repetición de beta-Transducina/metabolismo , Adulto , Animales , Secuencia de Bases , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Femenino , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Degeneración del Disco Intervertebral/diagnóstico por imagen , Masculino , MicroARNs/genética , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Análisis de Componente Principal , ARN Circular/genética , Ratas Sprague-Dawley , Transducción de Señal , Regulación hacia Arriba/genéticaRESUMEN
Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328-5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ-GRB10 might be a novel therapeutic target for IDD.
Asunto(s)
Apoptosis/genética , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/patología , Núcleo Pulposo/patología , ARN/metabolismo , Adulto , Supervivencia Celular , Femenino , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Anotación de Secuencia Molecular , ARN/genética , ARN Circular , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/genéticaRESUMEN
Objective To observe the clinical features of posterior cruciate ligament rupture and compare the efficacy of arthroscopic surgery and conservative treatment. Methods 128 patients, including 63 patients treated by arthroscopic surgery and 65 patients treated by conservative operation were included in the study. Statistical analysis was performed using SPSS 17.0 statistical software package. Results In the present study, after 24 month follow up, the PDT grade in the arthroscopic surgery group was better than that in conservative treatment group. The Lysol score in the arthroscopic surgery group was significantly higher that observed in the conservative treatment group (P < 0.05). There was no significantly difference for the Tiger score between the arthroscopic surgery group and conservative treatment group. Conclusion Arthroscopic treatment of posterior curiae ligament rupture is more effective than conservative treatment, especially in the treatment of joint stability and so on.
RESUMEN
STUDY DESIGN: A microRNA (miRNA) study. OBJECTIVE: The purpose of this study was to identify intervertebral disc degeneration (IDD)-specific miRNAs, followed by functional validation of results. SUMMARY OF BACKGROUND DATA: IDD is the major contributor to back radicular pain, and the molecular mechanisms underlying this disease are not completely understood. Accumulating evidence suggests that miRNAs play an important role in IDD, but the role of specific miRNAs involved in this disease remains elusive. METHODS: An initial screening of nucleus pulposus (NP) tissues, miRNA expression by miRNA microarray, was performed using samples from 10 patients with degenerative disc disease and 10 patients with lumbar fracture (as controls). Subsequently, differential expression was validated using quantitative reverse transcriptase PCR (qRT-PCR). The level of differentially expressed miRNAs in degenerative NP tissues was investigated, and then functional analysis of the miRNAs in regulating collagen II expression was carried out. Western blotting and luciferase reporter assays were also used to detect the target gene. RESULTS: We identified 23 miRNAs that were differentially expressed (16 upregulated and 7 downregulated) in patients compared with controls. After qRT-PCR confirmation, miR-27b was significantly downregulated in degenerative NP tissues when compared with controls. Moreover, its level was correlated with grade of disc degeneration. Overexpression of miR-27b promoted type II collagen expression in NP cells. Bioinformatics target prediction identified matrix metalloproteinase 13 (MMP13) as a putative target of miR-27b. Futhermore, luciferase reporter assays demonstrated that miR-27b directly targets MMP13 and affects the protein expression of MMP13 in NP cells. Expression of MMP13 negatively correlated with miR-27b expression in degenerative NP tissues. CONCLUSION: The downregulation of miR-27b induces type II collagen loss by directly targeting MMP13, leading to the development of IDD. Our study also underscores the potential of miR-27b as a novel therapeutic target in human IDD. LEVEL OF EVIDENCE: 3.