RESUMO
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.
Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Núcleo Pulposo/metabolismo , Adulto , Northern Blotting , Western Blotting , Biologia Computacional , Feminino , Humanos , Imunoprecipitação , Hibridização in Situ Fluorescente , Degeneração do Disco Intervertebral/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais/fisiologiaRESUMO
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.
Assuntos
Apoptose/genética , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/patologia , RNA/metabolismo , Adulto , Sobrevivência Celular , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , RNA/genética , RNA Circular , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/genéticaRESUMO
Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of NeuN-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14-56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1ß, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.