RESUMEN
Long noncoding RNAs (lncRNAs) and miRNAs have been reported to participate in intervertebral disc degeneration (IDD) progression. However, the key lncRNA-miRNA axis and its corresponding affected hub genes in IDD remain unknown. In this study, weighted gene coexpression network analysis (WGCNA) was first used to determine the key gene cluster and hub genes implicated in IDD progression. The expression levels of ADIRF-AS1, miR-214-3p, and SERPINA1 in nucleus pulposus (NP) tissues were detected. The ADIRF-AS1/miR-214-3p/SERPINA1 axis was identified, and its effects on the proliferation, senescence, and apoptosis of NP cells were investigated in vitro and in vivo. SERPINA1 overexpression in NP cells promoted cell viability and inhibited cell apoptosis and senescence. Moreover, SERPINA1 regulated the IDD grade in rat models. The lncRNA ADIRF-AS1 was downregulated in high-grade degeneration NP tissues and positively correlated with SERPINA1. ADIRF-AS1 overexpression attenuated cellular degenerative changes in NP cells. miR-214-3p directly bound to SERPINA1 and ADIRF-AS1 and negatively regulated ADIRF-AS1 expression. miR-214-3p inhibition exerted similar effects on cellular degenerative changes in NP cells to SERPINA1 or ADIRF-AS1 overexpression. Furthermore, miR-214-3p overexpression partially reversed the effects of ADIRF-AS1 overexpression. Collectively, these data suggest that ADIRF-AS1 overexpression could mitigate IDD by binding to miR-214-3p to upregulate SERPINA1. Additional studies (especially those using an axial loading-induced IDD animal model) will be needed to further validate the role of the ADIRF-AS1/miR-214-3p/SERPINA1 signaling axis in IDD progression.
Asunto(s)
Degeneración del Disco Intervertebral , MicroARNs , Núcleo Pulposo , ARN Largo no Codificante , Animales , Apoptosis/genética , Proliferación Celular/genética , Degeneración del Disco Intervertebral/genética , MicroARNs/genética , MicroARNs/metabolismo , Núcleo Pulposo/metabolismo , Fenotipo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , RatasRESUMEN
Nucleus pulposus cell (NPC) is the major cell type maintaining the physiological function of intervertebral discs by producing extracellular matrix (ECM). NPC apoptosis and senescence together contribute to NPC loss, finally leading to intervertebral disc degeneration (IDD). Herein, miR-623 showed to be downregulated within IDD tissue samples according to both bioinformatics and experimental analyses. In LPS-injured NPCs, miR-623 overexpression promoted LPS-suppressed cell proliferation; moreover, miR-623 overexpression inhibited cell apoptosis and senescence, increased ECM secretion, and reduced levels of inflammatory factors. In contrast to miR-623, CXCL12 expression was significantly upregulated in IDD tissues; miR-623 directly bound CXCL12 to inhibit its expression. In LPS-stimulated NPCs, CXCL12 silencing also LPS-induced changes in cell proliferation, cell senescence, ECM secretion, and inflammatory factor levels. More importantly, CXCL12 overexpression aggravated LPS-induced changes and significantly reversed the protective effects of miR-623 overexpression. In conclusion, the miR-623/CXCL12 axis could affect NPC apoptosis and senescence, ECM deposition, and inflammatory factor levels under LPS stimulation in vitro. The p65 signaling might be involved.