Hsa_circ_0134111 promotes intervertebral disc degeneration via sponging miR-578

Peng Yan,Yang Qu,Chong Sun,Jialuo Han,Derong Xu,Chuanli Zhou,Liangrui Luan

doi:10.1038/s41420-022-00856-2

Peng Yan, Yang Qu + Show 5 more

Open Access

https://doi.org/10.1038/s41420-022-00856-2

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Abstract

Intervertebral disc degeneration (IDD) is a chronic degenerative and age-dependent process characterized by aberrant apoptosis, proliferation, synthesis, and catabolism of the extracellular matrix of the nucleus pulposus (NP) cells. Recently, studies showed that circular RNAs play important roles in the development of many diseases. However, the role of circRNAs in IDD development remains unknown. We showed that circ_0134111 level was overexpressed in IDD tissue samples as compar-ed to control tissues. The upregulation of circ_0134111 was more drastic in the moderate and severe IDD cases than in those with mild IDD. In addition, we showed that interleukin-1β and tumor necrosis factor-α exposure significantly enhanced circ_0134111 expression in NP cells. Furthermore, ectopic expression of circ_0134111 induced proliferation, pro-inflammatory cytokine secretion, and ECM degradation in the NP cells. We also showed that circ_0134111 directly interacted with microRNA (miR)-578 in NP cells where elevated expression of circ_0134111 enhanced the ADAMTS-5 and MMP-9 expression. Moreover, miR-578 expression was significantly decreased in IDD patients and the miR-578 expression was negatively correlated with circ_0134111 expression in the IDD samples. Interleukin-1β and tumor necrosis factor-α exposure significantly decreased miR-578 levels in NP cells, in which ectopic miR-578 expression inhibited cell growth, pro-inflammatory cytokine expression, and ECM degradation. Finally, we showed that circ_0134111 overexpression induced the IDD-related phenotypic changes through inhibiting miR-578. These data suggested that circ_0134111 could promote the progression of IDD through enhancing aberrant NP cell growth, inflammation, and ECM degradation partly via regulating miR-578.

Highlights

Low back pain (LBP) is a leading cause of physical disability and is one of the most frequently encountered health problems in clinics, causing substantial global public health and economic burden [1,2,3,4]
Enforced expression of circ_0134111 enhanced transfection of the miR-578 mimic (Fig. 3B). circ_0134111 the mRNA level of MMP-9 and ADAMTS-5, both of which are expression was higher in nucleus pulposus (NP) cells after transfection of the Intervertebral disc degeneration (IDD)-related extracellular matrix (ECM)-degrading enzymes, in NP cells (Fig. 5E, F)
We showed that two pro-inflammatory cytokines—IL-1β and TNF-α could induce circ_0134111 expression in NP cells

Summary

INTRODUCTION

Low back pain (LBP) is a leading cause of physical disability and is one of the most frequently encountered health problems in clinics, causing substantial global public health and economic burden [1,2,3,4]. Circ_0134111 the mRNA level of MMP-9 and ADAMTS-5, both of which are expression was higher in NP cells after transfection of the IDD-related ECM-degrading enzymes, in NP cells (Fig. 5E, F). Consistent with the change of gene expression at the wild-type but not the binding site-mutated circ_0134111 was mRNA level, overexpression of circ_0134111 promoted MMP-9 downregulated upon transfection of miR-578 mimic, indicating and ADAMTS-5 protein expression in NP cells (Fig. 5J). The miR-578 expression ectopic expression of miR-578 enhanced the type II collagen level was lower in the IDD tissues as compared to the control and aggrecan expression (Fig. 6G, H) and inhibited MMP-9 and samples. Circ_0134111 produced IDD-related phenotypes through sponging miR-578 We further studied whether circ_0134111 regulated proliferation, cytokine secretion, and ECM degradation through regulating miR578 expression in NP cells. MiR-578 decreased circ_0134111-induced upregulation of IL-6 (Fig. 7C), IL-8 (Fig. 7D), MMP-9 (Fig. 7E), and ADAMTS-5 (Fig. 7F) in NP cells. miR-578 overexpression reversed the downregulation of type II collagen and aggrecan in the circ_0134111-overexpressing NP cells (Fig. 7G, H)

DISCUSSION

MATERIALS AND METHODS

Findings

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