Long non-coding HCG18 promotes intervertebral disc degeneration by sponging miR-146a-5p and regulating TRAF6 expression

Yanhai Xi,Weiheng Wang,Tingwang Jiang,Yang Wang,Xueming Wu,Yunfei He,Jiangming Yu

doi:10.1038/s41598-017-13364-6

Yanhai Xi, Weiheng Wang + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-13364-6

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Abstract

Intervertebral disc degeneration (IDD) is associated with the deterioration of nucleus pulposus (NP) cells due to hypertrophic differentiation and calcification. Emerging studies have shown that long noncoding RNAs (lncRNAs) play critical roles in the development of IDD. Using bioinformatics prediction, we hereby sought to identify the lncRNAs that regulate the expression of microRNA-146a-5p (miR-146a-5p), an IDD-related inflammatory factor. Our study demonstrated that lncRNA HCG18 acted as an endogenous sponge to down-regulate miR-146a-5p expression in the NP cells by directly binding to miR-146a-5p. In addition, HCG18 expression was up-regulated in the patients with IDD, bulging or herniated discs, and its level was positively correlated with the disc degeneration grade. In vitro, miR-146a-5p up-regulation HCG18 retarded the growth of NP cells by decreasing S phase of cell cycle, inducing cell apoptosis, recruitment of macrophages and hypercalcification. Conversely, down-regulation of miR-146a-5p exerted opposite effects. Furthermore, we elucidated that TRAF6, a target gene by miR-146a-5p, was modulated by HCG18 expression. Restore of TRAF6 expression by virus infection reserved the effect of HCG18 on the NP cells. Altogether, our data indicated that HCG18 suppressed the growth of NP cells and promoted the IDD development via the miR-146a-5p/TRAF6/NFκB axis.

Highlights

Intervertebral disc degeneration (IDD), the major cause of low-back pain, affects the majority of the population, with roughly 10% turning to be chronically disabled[1,2]
LncRNAs have been shown to be differentially expressed in human degenerative nucleus pulposus (NP) tissue, and involved in the pathological processes of IDD, including inflammatory responses, apoptosis, proteoglycans degradation and extracellular matrix (ECM) degeneration[3,8,15]
Emerging studies indicate that long noncoding RNAs (lncRNAs) play an essential role in the regulation of gene expression by acting as miRNA sponges[13,16,17,18]

Summary

Introduction

Intervertebral disc degeneration (IDD), the major cause of low-back pain, affects the majority of the population, with roughly 10% turning to be chronically disabled[1,2]. The osteogenic differentiation of the NP cells is involved in IDD development[7]. The dysregulation of gene expression is a very complex process, and the molecular mechanisms of IDD have still not been fully elucidated. LncRNAs don’t code for any protein, they still play important roles in physiological and pathological processes, including genome imprinting, gene expression regulation, cellular differentiation, and nuclear-cytoplasmic trafficking[10,11]. Accumulating evidences have shown that aberrantly expressed lncRNAs play a role in the IDD process. The results showed that HCG18 modulated the miR-146a-5p expression in the NP cells, and the elevated HCG18 was found in patients with IDD or herniated disc. We assessed the role of HCG18 on the proliferation and apoptosis of the NP cells, osteogenic differentiation, and macrophages recruitment. Our findings suggested that HCG18 serves as a stimulus in the development of IDD by targeting miR-146a-5p

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