Cationic Polymer Brush-Modified Carbon Nanotube-Meditated eRNA LINC02569 Silencing Attenuates Nucleus Pulposus Degeneration by Blocking NF-κB Signaling Pathway and Alleviate Cell Senescence.

Yulin Huang,Baozhu Zeng,Ningning Chen,Zemin Ling,Shaoyu Liu,Fuxin Wei,Xiaoshuai Wang,Jiaming Yang,Kai Zhu,Xizhe Liu

doi:10.3389/fcell.2021.837777

Abstract

Enhancer RNAs (eRNAs) are noncoding RNAs that synthesized at active enhancers. eRNAs have important regulatory characteristics and appear to be significant for maintenance of cell identity and information processing. Series of functional eRNAs have been identified as potential therapeutic targets for multiple diseases. Nevertheless, the role of eRNAs on intervertebral disc degeneration (IDD) is still unknown yet. Herein, we utilized the nucleus pulposus samples of patients and identified a key eRNA (LINC02569) with the Arraystar eRNA Microarray. LINC02569 mostly locates in nucleus and plays an important role in the progress of IDD by activating nuclear factor kappa-B (NF-κB) signaling pathway. We used a cationic polymer brush coated carbon nanotube (oCNT-pb)-based siRNA delivery platform that we previously designed, to transport LINC02569 siRNA (si-02569) to nucleus pulposus cells. The siRNA loaded oCNT-pb accumulated in nucleus pulposus cells with lower toxicity and higher transfection efficiency, compared with the traditional siRNA delivery system. Moreover, the results showed that the delivery of si-02569 significantly alleviated the inflammatory response in the nucleus pulposus cells via inhibiting P65 phosphorylation and preventing its transfer into the nucleus, and meanwhile alleviated cell senescence by decreasing the expression of P21. Altogether, our results highlight that eRNA (LINC02569) plays important role in the progression of IDD and could be a potential therapeutic target for alleviation of IDD.

Highlights

Low back pain (LBP) is one of the leading causes of disability worldwide, and the disability that caused by LBP increased by 54% between 1990 and 2015 globally (Hartvigsen et al, 2018)
To investigate the role of Enhancer RNAs (eRNAs) in the progression of NP degeneration, we set out to identify eRNAs modulated in degenerative NPs compared with normal ones with Arraystar Human SE-lncRNA Microarray (Figure 1A)
We verified that LINC02569 was significantly up-regulated in degenerative eRNA LINC02569 Silencing Attenuates intervertebral disc degeneration (IDD)

Summary

Introduction

Low back pain (LBP) is one of the leading causes of disability worldwide, and the disability that caused by LBP increased by 54% between 1990 and 2015 globally (Hartvigsen et al, 2018). IDD is a multifactorial process characterized by cellular and biomechanical changes that lead to loss of extracellular matrix (ECM) proteoglycans, increased fibrillation and reduction of water content (Antoniou et al, 1996). The inflammatory-associated factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) are widely reported to be associated with IDD (Le Maitre et al, 2005; Le Maitre et al, 2007). Both the in vitro and in vivo studies have demonstrated that inflammatory stimulation was able to trigger the degeneration of nucleus pulposus cells (NPCs) (Srivastava et al, 2017; Hernandez et al, 2020), (Rajan et al, 2013). Attenuation of the inflammatory response in the intervertebral discs has long been considered as a specific therapeutic molecular target for treatment of IDD (Chou et al, 2020; Shao et al, 2020; Lyu et al, 2021)

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Results

Conclusion