Increased Expression of Prolyl Endopeptidase Induced by Oxidative Stress in Nucleus Pulposus Cells Aggravates Intervertebral Disc Degeneration

Abstract

A healthy microenvironment of the intervertebral disc tissue is characterized by hypoxia owing to its sparse vascular distribution. Oxidative stress plays a pivotal role in the pathological development of intervertebral disc degeneration (IVDD). We found that the expression of prolyl endopeptidase (PREP) increased in degenerative nucleus pulposus (NP) tissues. The purpose of this study was to determine whether PREP is involved in oxidative-stress-induced IVDD. Tertbutyl hydroperoxide can inhibit the expression of PREP by activating the PI3K/AKT signaling pathway at low concentrations in NP cells. Knockdown of PREP protected NP cells from apoptosis induced by oxidative stress, whereas overexpression of PREP exacerbated the apoptosis of NP cells. We also investigated the connection between the PI3K/AKT signaling pathway and PREP and found that the activation of the PI3K/AKT signaling pathway downregulated the expression of PREP by inhibiting p53. As a crucial transcription factor, p53 binds to the PREP promoter region and promotes its transcription. Overexpression of PREP also impairs protein secretion in the extracellular matrix of NP cells. Furthermore, the in vivo knockout of PREP could attenuate puncture-induced IVDD. These findings suggested that the downregulation of PREP might maintain the viability of NP cells and attenuate IVDD under oxidative stress.

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

“…115 ROS can inhibit its downstream signal transduction by inhibiting the phosphorylation of PI3K and Akt and promoting PTEN expression. 116,117 In IDD, activation of the PI3K/Akt signalling pathway effectively ameliorated oxidative stress-induced apoptosis, ECM degradation, and cell proliferation of NPCs 118,119 .In addition, Guo et al 120 found that resveratrol (RSV) could promote ECM production and increase the expression of autophagy related markers (beclin-1 and LC-3) to induce cell autophagy to delay IDD. Mechanistic studies revealed that RSV exerted a protective effect through activation of the PI3K/Akt pathway.…”

Emerging role and therapeutic implications of p53 in intervertebral disc degeneration

“…These studies suggest that p53 induces ECM remodeling by promoting the expression of matrix-degrading enzymes and inhibiting the expression of matrix proteins. In IDD, IL-1β significantly increased the expression level of p53 in NPCs, which resulted in the upregulation of mRNA and protein levels of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 and the downregulation of Col II and Agg [ 103 ]. In addition, several studies have shown that abnormal activation of the NF-κB and JNK signaling pathways in IVD is an important factor contributing to IDD progression [ 143 ].…”

“…Activated NF-κB and JNK signaling pathways upregulate p53 expression, accelerating ECM degradation by promoting the expression of MMPs and ADAMTS and inhibiting the expression of Col II and Agg [ 71 , 217 ]. Recently, Zheng et al [ 103 ] reported that p53 binds to the promoter regions of prolyl endopeptidase to promote their transcription. Overexpression of prolyl endopeptidases impairs the ECM quality of NPCs by inhibiting the expression of Col II and Agg and promoting the expression of MMP3.…”

“…Compared with that in normal IVDs, the expression of p53 in degenerative IVDs is significantly increased, and the degree of increase is related to the grade of degeneration [ 37 , 64 – 66 , 71 , 102 ]. In addition, multiple stimuli can lead to the upregulation of p53 levels, including oxidative stress, inflammatory responses, high glucose levels, and abnormal mechanical loading [ 101 , 103 – 105 ]. However, the exact changes in p53 temporal dynamics under these stress conditions remain unclear.…”

Mesenchymal Stem Cells May Alleviate the Intervertebral Disc Degeneration by Reducing the Oxidative Stress in Nucleus Pulposus Cells

“…Oxidative stress has been demonstrated to play important roles in the development of IDD [ 13 , 14 ]. Under normal circumstances, the microenvironment of intervertebral disc (IVD) tissue is hypoxic, and there is a dynamic balance between the generation and scavenging of intracellular reactive oxide species [ 15 ]. However, the oxidative stress occurs when this balance is disrupted, which can lead to senescence and apoptosis of nucleus pulposus cells (NPCs), and degradation of extracellular matrix [ 16 ].…”