Mechanosensitive Ion Channel Piezo1 Activated by Matrix Stiffness Regulates Oxidative Stress-Induced Senescence and Apoptosis in Human Intervertebral Disc Degeneration.

Bingjin Wang,Gaocai Li,Rongjin Luo,Saideng Lu,Qian Xiang,Zhiwei Liao,Cao Yang,Xinghuo Wu,Liang Ma,Xianlin Zeng,Yu Song,Yukun Zhang,Wencan Ke,Wenbin Hua,Kun Wang,Wenyuan Ding

doi:10.1155/2021/8884922

Abstract

Mechanical stimulation plays a crucial part in the development of intervertebral disc degeneration (IDD). Extracellular matrix (ECM) stiffness, which is a crucial mechanical microenvironment of the nucleus pulposus (NP) tissue, contributes to the pathogenesis of IDD. The mechanosensitive ion channel Piezo1 mediates mechanical transduction. This study purposed to investigate the function of Piezo1 in human NP cells under ECM stiffness. The expression of Piezo1 and the ECM elasticity modulus increased in degenerative NP tissues. Stiff ECM activated the Piezo1 channel and increased intracellular Ca2+ levels. Moreover, the activation of Piezo1 increased intracellular reactive oxygen species (ROS) levels and the expression of GRP78 and CHOP, which contribute to oxidative stress and endoplasmic reticulum (ER) stress. Furthermore, stiff ECM aggravated oxidative stress-induced senescence and apoptosis in human NP cells. Piezo1 inhibition alleviated oxidative stress-induced senescence and apoptosis, caused by the increase in ECM stiffness. Finally, Piezo1 silencing ameliorated IDD in an in vivo rat model and decreased the elasticity modulus of rat NP tissues. In conclusion, we identified the mechanosensitive ion channel Piezo1 in human NP cells as a mechanical transduction mediator for stiff ECM stimulation. Our results provide novel insights into the mechanism of mechanical transduction in NP cells, with potential for treating IDD.

Highlights

Low back pain (LBP) caused by the intervertebral disc (IVD) degeneration (IDD) significantly influences the living quality in patients and causes a large financial burden
According to the elasticity modulus measured in human nucleus pulposus (NP) tissues, NP cells were cultured in polystyrene plates with different stiffnesses for 6, 12, 24, and 48 h
Western blotting, Quantitative Reverse Transcription PCR (qRT-PCR), and corresponding qualification revealed that stiff substrate significantly increased the expression of Piezo1-targeting siRNA (Piezo1) at protein and mRNA levels (Figures 2(c)–2(e))

Summary

Introduction

Low back pain (LBP) caused by the intervertebral disc (IVD) degeneration (IDD) significantly influences the living quality in patients and causes a large financial burden. The excessive mechanical load on nucleus pulposus (NP) cells, as keys to the development of degenerative disc diseases, exacerbates IDD progression [2, 3]. Until recently, detailed pathogenesis and effective treatment of disc degeneration after excessive mechanical load are still not fully elucidated. Mechanical loading is the physiological function of human NP tissues and an important characteristic of the NP tissue mechanical microenvironment. With changes in the body position and weight bearing, the pressure in the NP tissue can fluctuate greatly, which influences the balance of the mechanical microenvironment of the NP tissue [1]. Compression stress can result in the accelerated functional transition of NP cells and ECM remodeling during the progression of IVD [4]

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