Aberrant spinal mechanical loading stress triggers intervertebral disc degeneration by inducing pyroptosis and nerve ingrowth

Zhi-tao Sun,Chengliang Wu,Ming Yue,Zhiguo Zhang,Sai Yao,Shuxin Yan,Chengcong Zhou,Yanping Yang,Hongting Jin,Weibin Du,Peijian Tong,Fangda Fu,Huan Yu,Ronghua Bao,Yan Li,Di Chen,Huan Luo,Huihao Zhang,Hongfeng Ruan

doi:10.1038/s41598-020-80756-6

Abstract

Aberrant mechanical factor is one of the etiologies of the intervertebral disc (IVD) degeneration (IVDD). However, the exact molecular mechanism of spinal mechanical loading stress-induced IVDD has yet to be elucidated due to a lack of an ideal and stable IVDD animal model. The present study aimed to establish a stable IVDD mouse model and evaluated the effect of aberrant spinal mechanical loading on the pathogenesis of IVDD. Eight-week-old male mice were treated with lumbar spine instability (LSI) surgery to induce IVDD. The progression of IVDD was evaluated by μCT and Safranin O/Fast green staining analysis. The metabolism of extracellular matrix, ingrowth of sensory nerves, pyroptosis in IVDs tissues were determined by immunohistological or real-time PCR analysis. The apoptosis of IVD cells was tested by TUNEL assay. IVDD modeling was successfully produced by LSI surgery, with substantial reductions in IVD height, BS/TV, Tb.N. and lower IVD score. LSI administration led to the histologic change of disc degeneration, disruption of the matrix metabolism, promotion of apoptosis of IVD cells and invasion of sensory nerves into annulus fibrosus, as well as induction of pyroptosis. Moreover, LSI surgery activated Wnt signaling in IVD tissues. Mechanical instability caused by LSI surgery accelerates the disc matrix degradation, nerve invasion, pyroptosis, and eventually lead to IVDD, which provided an alternative mouse IVDD model.

Highlights

Aberrant mechanical factor is one of the etiologies of the intervertebral disc (IVD) degeneration (IVDD)
Multiple clinical investigations have showed that congenital malformations of spine[35,36], accidental back injury or ligament injury[37,38,39], occupational exposure[40,41,42] could induce aberrant mechanical loading of lumbar spine, and lead to IVDD
lumbar spine instability (LSI) surgery could promote the progression of IVD degeneration, including notable decreases in IVD height and histological score, ectopic new bone formation in EP, folds and tears in Annulus fibrosus (AF), reduction of the vacuole volume in nucleus pulposus (NP), acceleration of extracellular matrix (ECM) degradation, innervation into AF, and induction of pyroptosis after IVDD modeling

Summary

Introduction

Aberrant mechanical factor is one of the etiologies of the intervertebral disc (IVD) degeneration (IVDD). LSI administration led to the histologic change of disc degeneration, disruption of the matrix metabolism, promotion of apoptosis of IVD cells and invasion of sensory nerves into annulus fibrosus, as well as induction of pyroptosis. Mechanical instability caused by LSI surgery accelerates the disc matrix degradation, nerve invasion, pyroptosis, and eventually lead to IVDD, which provided an alternative mouse IVDD model. Due to a lack of an ideal animal model of persistent instability of IVDD, the exact molecular biological mechanisms by which aberrant spinal mechanical loading initiates and promotes IVDD has not been fully elucidated. Mechanical test on cadaveric lumbar motion segments suggested that complex mechanical loading simulating typical activities in vivo could damage IVDs, including gross structural disruption as well as cell-mediated matrix composition changes, and eventually result in I VDD8.

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