Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-κB Pathway.

Wenbo Liu,Fangfang Bi,Cuicui Chang,Zongtao Wu,Chen Ji

doi:10.1155/2020/8319516

Abstract

Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.

Highlights

Degeneration of the intervertebral disc is the main cause of lumbar protrusion
The expression of Toll-like receptor 4 (TLR4) and p-IκBα is elevated, accompanied by IκBα protein reduction and hyperinflammatory cytokine inductions of IL-1β, NOS2, and IL-18 (Figure 1(d)). These indicated that the expression of Klotho decreased and the activation of TLR4-NF-κB signaling in degenerative intervertebral disc
We have presented a novel finding in this study: TLR4-NF-κB signaling and Klotho form a negative-feedback loop in nucleus pulposus (NP) cells, and the expression of Klotho is regulated by the balance between upregulation and downregulation of HA-con HA-Klotho Con H2O2 Con H2O2

Summary

Introduction

Degeneration of the intervertebral disc is the main cause of lumbar protrusion. The lumbar intervertebral disc is the heaviest part of the human body. It is generally believed that the intervertebral disc begins to degenerate after the age of 20, but it is further proved that the degeneration started to occur at the age of 15. The water content of the nucleus gradually declines. The elasticity and loadresistance of intervertebral disc lessen. Recent studies found that a series of inflammatory factors involved in the IDD process, which closely related to the occurrence and development of IDD [1,2,3]. The role of various inflammatory factors and the molecular mechanisms involved in IDD is not fully definitude

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