DUSP-1 Induced by PGE2 and PGE1 Attenuates IL-1β-Activated MAPK Signaling, Leading to Suppression of NGF Expression in Human Intervertebral Disc Cells.

Takuya Kusakabe,Kenji Endo,Kengo Yamamoto,Kazuma Murata,Yasunobu Sawaji,Asato Maekawa,Hidekazu Suzuki,Takamitsu Konishi

doi:10.3390/ijms23010371

Takuya Kusakabe, Kenji Endo + Show 6 more

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https://doi.org/10.3390/ijms23010371

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Abstract

The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory mediator prostaglandin E2 (PGE2), which is induced by inflammatory stimuli, such as interleukin-1β (IL-1β). However, in our previous in vitro study using cultured human IVD cells, we demonstrated that the induction of NGF by IL-1β is augmented by a selective COX-2 inhibitor, and that PGE2 and PGE1 suppress NGF expression. Therefore, in this study, to elucidate the mechanism of NGF suppression by PGE2 and PGE1, we focused on mitogen-activated protein kinases (MAPKs) and its phosphatase, dual-specificity phosphatase (DUSP)-1. IL-1β-induced NGF expression was altered in human IVD cells by MAPK pathway inhibitors. PGE2 and PGE1 enhanced IL-1β-induced DUSP-1 expression, and suppressed the phosphorylation of MAPKs in human IVD cells. In DUSP-1 knockdown cells established using small interfering RNA, IL-1β-induced phosphorylation of MAPKs was enhanced and prolonged, and NGF expression was significantly enhanced. These results suggest that PGE2 and PGE1 suppress IL-1β-induced NGF expression by suppression of the MAPK signaling pathway, accompanied by increased DUSP-1 expression.

Highlights

Publisher’s Note: MDPI stays neutralThe point prevalence of low back pain (LBP) in 2017 was estimated to be 7.8% of the global population, meaning that 577 million people were affected at any one time
In this study, we focused on mitogen-activated protein kinases (MAPKs) and dual-specificity phosphatase (DUSP)-1 in human intervertebral disc (IVD) cells to elucidate the repressive mechanism of prostaglandin E2 (PGE2) and PGE1 in IL-1β-induced nerve growth factor (NGF) expression
We demonstrated that both PGE2 and PGE1 induce the expression of DUSP-1, which suppresses the phosphorylation of MAPKs and NGF expression

Summary

Introduction

Publisher’s Note: MDPI stays neutralThe point prevalence of low back pain (LBP) in 2017 was estimated to be 7.8% of the global population, meaning that 577 million people were affected at any one time. The number of people with LBP has been increasing since 1990, mainly because of the ageing and increasing global population [1]. Discogenic LBP is one type of LBP, which is associated with intervertebral disc (IVD) pathology [2]. Nonphysiological nerve invasion into degenerated IVDs, owing to aging or inflammation, is considered as the molecular mechanism of discogenic LBP. Normal IVDs consist of the annulus fibrosus (AF) and nucleus pulposus (NP), and contain a large amount of extracellular matrix (ECM) components, such as aggrecan and type II collagen, which contribute to its unique avascular and aneural structure, except for the outer third of the AF. ECM components, chondroitin sulfate of aggrecan, play an important role in protecting IVDs from peripheral nerve innervation [4,5]. The degeneration of IVDs occurs by the upregulation of proteinases, such as family of matrix metalloproteinases with regard to jurisdictional claims in published maps and institutional affiliations

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