MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons.

Longfei Ma,Dave Schwinn Gao,Min Yan,Jia Li,Bao-Chun Jiang,Yangyuxin Huang,Jinxuan Ren,Suyun Xia,Fengjiang Zhang,Xinyi Peng,Na Sun,Lina Yu

doi:10.3389/fphar.2021.673831

Abstract

Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis.

Highlights

Nerve injury-induced neuropathic pain is a refractory and debilitating disease (Mitka, 2003)
We first examined whether the matrix metallopeptidase 24 (MMP24) enrichment was altered in the spinal cord after spinal nerve ligation (SNL), a preclinical animal model that mimics nerve injury-induced neuropathic pain in the clinical setting (Rigaud et al, 2008)
This study demonstrates that SNL results in an accelerated translation of Mmp24 mRNA in the spinal cord

Summary

Introduction

Nerve injury-induced neuropathic pain is a refractory and debilitating disease (Mitka, 2003). The development of more efficient treatment of this disease comes to a standstill due to our incomplete understanding of mechanisms underlying the neuropathic pain induction and maintenance (Ji et al, 2009). Abnormal gene expression changes in the dorsal root ganglion (DRG) and spinal cord are the crucial molecular basis for developing and maintaining neuropathic pain (Jiang et al, 2016; Pokhilko et al, 2020). Epigenetic processes, such as DNA methylation, histone modifications, and non-coding RNAs, frequently regulate pain-related gene expression (Jiang et al, 2018; Wu et al, 2019; Lin et al, 2020). N6-methyladenosine (m6A) is the most prevalent and dynamic modification in mRNA with a preference for the 3′-untranslated region

Methods

Results

Conclusion