Voluntary running attenuates behavioural signs of low back pain: dimorphic regulation of intervertebral disc inflammation in male and female SPARC-null mice

S Lee,S.H Jang,M Suzuki-Narita,S Gregoire,M Millecamps,L.S Stone

doi:10.1016/j.joca.2021.06.014

Abstract

To examine the effect of running exercise on behavioral measures of pain and intervertebral disc (IVD) inflammation in the SPARC-null mouse model. Male and female 8-month old SPARC-null and age-matched control mice received a home cage running wheel or a control, fixed wheel for 6 months. Behavioral assays were performed to assess axial discomfort (grip test) and radiating leg pain (von Frey, acetone tests) and voluntary running was confirmed. Expression of inflammatory mediators (TNF-α, IL-1β, IL-2, IL-10, CCL5, CXCL1, CXCL5, RANKL, M-CSF, and VEGF) in IVDs was determined. Additional inflammatory (IL-1β, IL-1Ra, CXCR1, CXCR2) and macrophage phenotypic markers (ITGAM, CD80, CD86, CD206, Arg1) in IVDs were investigated by qPCR. Voluntary running attenuated behavioral measures of pain in male and female SPARC-null mice. Increases in mediators including IL-1β, CXCL1 and CXCL5 were observed in SPARC-null compared to control IVDs. After 6 months of running, increases in M-CSF and VEGF were observed in male SPARC-null IVDs. In females, pro-inflammatory mediators, including CXCL1 and CXCL5 were downregulated by running in SPARC-null mice. qPCR analysis further confirmed the anti-inflammatory effect of running in female IVDs with increased IL-1Ra mRNA. Running induced upregulation of the macrophage marker ITGAM mRNA in males. Voluntary running reversed behavioral signs of pain in male and female mice and reduced inflammatory mediators in females, but not males. Thus, the therapeutic mechanism of action may be sex-specific.

Highlights

Persistent low back pain (LBP) causes more global disability than any other condition[1] with current treatments having limited efficacy
This study demonstrates pain-reducing and intervertebral discs (IVDs) inflammationmodifying effects of long-term voluntary running in a pre-clinical model of disc degeneration associated with LBP
The sex differences observed in expression of inflammatory molecules and macrophage activation after long-term voluntary running suggest that while increased physical activity is beneficial for LBP, the mechanisms underlying those benefits may differ in males and females

Summary

Introduction

Persistent low back pain (LBP) causes more global disability than any other condition[1] with current treatments having limited efficacy. One cause of LBP is degeneration in intervertebral discs (IVDs). IVDs are composed of a gelatinous inner nucleus pulposus (NP) surrounded by layers of annulus fibrosus (AF). Disruption of the NP and AF structures or disc narrowing, bulging and herniation is associated with LBP in some cases[2], many individuals with degenerating discs (DD) are asymptomatic[3]. Pathological consequences of disc degeneration include increased apoptosis[4], innervation[5], vascularization, release of inflammatory molecules and immune cell infiltration[6], which in turn may exacerbate the severity of DD and LBP

Methods

Results

Discussion

Conclusion