Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.
Adult
Animals
Cytokines
/ metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Female
Humans
Interleukin-8
/ cerebrospinal fluid
Intervertebral Disc Degeneration
/ complications
Low Back Pain
/ diagnosis
Magnetic Resonance Imaging
Male
Mice
Mice, Knockout
Middle Aged
Osteonectin
/ deficiency
Signal Transduction
Sulfonamides
/ pharmacology
CXCL1
CXCL5
CXCR1/2
Cerebrospinal fluid
Intervertebral disc degeneration
Reparixin
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
15
01
2019
revised:
22
03
2019
accepted:
17
04
2019
pubmed:
3
5
2019
medline:
26
11
2019
entrez:
4
5
2019
Statut:
ppublish
Résumé
Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.
Sections du résumé
BACKGROUND
BACKGROUND
Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study.
METHODS
METHODS
Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array.
FINDINGS
RESULTS
IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice.
INTERPRETATION
CONCLUSIONS
These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.
Identifiants
pubmed: 31047862
pii: S2352-3964(19)30271-3
doi: 10.1016/j.ebiom.2019.04.032
pmc: PMC6558025
pii:
doi:
Substances chimiques
Cytokines
0
Interleukin-8
0
Osteonectin
0
SPARC protein, mouse
0
Sulfonamides
0
reparixin
U604E1NB3K
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
487-500Subventions
Organisme : NIDA NIH HHS
ID : R21 DA020108
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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