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

Emerson Krock, Magali Millecamps, Kathleen M. Anderson, Akanksha Srivastava, Troy E. Reihsen, Pawan Hari, Yue Ran Sun, Seon Ho Jang, George L. Wilcox, Kumar G. Belani, David S. Beebe, Jean Ouellet, Manuel R. Pinto, Lois J. Kehl, Lisbet Haglund, Laura S. Stone

Research output: Contribution to journalArticle

Abstract

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: 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: 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: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS.

Original languageEnglish (US)
Pages (from-to)487-500
Number of pages14
JournalEBioMedicine
Volume43
DOIs
StatePublished - May 2019

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Cerebrospinal fluid
Intervertebral Disc Degeneration
Low Back Pain
Interleukin-8
Cerebrospinal Fluid
Up-Regulation
Interleukin-8 Receptors
Interleukin-2 Receptors
Therapeutics
Conditioned Culture Medium
Magnetic resonance imaging
Assays
Interleukin-8A Receptors
Cytokines
2-(4-isobutylphenyl)propionylmethanesulfonamide
Pain
Protein Array Analysis
Intervertebral Disc
Pain-Free
Proteins

Keywords

  • CXCL1
  • CXCL5
  • CXCR1/2
  • Cerebrospinal fluid
  • Intervertebral disc degeneration
  • Reparixin

Cite this

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. / Krock, Emerson; Millecamps, Magali; Anderson, Kathleen M.; Srivastava, Akanksha; Reihsen, Troy E.; Hari, Pawan; Sun, Yue Ran; Jang, Seon Ho; Wilcox, George L.; Belani, Kumar G.; Beebe, David S.; Ouellet, Jean; Pinto, Manuel R.; Kehl, Lois J.; Haglund, Lisbet; Stone, Laura S.

In: EBioMedicine, Vol. 43, 05.2019, p. 487-500.

Research output: Contribution to journalArticle

Krock, Emerson ; Millecamps, Magali ; Anderson, Kathleen M. ; Srivastava, Akanksha ; Reihsen, Troy E. ; Hari, Pawan ; Sun, Yue Ran ; Jang, Seon Ho ; Wilcox, George L. ; Belani, Kumar G. ; Beebe, David S. ; Ouellet, Jean ; Pinto, Manuel R. ; Kehl, Lois J. ; Haglund, Lisbet ; Stone, Laura S. / 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. In: EBioMedicine. 2019 ; Vol. 43. pp. 487-500.
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abstract = "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: 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: 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: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS.",
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T1 - Interleukin-8 as a therapeutic target for chronic low back pain

T2 - Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model

AU - Krock, Emerson

AU - Millecamps, Magali

AU - Anderson, Kathleen M.

AU - Srivastava, Akanksha

AU - Reihsen, Troy E.

AU - Hari, Pawan

AU - Sun, Yue Ran

AU - Jang, Seon Ho

AU - Wilcox, George L.

AU - Belani, Kumar G.

AU - Beebe, David S.

AU - Ouellet, Jean

AU - Pinto, Manuel R.

AU - Kehl, Lois J.

AU - Haglund, Lisbet

AU - Stone, Laura S.

PY - 2019/5

Y1 - 2019/5

N2 - 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: 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: 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: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS.

AB - 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: 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: 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: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS.

KW - CXCL1

KW - CXCL5

KW - CXCR1/2

KW - Cerebrospinal fluid

KW - Intervertebral disc degeneration

KW - Reparixin

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