2. Academic Validation
  3. 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

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

  • EBioMedicine. 2019 May;43:487-500. doi: 10.1016/j.ebiom.2019.04.032.
Emerson Krock 1,  Magali Millecamps 2,  Kathleen M Anderson 3,  Akanksha Srivastava 4,  Troy E Reihsen 5,  Pawan Hari 6,  Yue Ran Sun 7,  Seon Ho Jang 8,  George L Wilcox 9,  Kumar G Belani 10,  David S Beebe 11,  Jean Ouellet 12,  Manuel R Pinto 13,  Lois J Kehl 14,  Lisbet Haglund 15,  Laura S Stone 16
Affiliations

Affiliations

  • 1 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
  • 2 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
  • 3 Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 4 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
  • 5 Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 6 Department of Epidemiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 7 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
  • 8 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
  • 9 Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 10 Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 11 Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
  • 12 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada; Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Quebec H4A 0A9, Canada.
  • 13 Twin Cities Spine Center, Minneapolis, MN 55404, USA. Electronic address: [email protected].
  • 14 Minnesota Head & Neck Pain Clinic, St. Paul, MN 55114, USA. Electronic address: [email protected].
  • 15 McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada; Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Quebec H4A 0A9, Canada. Electronic address: [email protected].
  • 16 Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Anesthesia Research Unit, Montreal, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Pharmacology and Therapeutics, Montreal, Quebec H3A 1G1, Canada. Electronic address: [email protected].
PMID: 31047862 DOI: 10.1016/j.ebiom.2019.04.032
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.

Keywords

CXCL1; CXCL5; CXCR1/2; Cerebrospinal fluid; Intervertebral disc degeneration; Reparixin.

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