Emerson Krock1, Magali Millecamps2, J Brooke Currie3, Laura S Stone4, Lisbet Haglund5. 1. Orthopaedic Research Laboratory, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, Montreal, QC, Canada. Electronic address: emerson.krock@mail.mcgill.ca. 2. Alan Edwards Centre for Research on Pain, Montreal, QC, Canada; Faculty of Dentistry, McGill University, Montreal, QC, Canada. Electronic address: magali.millecamps@mcgill.ca. 3. Orthopaedic Research Laboratory, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, Montreal, QC, Canada. Electronic address: brooke.currie@mail.mcgill.ca. 4. McGill Scoliosis and Spine Research Group, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, Montreal, QC, Canada; Faculty of Dentistry, McGill University, Montreal, QC, Canada. Electronic address: laura.s.stone@mcgill.ca. 5. Orthopaedic Research Laboratory, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada; The Shriners Hospital for Children, Montreal, QC, Canada. Electronic address: lisbet.haglund@mcgill.ca.
Abstract
OBJECTIVE: Intervertebral disc degeneration is a leading cause of chronic low back pain (LBP) but current treatment is limited. Toll-like receptors (TLRs) on disc cells are activated by endogenous extracellular matrix (ECM) fragments and modulate degeneration in vitro. This study investigated whether inhibiting TLR4 slows disc degeneration and reduces behavioral signs of LBP in vivo. DESIGN: 7-9-month old wild-type and secreted protein acidic and rich in cysteine (SPARC)-null (a model of disc degeneration and LBP) male mice were treated with TAK-242 (TLR4 inhibitor) once, and following a 10-day washout, mice were treated 3 times/week for 8 weeks. Behavioral signs of axial discomfort and radiating leg pain were assessed weekly with the grip force assay and acetone test, respectively. Following treatment, pain-related spinal cord changes were evaluated and lumbar discs were excised and cultured. Cytokine secretion from discs was evaluated with protein arrays. RESULTS: SPARC-null mice displayed elevated signs of axial and radiating pain at baseline compared to wild-type. Chronic, but not acute, TLR4 inhibition reduced behavioral signs of pain compared to vehicle. SPARC-null mice have increased calcitonin gene-related peptide (CGRP)- and glial fibrillary acidic protein (GFAP)-immunoreactivity (astrocyte marker) in the dorsal horn compared to wild-type, which is reduced by chronic TLR4 inhibition. Ex vivo degenerating discs from SPARC-null mice secrete increased levels of many pro-inflammatory cytokines, which chronic TLR4 inhibition reduced. CONCLUSION: Chronic TLR4 inhibition decreased behavioral signs of LBP, pain-related neuroplasticity and disc inflammation in SPARC-null mice. TAK-242 inhibits TLR4 activation within discs, as evidenced by decreases in cytokine release. Therefore, TLRs are potential therapeutic targets to slow disc degeneration and reduce pain.
OBJECTIVE:Intervertebral disc degeneration is a leading cause of chronic low back pain (LBP) but current treatment is limited. Toll-like receptors (TLRs) on disc cells are activated by endogenous extracellular matrix (ECM) fragments and modulate degeneration in vitro. This study investigated whether inhibiting TLR4 slows disc degeneration and reduces behavioral signs of LBP in vivo. DESIGN: 7-9-month old wild-type and secreted protein acidic and rich in cysteine (SPARC)-null (a model of disc degeneration and LBP) male mice were treated with TAK-242 (TLR4 inhibitor) once, and following a 10-day washout, mice were treated 3 times/week for 8 weeks. Behavioral signs of axial discomfort and radiating leg pain were assessed weekly with the grip force assay and acetone test, respectively. Following treatment, pain-related spinal cord changes were evaluated and lumbar discs were excised and cultured. Cytokine secretion from discs was evaluated with protein arrays. RESULTS:SPARC-null mice displayed elevated signs of axial and radiating pain at baseline compared to wild-type. Chronic, but not acute, TLR4 inhibition reduced behavioral signs of pain compared to vehicle. SPARC-null mice have increased calcitonin gene-related peptide (CGRP)- and glial fibrillary acidic protein (GFAP)-immunoreactivity (astrocyte marker) in the dorsal horn compared to wild-type, which is reduced by chronic TLR4 inhibition. Ex vivo degenerating discs from SPARC-null mice secrete increased levels of many pro-inflammatory cytokines, which chronic TLR4 inhibition reduced. CONCLUSION: Chronic TLR4 inhibition decreased behavioral signs of LBP, pain-related neuroplasticity and disc inflammation in SPARC-null mice. TAK-242 inhibits TLR4 activation within discs, as evidenced by decreases in cytokine release. Therefore, TLRs are potential therapeutic targets to slow disc degeneration and reduce pain.
Authors: Mitchel C Whittal; Sarah J Poynter; Kayla Samms; K Josh Briar; Sabrina I Sinopoli; Magali Millecamps; Laura S Stone; Stephanie J DeWitte-Orr; Diane E Gregory Journal: Eur Spine J Date: 2022-07-11 Impact factor: 2.721
Authors: Shirley N Tang; Benjamin A Walter; Mary K Heimann; Connor C Gantt; Safdar N Khan; Olga N Kokiko-Cochran; Candice C Askwith; Devina Purmessur Journal: Front Pain Res (Lausanne) Date: 2022-06-22
Authors: 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 Journal: EBioMedicine Date: 2019-04-30 Impact factor: 8.143