Abstract | OBJECTIVE: 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.
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Authors | Emerson Krock, Magali Millecamps, J Brooke Currie, Laura S Stone, Lisbet Haglund |
Journal | Osteoarthritis and cartilage
(Osteoarthritis Cartilage)
Vol. 26
Issue 9
Pg. 1236-1246
(09 2018)
ISSN: 1522-9653 [Electronic] England |
PMID | 29908959
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved. |
Chemical References |
- Osteonectin
- SPARC protein, mouse
- Sulfonamides
- Toll-Like Receptor 4
- ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
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Topics |
- Animals
- Disease Models, Animal
- Drug Delivery Systems
- Injections, Intraperitoneal
- Intervertebral Disc Degeneration
(drug therapy, pathology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Osteonectin
(metabolism)
- Pain Measurement
- Random Allocation
- Reference Values
- Sulfonamides
(pharmacology)
- Toll-Like Receptor 4
(drug effects, metabolism)
- Treatment Outcome
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