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- W2600657357 abstract "Intervertebral disc degeneration is a major cause of chronic low back pain. During degeneration, proteolytic enzymes degrade the extracellular matrix of the disc and proinflammatory cytokines and neurotrophins increase. These processes contribute to chronic pain, but poor understanding of the pathomechanisms limits treatment. Toll-like receptors (TLR) are activated by endogenous ‘alarmins’ such as extracellular matrix fragments, HMGB1 or S100 proteins. Recent evidence indicates TLR2 regulates neurotrophin, cytokine and protease production in human disc cells and thus likely has a role in degeneration. This study investigates whether TLR2 activation induces degeneration in intact ex vivo human discs and if TLR4 inhibition improves pain and disc phenotype in a mouse model of degeneration and back pain (Sparc-null mice). TLR4 was chosen as a target in rodents and TLR2 in humans based on receptor responsiveness to alarmins in each species. Ex vivo non-degenerating human discs from organ donors were injected with vehicle, Pam2CSK4, a TLR2/6 agonist, or 30 kDa fibronectin fragments (FN-f), which can activate TLR2, and cultured for 28 days. TLR2 activation decreased proteoglycan content and increased the matrix proteases MMP 3 and 13, and proinflammatory cytokines, such as TNFα and IL-1. 8-month-old mice were given i.p. injections of TAK-242, a TLR4 specific inhibitor, every 2-3 days for 8 weeks. Compared to wild type mice, Sparc-null mice display behavioral signs of back pain, including increased acetone evoked behavior and decreased grip strength, and when cultured their discs secrete increased levels of proinflammatory cytokines. In Sparc-null mice TLR4 inhibition increased grip strength, and decreased acetone evoked behavior and proinflammatory cytokine secretion. Taken together, these results indicate TLR2 activation induces degeneration and TLR4 inhibition reduces pain and improves disc phenotype. Therefore, inhibiting alarmin receptors, such as TLRs, could be a therapeutic strategy to treat degeneration and chronic low back pain." @default.
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- W2600657357 date "2017-04-01" @default.
- W2600657357 modified "2023-10-17" @default.
- W2600657357 title "(112) Toll-like receptors in intervertebral disc degeneration and Pain: from man to mouse" @default.
- W2600657357 doi "https://doi.org/10.1016/j.jpain.2017.02.018" @default.
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