Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Abstract

Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1␤ (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1␤ gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1␤ treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-B, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-B signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-B inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

MicroRNA‐223 inhibits lipopolysaccharide‐induced inflammatory response by directly targeting Irak1 in the nucleus pulposus cells of intervertebral disc

“…It is interesting that Krock et al . claimed that peptidoglycan (TLR2 agonist) induced the strongest response in human NP cells instead of LPS (TLR4 agonist) . In this study, we found that LPS could significantly induce rat NP cell response.…”

Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications

“…IVDs are mostly avascular, have very low cell density and a poor capacity for regeneration following injury and early degeneration (Liebscher et al, 2011;Maroudas et al, 1975). Degenerative disc disease (DDD) is characterised by an imbalance between matrix breakdown and synthesis, decreased proteoglycan and water content, increased cell death, inflammatory factors and protease activity, which all lead to mechanical failure and pain (Krock et al, 2016;Krock et al, 2015;Sato et al, 1999;Wuertz et al, 2013). Prevention of degeneration and matrix re-synthesis could be achieved by replenishment of the NP cell population through autologous cell implantation.…”

NPAS3 Regulates Transcription and Expression of VGF: Implications for Neurogenesis and Psychiatric Disorders

“…Besides the κB site, other elements in VGF promoter might be indirectly involved in the regulation of NPAS3 as well. As known, Various NF-κB transcriptional targets, such as Brain-Derived Neurotrophic Factor (BDNF) and Nerve growth factor (NGF; Zaheer et al, 2001; Krock et al, 2016), could regulate VGF (Thakker-Varia and Alder, 2009). Thus, NF-κB (p65) may regulate VGF in part by binding to κB site as well as by modulating BDNF and NGF.…”