Nerve growth factor is regulated by toll-like receptor 2 in human intervertebral discs. Krock, E., Currie, J. B., Weber, M. H., Ouellet, J. A., Stone, L. S., Rosenzweig, D. H., & Haglund, L. Journal of Biological Chemistry, 291(7):3541–3551, 2016. doi abstract bibtex 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-1beta (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1beta gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1beta 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-kappaB, 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-kappaB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-kappaB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.
@article{Krock20163541,
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-1beta (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1beta gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1beta 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-kappaB, 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-kappaB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-kappaB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.},
annote = {cited By 26},
author = {Krock, Emerson and Currie, J. Brooke and Weber, Michael H. and Ouellet, Jean A. and Stone, Laura S. and Rosenzweig, Derek H. and Haglund, Lisbet},
doi = {10.1074/jbc.M115.675900},
issn = {1083351X},
journal = {Journal of Biological Chemistry},
number = {7},
pages = {3541--3551},
title = {{Nerve growth factor is regulated by toll-like receptor 2 in human intervertebral discs}},
volume = {291},
year = {2016}
}
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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-1beta (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1beta gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1beta 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-kappaB, 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-kappaB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. 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