TNF-ɑ Induces Methylglyoxal Accumulation in Lumbar Herniated Disc of Patients With Radicular Pain

Zhang, Xinsheng; Wang, Xiaogang; Gao, Liang; Yang, Bin; Wang, Yahan; Niu, Kerun; Lai, Jiahui; Wan, Shun; Luo, Jian‐Ping

doi:10.3389/fnbeh.2021.760547

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…Nucleus pulposus has been implicated in pain arising from herniation of spinal discs. 36 , 86 In experimental models of such pain, NP is applied to the spinal dorsal roots. Placing NP in this location may result in surgical damage to the spinal column and may also cause damage or compression of the dorsal roots themselves and dorsal root ganglia.…”

Section: Discussionmentioning

confidence: 99%

Microglia-independent peripheral neuropathic pain in male and female mice

Muley

Beggs³

et al. 2022

Pain

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The dominant view in the field of pain is that peripheral neuropathic pain is driven by microglia in the somatosensory processing region of the spinal dorsal horn. Here, to the contrary, we discovered a form of neuropathic pain that is independent of microglia. Mice in which the nucleus pulposus (NP) of the intervertebral disc was apposed to the sciatic nerve developed a constellation of neuropathic pain behaviours: hypersensitivity to mechanical, cold, and heat stimuli. However, NP application caused no activation of spinal microglia nor was pain hypersensitivity reversed by microglial inhibition. Rather, NP-induced pain hypersensitivity was dependent on cells within the NP which recruited macrophages to the adjacent nerve. Eliminating macrophages systemically or locally prevented NP-induced pain hypersensitivity. Pain hypersensitivity was also prevented by genetically disrupting the neurotrophin brain-derived neurotrophic factor selectively in macrophages. Moreover, the behavioural phenotypes as well as the molecular mechanisms of NP-induced pain hypersensitivity were not different between males and females. Our findings reveal a previously unappreciated mechanism for by which a discrete peripheral nerve lesion may produce pain hypersensitivity, which may help to explain the limited success of microglial inhibitors on neuropathic pain in human clinical trials.

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Section: Discussionmentioning

confidence: 99%

Microglia-independent peripheral neuropathic pain in male and female mice

Muley

Beggs³

et al. 2022

Pain

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“…Extracellular ROS scavenging enzymes may also inhibit ROS/H 2 O 2 from acting as a signaling molecule within the disc, which may decrease with increasing degeneration (30). Additionally, the concentrations of TNFα (40ng/mL) and H 2 O 2 (50µM) used in this study are significantly higher than concentrations found in-vivo (TNFα: 0.05-0.15ng/mL, H 2 O 2 : 0.25μM (12,76)). Finally, NP/iAF cultures were performed at a cell ratio of 1:1, higher than the ratio of NP:iAF in bovine caudal intervertebral discs (NP:iAF ratio in-vivo is approximately 1:2 from cell isolations from bovine caudal spines, data not shown).…”

Section: Unlike Np Cells Iaf Cells Did Not Increase Intracellular Ros...mentioning

confidence: 73%

Senescent response in inner annulus fibrosus cells in response to TNFα, H₂O₂, and TNFα-induced nucleus pulposus senescent secretome

Montgomery-Song

Ashraf

Santerre

et al. 2022

Preprint

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Senescence, particularly in the nucleus pulposus (NP) cells, has been implicated in the pathogenesis of disc degeneration, however, the mechanism(s) of annulus fibrosus (AF) cell senescence is still not well understood. Both TNFα and H2O2, have been implicated as contributors to the senescence pathways, and their levels are increased in degenerated discs when compared to healthy discs. This the objective of this study is to identify factor(s) that induces inner AF (iAF) cell senescence Under TNFα exposure, at a concentration that can induce senescence in NP cells, bovine iAF cells did not undergo senescence, indicated by their ability to continue to proliferate as demonstrated by Ki67 staining and growth curves and lack of expression of the senescent markers, p16 and p21. Unlike iAF cells, NP cells treated with TNFα accumulated more intracellular ROS and secreted more H2O2. Following TNFα treatment, only iAF cells had increased expression of the superoxide scavengers SOD1 and SOD2 whereas NP cells had increased NOX4 gene expression, an enzyme that can generate H2O2. Treating iAF cells with low dose H2O2 (50 μM) induced senescence, however unlike TNFα, H2O2 did not induce degenerative-like changes as there was no difference in COL2, ACAN, MMP13, or IL6 gene expression or number of COL2 and ACAN immunopositive cells compared to untreated controls. The latter result suggests that iAF cells have distinct degenerative and senescent phenotypes. To evaluate paracrine signalling, iAF and TNFα-treated NP cells were co-cultured. In contact co-culture the NP cells did induce iAF senescence. Thus, senescent NP cells may secrete soluble factors that induce degenerative and senescent changes within the iAF. This may contribute to a positive feedback loop of disc degeneration, and these processes could include H2O2 and cytokines (TNFα). Further studies will investigate if human disc cells respond similarly.

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“…Extracellular ROS scavenging enzymes may also inhibit ROS/H 2 O 2 from acting as a signaling molecule within the disc, and these may decrease with increasing degeneration [40]. Secondly, the concentrations of TNFα (40ng/mL) and H 2 O 2 (50μM) used in this study are significantly higher than concentrations found in-vivo (TNFα: 0.05-0.15ng/mL, H 2 O 2 : 0.25μM [18,90]). Thirdly, sample size for most of this study was at least 3 independent biological samples (N = 3) repeated in triplicate.…”

Section: Plos Onementioning

confidence: 73%

Senescent response in inner annulus fibrosus cells in response to TNFα, H2O2, and TNFα-induced nucleus pulposus senescent secretome

Montgomery-Song,

Ashraf,

Santerre

et al. 2024

PLoS ONE

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Senescence, particularly in the nucleus pulposus (NP) cells, has been implicated in the pathogenesis of disc degeneration, however, the mechanism(s) of annulus fibrosus (AF) cell senescence is still not well understood. Both TNFα and H2O2, have been implicated as contributors to the senescence pathways, and their levels are increased in degenerated discs when compared to healthy discs. Thus, the objective of this study is to identify factor(s) that induces inner AF (iAF) cell senescence. Under TNFα exposure, at a concentration previously shown to induce senescence in NP cells, bovine iAF cells did not undergo senescence, indicated by their ability to continue to proliferate as demonstrated by Ki67 staining and growth curves and lack of expression of the senescent markers, p16 and p21. The lack of senescent response occurred even though iAF express higher levels of TNFR1 than NP cells. Interestingly, iAF cells showed no increase in intracellular ROS or secreted H2O2 in response to TNFα which contrasted to NP cells that did. Following TNFα treatment, only iAF cells had increased expression of the superoxide scavengers SOD1 and SOD2 whereas NP cells had increased NOX4 gene expression, an enzyme that can generate H2O2. Treating iAF cells with low dose H2O2 (50 μM) induced senescence, however unlike TNFα, H2O2 did not induce degenerative-like changes as there was no difference in COL2, ACAN, MMP13, or IL6 gene expression or number of COL2 and ACAN immunopositive cells compared to untreated controls. The latter result suggests that iAF cells may have distinct degenerative and senescent phenotypes. To evaluate paracrine signalling by senescent NP cells, iAF and TNFα-treated NP cells were co-cultured. In contact co-culture the NP cells induced iAF senescence. Thus, senescent NP cells may secrete soluble factors that induce degenerative and senescent changes within the iAF. This may contribute to a positive feedback loop of disc degeneration. It is possible these factors may include H2O2 and cytokines (such as TNFα). Further studies will investigate if human disc cells respond similarly.

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TNF-ɑ Induces Methylglyoxal Accumulation in Lumbar Herniated Disc of Patients With Radicular Pain

Cited by 6 publications

References 32 publications

Microglia-independent peripheral neuropathic pain in male and female mice

Microglia-independent peripheral neuropathic pain in male and female mice

Senescent response in inner annulus fibrosus cells in response to TNFα, H₂O₂, and TNFα-induced nucleus pulposus senescent secretome

Senescent response in inner annulus fibrosus cells in response to TNFα, H2O2, and TNFα-induced nucleus pulposus senescent secretome

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