Estrogen receptors involvement in intervertebral discogenic pain of the elderly women: colocalization and correlation with the expression of Substance P in nucleus pulposus

Song, Xiaoxin; Shi, Sheng; Guo, Zhen; Li, Xinfeng; Yu, Bo

doi:10.18632/oncotarget.15421

Cited by 19 publications

(28 citation statements)

References 60 publications

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“…An upregulated CGRP and SP expression has been reported in sensory nerves innervating degenerated IVD in DDD patients [5,6,7]. Furthermore, an increased SP expression has been reported in TNF-α stimulated human NP cells and in NP tissues extracted from elderly female DDD patients [39,40]. However, we could not observe higher SP levels in IVD tissues collected from DDD patients in comparison to PM controls.…”

Section: Discussioncontrasting

confidence: 60%

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease

Ahmed

Berg²,

Alkass

et al. 2019

IJMS

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The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1–DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1–DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1–DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1–DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients.

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Section: Discussioncontrasting

confidence: 60%

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease

Ahmed

Berg²,

Alkass

et al. 2019

IJMS

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“…It has been reported that in DDD patients, the sensory nerves innervating degenerative IVD will up-regulate the expression of CGRP and SP ( Richardson et al, 2009 ; Krock et al, 2014 ). In addition, increased expression of SP was found in human nucleus pulposus (NP) cells stimulated by TNF-α and NP tissues extracted from elderly female DDD patients ( Song et al, 2017 ). Studies have shown that SP and CGRP are the main peptidergic neurotransmitters.…”

Section: Discussionmentioning

confidence: 99%

The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats

et al. 2021

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To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).

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“…We show that raloxifene also has promise as an IVD therapeutic and we suggest that raloxifene may impact the IVD by at least three mechanisms. Firstly, compared to men, women have low discogenic expression of er-α protein, which may limit raloxifene-induced proliferation (30,34) and both lower er-α and aging can increase pain-related SP in the IVD (38) . Therefore, raloxifene may reduce back (21) and joint pain (49) in post-menopausal women because of estrogen-induced reduction of SP in the IVD and bone.…”

Section: Discussionmentioning

confidence: 99%

“…For cell quantification in the NP or AF, the image was thresholded for intensity to demarcate the positive cell by semi-automation using ImageJ (NIH). Quantitative PCR was accomplished as previously described (38) . Briefly, relative gene expression was normalized to 18s (Hs99999901_s1) for each sample and then experimental values were normalized to the CON average CT value (2 −ΔΔCT ).…”

Section: Methodsmentioning

confidence: 99%

“…Discogenic pain by substance P (neurokinin-1) has long been associated with IVD degeneration (37) . Substance P (SP) is a nerve signaling neurotransmitter and nociceptive pain marker that is negatively associated with er-α protein expression in the IVD of postmenopausal women (38) . Considering that raloxifene binds Erα, raloxifene may in turn reduce substance P.…”

Section: Introductionmentioning

confidence: 99%

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Raloxifene reduces sex- and age-related intervertebral disc degeneration in mice by estrogen signaling

Bhadouria

Niziolek

Jordi

et al. 2021

Preprint

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Estrogen agonist raloxifene is an FDA-approved treatment for osteoporosis in postmenopausal women that may also be a promising prophylactic for painful intervertebral disc (IVD) degeneration. Here, we hypothesized that raloxifene would augment IVD structure and reduce neurokinin-1 (substance P) in young and old mice by stimulating estrogen signaling. 2.5mo (male and female) and 22.5 mo (female) C57Bl/6J mice were subcutaneously injected with Raloxifene Hydrochloride (5x/week, 6week, n=7-9/grp). Next, to determine the impact of estrogen-deficiency to IVD structure and substance P, female mice were ovariectomized (OVX) at 4mo and tissues from OVX and sham-operated mice were harvested at 6mo (n=5-6/grp). First, compared to male IVD, female IVD expressed less col2 and osterix transcription, early markers of IVD degeneration. Irrespective of sex, raloxifene increased the transcriptional expression for extracellular matrix anabolism, proliferation, notochordal cells (vs chondrocyte-like cells) and estrogen signaling in young IVD. Next, we confirmed that biological sex and aging each induced structural features of lumbar IVD degeneration. Therapeutically, injection of raloxifene countered these features by increasing IVD height in young mice, preventing mild sex-related IVD degeneration in young female mice and partially reversing age-related IVD degeneration in old female mice. Further, estrogen agonist raloxifene upregulated ER-α protein and downregulated substance P protein in young and old IVD. By contrast, estrogen-deficiency by OVX increased IVD degeneration and substance P protein in IVD cells. Similarly, substance P protein in vertebral osteocytes was upregulated by sex (female > male) and estrogen-deficiency and downregulated by raloxifene. Overall, systemic injection of raloxifene augmented IVD structure and reduced substance P expression in young and old female murine IVD. These data suggest that raloxifene may potentially relieve painful IVD degeneration in postmenopausal women induced by biological sex, estrogen-deficiency and advanced age.

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Estrogen receptors involvement in intervertebral discogenic pain of the elderly women: colocalization and correlation with the expression of Substance P in nucleus pulposus

Cited by 19 publications

References 60 publications

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease

The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats

Raloxifene reduces sex- and age-related intervertebral disc degeneration in mice by estrogen signaling

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