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Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

ABSTRACT: Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR-1 tyrosine-kinase deficient mice (vegfr-1^TK-/- ). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr-1^TK-/- and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix-degrading enzymes. Despite the similar pathological patterns, vegfr-1^TK-/- mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr-1^TK- /^- mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr-1 by small-interfering-RNA decreased VEGF-induced expression of pain markers, while silencing vegfr-2 decreased VEGF-induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR-1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR-1 is critical for discogenic LBP transmission independent of the degree of disc pathology.

SUBMITTER: Qiu S

PROVIDER: S-EPMC9782756 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

Qiu Sujun S Shi Changgui C Anbazhagan Arivarasu Natarajan AN Das Vaskar V Arora Vipin V Kc Ranjan R Li Xin X O-Sullivan InSug I van Wijnen Andre A Chintharlapalli Sudhakar S Gott-Velis Gina G Richard Ripper R Mwale Fackson F Shibuya Masabumi M Min Shaoxiong S Im Hee-Jeong HJ

Journal of cellular physiology 20191225 6

Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR-1 tyrosine-kinase deficient mice (vegfr ...[more]

PMID: 31875985

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Project description:PurposesTo evaluate the usefulness of our original five questions in a medical interview for diagnosing discogenic low back pain (LBP), and to establish a support tool for diagnosing discogenic LBP.Materials and methodsThe degenerative disc disease (DDD) group (n = 42) comprised patients diagnosed with discogenic LBP associated with DDD, on the basis of magnetic resonance imaging findings and response to analgesic discography (discoblock). The control group (n = 30) comprised patients with LBP due to a reason other than DDD. We selected patients from those who had been diagnosed with lumbar spinal stenosis and had undergone decompression surgery without fusion. Of them, those whose postoperative LBP was significantly decreased were included in the control group. We asked patients in both groups whether they experienced LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one's face, and in the standing position with flexion. We analyzed the usefulness of our five questions for diagnosing discogenic LBP, and performed receiver operating characteristic (ROC) curve analysis to develop a diagnostic support tool.ResultsThere were no significant differences in baseline characteristics, except age, between the groups. There were significant differences between the groups for all five questions. In the age-adjusted analyses, the odds ratios of LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one's face, and in standing position with flexion were 10.5, 8.5, 4.0, 10.8, and 11.8, respectively. The integer scores were 11, 9, 4, 11, and 12, respectively, and the sum of the points of the five scores ranged from 0 to 47. Results of the ROC analysis were as follows: cut-off value, 31 points; area under the curve, 0.92302; sensitivity, 100%; and specificity, 71.4%.ConclusionsAll five questions were useful for diagnosing discogenic LBP. We established the scoring system as a support tool for diagnosing discogenic LBP.

Project description:Background: Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP) in humans and canines. IVD degeneration affects the structure and function of both the disc and the innervating dorsal root ganglion (DRG) neurons. Pre-clinical animal models are necessary for elucidating the mechanisms of IVD degeneration (IVDD) and the pain signaling pathways involved in discogenic back pain. The chondrodystrophic (CD) dog exhibits similar characteristics to the clinical population affected by IVDD-associated LBP. However, further investigation of the translational tools to study these conditions and the efficacy of novel treatments is needed in this canine model. The objectives of the present study are to: (1) assess the changes in the structure and function of the IVD and DRG, including pain behaviors, in response to injury using a comprehensive set of outcome measures and (2) evaluate the efficacy of potential therapeutics in mitigating these pathologic changes due to injury in the CD canine model. Methods: Retired female research beagles underwent spinal surgery where T11/T12, T12/T13, and T13/L1 IVDs were identified and punctured with a needle containing either a protease-activated receptor 2 antagonist (PAR2A) and cromolyn sodium (CS) solution (N=3) or phosphate-buffered saline (PBS) (N=3). Pain phenotyping and related outcomes were assessed longitudinally or at the 12-week endpoint via RNA-seq on the DRG, von Frey analysis, FitBark activity, and C-reactive protein (CRP) plasma levels. Changes in the structure/function of the IVD were assessed via MRI, mechanics, Dimethylmethylene Blue Assay (DMMB), histological staining using Picrosirius red/ Alcian Blue (PR/AB) and fluoroscopy, and electrophysiology on the DRG neurons. Results: We evaluated a comprehensive series of outcome measures to determine the effects of IVD injury on the structure/function of the canine IVD and DRG, and pain in the in vivo CD dog model of IVDD and back pain. Specifically, we established methods to obtain high-quality messenger RNA from canine DRGs to perform bulk RNA-seq. We demonstrated that injury to the disc resulted in significant upregulation of inflammatory and pain-signaling genes, and downregulation of developmental genes in the adjacent innervating DRG neurons. Additionally, we isolated and cultured viable neurons from canine DRGs and found through whole-cell patch-clamp that that DRGs innervating the injured disc demonstrated altered voltage-gated sodium channel (VGSCs) activity compared to controls. Using T2 weighted MRI, we demonstrated that relaxation time in punctured discs was reduced in four out of the six dogs compared to internal control discs, indicating potential compositional changes in these injured IVDs. No significant effect of PAR2A and CS treatment was observed in this small cohort.Conclusion: This study evaluated a rigorous series of outcome measures to determine the effects of IVD injury on the disc joint and pain in a CD canine in vivo model of back pain. This was the first study to investigate the effects of disc injury on canine DRG transcriptome and whole-cell patch clamping on canine DRG neurons. Results support the CD dog as a clinically relevant translational model for studying IVDD and LBP, and for evaluating the potential efficacy of novel therapeutics in mitigating the changes associated with these conditions.

Project description:BackgroundDiscogenic low back pain (DLBP) is considered the most common type of chronic low back pain (CLBP). Sinuvertebral nerve block (SVNB) is a rapid and precise intervention performed under local anesthesia to treat DLBP induced CLBP. Thus, in this study, we aimed to explore the clinical efficacy of SVNB for DLBP.MethodsWe retrospectively included 32 DLBP patients from July 2020 and April 2021. Inclusion criteria: The patients had chronic pain, diagnosed as single-segment disc degeneration induced DLBP, and suffered from one-year ineffective conservative treatment. SVNB was performed and the patients were followed up at 3 and 7 days, and at 1 and 3 months after SVNB. The basic clinical characteristics, including age and gender, were collected. The measurements of Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) were assessed.ResultsThe average age was 49.31±14.37 years, and females vs. males was 20 (62.50%) vs. 12 (37.50%). The preoperative VAS and ODI score were 5.75±1.41 and 32.59±21.56, respectively. The VAS score was reduced to 2.50±1.46, 2.63±1.60, 3.53±2.17, and 3.78±2.18 at 3 and 7 days, and 1 and 3 months after SVNB, respectively (P<0.05). The improvement rates in the VAS score were 56.52%, 54.34%, 38.61%, and 34.26% at 3 and 7 days, and 1 and 3 months after SVNB, respectively. 18 patients (56.25%) experienced varying degrees of pain recurrence within 3 months. The ODI score was reduced by 17.28±13.06, 16.84±13.51, 19.63±17.12, and 21.44±19.03 points at 3, 7 days and 1, 3 months after SVNB, respectively (P<0.05). At 3 day and 3 month after SVNB, the ODI scores of 22 patients (68.75%) and 20 patients (62.50%) decreased to ≤20, respectively. The ODI improvement rates were 46.98%, 48.33%, 39.80%, and 34.24% at 3, 7 days and 1, 3 months after SVNB, respectively.ConclusionsWe conducted a retrospective study of the clinical efficacy of SVNB for DLBP. As a rapid and cost-effective minimally invasive treatment, SVNB provided some assistance for the short-term pain relief and physical functional improvement of DLBP. SVNB could be a good choice for the treatment of DLBP.

Project description:Study designRetrospective cohort study.PurposeThis study aimed to determine whether the initiation of anti-calcitonin gene-related peptide (CGRP inhibitor) medication therapy for migraines was also associated with improvements in back/neck pain, mobility, and function in a patient population with comorbid degenerative spinal disease and migraine.Overview of literatureCGRP upregulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, brain-derived neurotrophic factor, and nerve growth factor in spinal spondylotic disease, which results in disc degeneration and sensitization of nociceptive neurons. Although CGRP inhibitors can quell neurogenic inflammation in migraines, their off-site efficacy as a therapeutic target for discogenic back/neck pain conditions remains unknown.MethodsAll adult patients diagnosed with spinal spondylosis and migraine treated with CGRP inhibitors at a single academic institution between 2017 and 2020 were retrospectively identified. Patient demographic and medical data, follow-up duration, migraine severity and frequency, spinal pain, functional status, and mobility before and after the administration of CGRP inhibitors were collected. Paired univariate analysis was conducted to determine significant changes in spinal pain, headache severity, and headache frequency before and after the administration of CGRP inhibitors. The correlation between changes in the spinal pain score and functional or mobility improvement was assessed with Spearman's rho.ResultsIn total, 56 patients were included. The mean follow-up time after the administration of CGRP inhibitors was 123 days for spinal pain visits and 129 days for migraine visits. Back/neck pain decreased significantly (p <0.001) from 6.30 to 4.36 after starting CGRP inhibitor therapy for migraine control. As recorded in the spine follow-up notes, 25% of patients experienced a functional improvement in the activities of daily living, and 17.5% experienced mobility improvement while taking CGRP inhibitors. Change in back/ neck pain moderately correlated (ρ=-0.430) with functional improvement but was not correlated with mobility improvement (ρ=-0.052).ConclusionsPatients taking CGRP inhibitors for chronic migraines with comorbid degenerative spinal conditions experienced significant off-target reduction of back/neck pain.

Dataset Information

Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

Publications

Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

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