Senotherapeutic drugs for human intervertebral disc degeneration and low back pain.
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ABSTRACT:
SUBMITTER: Cherif H
PROVIDER: S-EPMC7442487 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Reactive oxygen species (ROS) are thought to have a strong correlation with a number of intervertebral disc (IVD) diseases. Here, we aimed to determine whether ROS represent an etiology of low back pain (LBP) during IVD degeneration. Thirty degenerated intervertebral disc samples were obtained from patients, and ROS levels were quantified using dihydroethidium (DHE) staining. The results suggested a significant correlation between the ROS level and the severity of LBP. Subsequently, a puncture-induced LBP model was established in rats, and ROS levels significantly increased compared with those in the sham surgery group, accompanied with severe puncture-induced IVD degeneration. In addition, when ROS levels were increased by H2O2 administration or decreased by NAC treatment, the rats showed increased or decreased LBP, respectively. Based on this evidence, we further determined that stimulation with H2O2 in nucleus pulposus cells (NPCs) in vivo or in vitro resulted in upregulation of substance P (SP), a peptide thought to be involved in the synaptic transmission of pain, and that the severity of LBP decreased when SP levels were increased by exogenous SP administration or neutralized via aprepitant treatment in the IVDs of rats. In conclusion, ROS are primary inducers of LBP based on clinical and animal data, and the mechanism involves ROS stimulation of NPCs to secrete SP, which is a critical neurotransmitter peptide, to promote LBP in IVDs. Therefore, reducing the level of ROS with specific drugs and inhibiting SP may be alternative methods to treat LBP in the clinic.
| S-EPMC8140854 | biostudies-literature
Project description:Objective: Previous studies are insufficient to confirm a causal association between physical activity (PA) and low back pain (LBP), intervertebral disc degeneration (IDD), and sciatica. The present study used a two-sample Mendelian randomization (MR) analysis method to demonstrate whether or not there was a causal connection. Methods: First, four PA phenotypes were selected [accelerometer-based PA (average acceleration), accelerometer-based PA (acceleration fraction >425 mg), self-reported moderate-to-vigorous PA, and self-reported vigorous PA], setting thresholds for single nucleotide polymorphisms (SNPs) significantly concerned with PA p < 5 × 10-8, linkage disequilibrium (LD) r 2 < 0.01, genetic distance >5,000 kb, and F-value >10. SNPs associated with the outcome and confounding factors were then excluded using the PhenoScanncer database. Finally, after coordinating the genetic instruments from genome-wide association studies (GWAS) effect alleles for exposure and outcomes, multiplicative random effects inverse variance weighting (IVW), MR-Egger, weighted median method (WMM), and weighted mode method were used to assess exposure-outcome causality and perform sensitivity analysis on the estimated results. Results: The current study's IVW findings revealed proof of a causal connection between PA and LBP. While there was a positive causal tie between accelerometer-based PA (acceleration fraction >425 mg) and LBP [OR: 1.818, 95% CI:1.129-2.926, p = 0.012], there was a negative causal link between accelerometer-based PA (average acceleration) and LBP [OR: 0.945, 95% CI: 0.909-0.984, p = 0.005]. However causal relationship between PA and IDD or sciatica was not found. Conclusion: Increasing average PA but needing to avoid high-intensity PA may be an effective means of preventing low back pain. Although PA is not directly causally related to disc degeneration and sciatica, it can act through indirect pathways.
| S-EPMC10665496 | biostudies-literature
Project description:Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.
| S-EPMC6906425 | biostudies-literature
Project description:Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.
| S-EPMC4151534 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-05 | GSE230809 | GEO
Project description:Intervertebral disc degeneration
| PRJNA962588 | ENA
Project description:PurposeThe composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration.MethodsMRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19-65 [mean ± SD, min-max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables.ResultsCEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43).ConclusionPoor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.
| S-EPMC9252939 | biostudies-literature
Project description:With the increased burden of low back pain (LBP) in our globally aging population there is a need to develop preclinical models of LBP that capture clinically relevant features of physiological aging, degeneration, and disability. Here we assess the validity of using a mouse model system for age-related LBP by characterizing aging mice for features of intervertebral disc (IVD) degeneration, molecular markers of peripheral sensitization, and behavioral signs of pain. Compared to three-month-old and one-year-old mice, two-year-old mice show features typical of IVD degeneration including loss of disc height, bulging, innervation and vascularization in the caudal lumbar IVDs. Aging is also associated with the loss of whole-body bone mineral density in both male and female mice, but not associated with percent lean mass or body fat. Additionally, two-year-old mice have an accumulation of TRPA1 channels and sodium channels NaV1.8 and NaV1.9 in the L4 and L5 lumbar dorsal root ganglia consistent with changes in nociceptive signaling. Lastly, the effect of age, sex, and weight on mobility, axial stretching and radiating pain measures was assessed in male and female mice ranging from two months to two years in a general linear model. The model revealed that regardless of sex or weight, increased age was a predictor of greater reluctance to perform axial stretching and sensitivity to cold, but not heat in mice.
| S-EPMC6549718 | biostudies-literature
Project description:ObjectivesWe aim to evaluate the benefits and harms of intervertebral disc therapies (IDTs) in people with non-specific chronic low back pain (NScLBP).MethodsWe conducted a systematic review and meta-analysis of randomized trials of IDTs versus placebo interventions, active comparators or usual care. EMBASE, MEDLINE, CENTRAL and CINHAL databases and conference abstracts were searched from inception to June 2020. Two independent investigators extracted data. The primary outcome was LBP intensity at short term (1 week-3 months), intermediate term (3-6 months) and long term (after 6 months).ResultsOf 18 eligible trials (among 1396 citations), five assessed glucocorticoids (GCs) IDTs and were included in a quantitative synthesis; 13 assessed other products including etanercept (n = 2), tocilizumab (n = 1), methylene blue (n = 2), ozone (n = 2), chymopapaine (n = 1), glycerol (n = 1), stem cells (n = 1), platelet-rich plasma (n = 1) and recombinant human growth and differentiation factor-5 (n = 2), and were included in a narrative synthesis. Standardized mean differences (95% CI) for GC IDTs for LBP intensity and activity limitations were -1.33 (-2.34; -0.32) and -0.76 (-1.85; 0.34) at short term, -2.22 (-5.34; 0.90) and -1.60 (-3.51; 0.32) at intermediate term and -1.11 (-2.91; 0.70) and -0.63 (-1.68; 0.42) at long term, respectively. Odds ratios (95% CI) for serious and minor adverse events with GC IDTs were 1.09 (0.25; 4.65) and 0.97 (0.49; 1.91).ConclusionGC IDTs are associated with a reduction in LBP intensity at short term in people with NScLBP. Positive effects are not sustained. IDTs have no effect on activity limitations. Our conclusions are limited by high heterogeneity and a limited methodological quality across studies.RegistrationPROSPERO: CRD42019106336.
| S-EPMC8287365 | biostudies-literature
Project description:In this study, we used microarray analysis to investigate the biogenesis and progression of intervertebral disc degeneration. The gene expression profiles of 37 disc tissue samples obtained from patients with herniated discs and degenerative disc disease collected by the National Cancer Institute Cooperative Tissue Network were analyzed. Differentially expressed genes between more and less degenerated discs were identified by significant analysis of microarray. A total of 555 genes were significantly overexpressed in more degenerated discs with a false discovery rate of < 3%. Functional annotation showed that these genes were significantly associated with membrane-bound vesicles, calcium ion binding and extracellular matrix. Protein-protein interaction analysis showed that these genes, including previously reported genes such as fibronectin, COL2A1 and β-catenin, may play key roles in disc degeneration. Unsupervised clustering indicated that the widely used morphology-based Thompson grading system was only marginally associated with the molecular classification of intervertebral disc degeneration. These findings indicate that detailed, systematic gene analysis may be a useful way of studying the biology of intervertebral disc degeneration.
| S-EPMC3795174 | biostudies-literature