scholarly journals Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Hosni Cherif ◽  
Daniel G Bisson ◽  
Matthew Mannarino ◽  
Oded Rabau ◽  
Jean A Ouellet ◽  
...  
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Cell Cycle Progression ◽  
Ex Vivo ◽  
Low Back ◽  
Cycle Progression ◽  
Apoptosis Gene ◽  
And Function ◽  
Ivd Degeneration

Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.

scholarly journals Reactive Oxygen Species Mediate Low Back Pain by Upregulating Substance P in Intervertebral Disc Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jiancheng Zheng ◽  
Jian Zhang ◽  
Xingkai Zhang ◽  
Zhiping Guo ◽  
Wenjian Wu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Low Back Pain ◽  
Back Pain ◽  
Substance P ◽  
Intervertebral Disc ◽  
Reactive Oxygen ◽  
Alternative Methods ◽  
Low Back ◽  
Oxygen Species ◽  
Ivd Degeneration

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.

Mechanical Consequence of Induced Intervertebral Disc Degeneration in the SPARC-Null Mouse

2020 ◽  
Vol 143 (2) ◽  
Author(s):  
Mitchel C. Whittal ◽  
Sara Molladavoodi ◽  
Derek P. Zwambag ◽  
Magali Millecamps ◽  
Laura S. Stone ◽  
...  
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Mechanical Tests ◽  
Null Mouse ◽  
Low Back ◽  
Spine Mechanics ◽  
Tension And Compression ◽  
In Series ◽  
Ivd Degeneration

Abstract Intervertebral disc (IVD) degeneration is associated with low back pain (LBP) and accompanied by mechanical changes to the spine. Secreted protein acidic and rich in cysteine (SPARC) is a protein that contributes to the functioning and maintenance of the extracellular matrix. SPARC-null mice display accelerated IVD degeneration and pain-associated behaviors. This study examined if SPARC-null mice also display altered spine mechanics as compared to wild-type (WT) mice. Lumbar spines from SPARC-null (n = 36) and WT (n = 18) mice aged 14–25 months were subjected to cyclic axial tension and compression to determine neutral zone (NZ) length and stiffness. Three separate mechanical tests were completed for each spine to determine the effect of the number of IVDs tested in series (one versus two versus three IVDs). SPARC-null spine NZs were both stiffer (p < 0.001) and smaller in length (p < 0.001) than WT spines. There was an effect of the number of IVDs tested in series for NZ length but not NZ stiffness when collapsed across condition (SPARC-null and WT). Correlation analysis revealed a weak negative correlation (r = −0.24) between age and NZ length in SPARC-null mice and a weak positive correlation (r = 0.30) between age and NZ stiffness in WT mice. In conclusion, SPARC-null mice had stiffer and smaller NZs than WT mice, regardless of the number of IVDs in series being tested. The increased stiffness of these IVDs likely influences mobility at these spinal joints thereby potentially contributing to low back pain.

scholarly journals Quantitative MRI to Characterize the Nucleus Pulposus Morphological and Biomechanical Variation According to Sagittal Bending Load and Radial Fissure, an ex vivo Ovine Specimen Proof-of-Concept Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Jean-Philippe Deneuville ◽  
Maksym Yushchenko ◽  
Tanguy Vendeuvre ◽  
Arnaud Germaneau ◽  
Maxime Billot ◽  
...  
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Mechanical Load ◽  
Ex Vivo ◽  
Element Model ◽  
Quantitative Mri ◽  
Low Back ◽  
Proof Of Concept ◽  
Radial Fissure

Background and context: Low back pain is a dramatic burden worldwide. Discography studies have shown that 39% of chronic low back pain patients suffer from discogenic pain due to a radial fissure of intervertebral disc. This can have major implications in clinical therapeutic choices. The use of discography is restricted because of its invasiveness and interest in it remains low as it represents a static condition of the disc morphology. Magnetic Resonance Imaging (MRI) appears to be less invasive but does not describe the biomechanical dynamic behavior of the fissure.Purpose: We aimed to seek a quantitative MRI protocol combined with ex vivo sagittal loading to analyze the morphological and biomechanical changes of the intervertebral disc structure and stress distribution.Study design: Proof of concept.Methods: We designed a proof-of-concept ovine study including 3 different 3.0 T-MRI sequences (T2-weighted, T1 and T2 mapping). We analyzed 3 different mechanical states (neutral, flexion and extension) on a fresh ovine spine specimen to characterize an intervertebral disc before and after puncturing the anterior part of the annulus fibrosus. We used a mark tracking method to calculate the bending angles and the axial displacements of the discal structures. In parallel, we created a finite element model to calculate the variation of the axial stress and the maximal intensity shear stress, extrapolated from our experimental boundary conditions.Results: Thanks to an original combination of specific nuclear relaxation time quantifications (T1, T2) of the discal tissue, we characterized the nucleus movement/deformation into the fissure according to the synchronous mechanical load. This revealed a link between disc abnormality and spine segment range of motion capability. Our finite element model highlighted significant variations within the stress distribution between intact and damaged disc.Conclusion: Quantitative MRI appears to provide a new opportunity to characterize intra-discal structural morphology, lesions and stress changes under the influence of mechanical load. This preliminary work could have substantial implications for non-invasive disc exploration and could help to validate novel therapies for disc treatment.

Quantification of In Vivo Deformation of Healthy Lumbar Intervertebral Discs in Flexion

2012 ◽  
Author(s):  
Tina M. Nagel ◽  
Victor H. Barocas ◽  
David J. Nuckley
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Annulus Fibrosus ◽  
Intervertebral Discs ◽  
Low Back ◽  
Ivd Degeneration ◽  
Level 2 ◽  
Walled Cylinder

Intervertebral disc (IVD) degeneration is hypothesized to be the precursor to non-specific low back pain, which is a widespread problem [1]. However, before disc degeneration can be understood, a better understanding of healthy discs must be gained. The disc is a short thick-walled cylinder with a gelatinous center, the nucleus pulposus, and a largely concentric, layered collagenous ring, the annulus fibrosus, Figure 1. The layers are referred to as lamella. The IVD is integral to the strength and flexibility of the spine. Whole disc mechanics have been widely studied, but degeneration occurs at the fiber level [2]. To understand the mechanics of degeneration, testing needs to be performed at a finer level where degenerative / injury effects occur. These effects such as tears occur in the annular lamella.

scholarly journals Intervertebral disc therapies for non-specific chronic low back pain: a systematic review and meta-analysis

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110280
Author(s):  
Camille Daste ◽  
Stéphanie Laclau ◽  
Margaux Boisson ◽  
François Segretin ◽  
Antoine Feydy ◽  
...  
Keyword(s):  
Systematic Review ◽  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Chronic Low Back Pain ◽  
Meta Analysis ◽  
Activity Limitations ◽  
Low Back ◽  
Short Term

Objectives: We aim to evaluate the benefits and harms of intervertebral disc therapies (IDTs) in people with non-specific chronic low back pain (NScLBP). Methods: We 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). Results: Of 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). Conclusion: GC 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. Registration PROSPERO: CRD42019106336.

Lumbar Facet–Mediated Pain

2016 ◽  
Author(s):  
Vikram B Patel
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Lower Back Pain ◽  
Joint Pain ◽  
Facet Joint ◽  
Low Back ◽  
Lower Back ◽  
Facet Joint Pain ◽  
And Function ◽  
Lumbar Facet

Lumbar or lower back pain is a very debilitating condition that affects  almost one fifth of the adult population during a given year. Almost everyone walking on two feet is bound to suffer from some back pain during their lifetime. The health care burden for treating low back pain is enormous, especially if the lost work hours are combined with the amount used in diagnosing and treating low back pain. Lumbar facet (zygapophysial) joints are one of the major components involved in causing lower back pain. Diagnosing the pain generator is more of an art than a science. Combining various parameters in the patient’s history, physical examination, and diagnostic studies is not much different from solving a murder mystery. Although facet joint pain may be accompanied by other pain generators, that is, lumbar intervertebral disks, nerve roots, and vertebral bodies, once treated, the relief in pain is more helpful in performing proper rehabilitation and improving further deterioration in low back pain. Muscles are almost always painful due to myofascial pain syndrome that accompanies the facet joint–related pain. Treating one without addressing the other leads to failure in management and optimization of patient’s pain and function. Several treatments are available for treatment of facet joint–mediated pain, including steroid injections using a miniscule amount and radiofrequency ablation of the nerves supplying the facet joints (medial branches of the dorsal primary ramus of the lumbar nerve root). With proper diagnosis and treatment, a patient’s pain and function can be optimized to a level where it may not impact the day-to-day activities or even resumption of the patient’s routine job function. The following review describes the anatomy, pathophysiology, diagnosis, and treatment of lumbar facet joint–mediated pain.   Key words: facet joint pain, facet joint syndrome, low back pain, medial branch radiofrequency, spondylolisthesis

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