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Lumbar intervertebral disc degeneration in low back pain
Abstract
Intervertebral disc degeneration is characterized by deterioration in structural support that is potentially followed by stimulated neuronal ingrowth, and dysfunction of cellular physiology in the disc. Discogenic low back pain originates from nociceptors within the intervertebral disc or the cartilage endplate. This narrative review examines the mechanisms of disc degeneration, the association between degeneration and pain, and the current diagnosis and treatment of discogenic low back pain. Mechanisms of disc degeneration include dysregulated homeostasis of the extracellular matrix of the disc, altered spine mechanics, DNA damage, oxidative stress, perturbed cell signaling pathways, and cellular senescence. Although disc degeneration is more common in individuals with low back pain than in asymptomatic ones, degeneration occurs in a large proportion of asymptomatic individuals. Therefore, degeneration itself is not sufficient to trigger low back pain. Imaging and discography are common diagnostic tools of discogenic low back pain but have limited validity to diagnose discogenic pain. Most of current treatments options are not specific to discogenic pain but are unspecific treatments of low back pain of any origin. There is an urgent need to clarify and distinguish the molecular mechanisms of discogenic pain from mechanisms of disc degeneration that are not involved in nociception. Future research should make use of current methods to study molecular mechanisms of human pain in comprehensively and quantitatively phenotyped patients with low back pain, with the objective to identify molecular triggers of discogenic pain and determine the relationship between molecular mechanisms, pain, and patient-relevant outcomes.
... Backache is a leading cause of movement disorders and disability. Research indicates that lumbar intervertebral disc degeneration is identified as a potential cause of backache (Chiu et al., 2024). Within the intervertebral discs, mitochondrial damage in nucleus pulposus cells leads to an increase in intracellular ROS, exacerbating lumbar intervertebral disc degeneration (Chiu et al., 2024). ...
... Research indicates that lumbar intervertebral disc degeneration is identified as a potential cause of backache (Chiu et al., 2024). Within the intervertebral discs, mitochondrial damage in nucleus pulposus cells leads to an increase in intracellular ROS, exacerbating lumbar intervertebral disc degeneration (Chiu et al., 2024). Chen X et al. discovered that oxeiptosis is triggered in nucleus pulposus cells (Chen et al., 2024). ...
Oxeiptosis is a novel cell death pathway that was introduced in 2018. As a form of regulated cell death, it operates independently of caspases and is induced by ROS. Distinguished from other cell death pathways such as apoptosis, necroptosis, pyroptosis, and ferroptosis, oxeiptosis features unique damage causes pivotal genes, and signaling pathways (KEAP1/PGAM5/AIFM1). Emerging studies indicate that oxeiptosis plays a significant role in the progression of various diseases and its regulation could serve as a promising therapeutic target. However, the precise molecular mechanisms underlying oxeiptosis remain to be fully elucidated. In this mini-review, we systematically summarize the latest developments in oxeiptosis-related diseases while detailing the molecular mechanisms and regulatory networks of oxeiptosis. These insights offer a foundation for a deeper understanding of oxeiptosis.
... These findings integrate well with prior research [53] linking quantitative MRI biomarkers to lumbar spine conditions. For example, studies have shown that reduced water content and proteoglycan loss in the NP weaken its load-bearing capacity, increasing stress on adjacent tissues and contributing to pain [6,54,55]. Similarly, increased BMFF has been associated with impaired nutrient supply to the IVD [20], further linking tissue-level alterations to clinical symptoms. ...
Background
Low back pain(LBP) is very common among the population, and intervertebral disc(IVD) degeneration is considered to be the most common cause of LBP, but the pathophysiological process between IVD degeneration and LBP is not very clear. We conducted this study to clarify the interplay between quantitative magnetic resonance imaging (MRI) parameters, including q-Dixon and T2 mapping, and clinical symptomatology in patients with LBP.
Methods
All LBP patients underwent lumbar spine MRI, encompassing q-Dixon and T2 mapping. The severity of pain was classified based on Oswestry Disability Index (ODI) scores. Midsagittal T2 and T2* mapping were used to assess anterior annulus fibrosus (AAF), nucleus pulposus (NP), and posterior annulus fibrosus (PAF), as well as vertebral bone marrow fat fraction (BMFF). ANOVA and Pearson’s correlation analyses facilitated the comparative evaluation of MRI parameters with respect to Pfirrmann grades and ODI scores.
Results
95 LBP patients were included (41 males, 54 females), with an average age of 44.39 ± 17.44. The T2 values of AAF and PAF were different and weakly correlated between most Pfirrmann grades (r = 0.435, 0.414). T2 and T2* values of NP were different and negatively correlated between all Pfirrmann grades (r=-0.844, -0.704), except for grade IV vs. V, revealing decreasing values for grades I-V. BMFF was different and moderately correlated (r = 0.646) between most Pfirrmann grades, except for grade V vs. grade III and IV. The T2 values of AAF, NP, and PAF, the T2* values of the NP, and the BMFF of the vertebrae could distinguish low pain from moderate and severe pain.
Conclusion
The T2 and T2* values of AAF, NP, PAF, as well as the BMFF of the vertebrae, can reflect intervertebral disc (IVD) degeneration and may be potentially used to quantitatively detect causes behind LBP.
Intervertebral disc (IVD) degeneration is a major contributing factor for discogenic low back pain (LBP), causing a significant global disability. The IVD consists of an inner core proteoglycan-rich nucleus pulposus (NP) and outer lamellae collagen-rich annulus fibrosus (AF) and is confined by a cartilage end plate (CEP), providing structural support and shock absorption against mechanical loads. Changes to degenerative cascades in the IVD cause dysfunction and instability in the lumbar spine. Various treatments include pharmacological, rehabilitation or surgical interventions that aim to relieve pain; however, these modalities do not halt the pathologic events of disc degeneration or promote tissue regeneration. Loss of stem and progenitor markers, imbalance of the extracellular matrix (ECM), increase of inflammation, sensory hyperinnervation and vascularization, and associated signaling pathways have been identified as the onset and progression of disc degeneration. To better understand the pain originating from IVD, our review focuses on the anatomy of IVD and the pathophysiology of disc degeneration that contribute to the development of discogenic pain. We highlight the key mechanisms and associated signaling pathways underlying disc degeneration causing discogenic back pain, current clinical treatments, clinical perspective and directions of future therapies. Our review comprehensively provides a better understanding of healthy IVD and degenerative events of the IVD associated with discogenic pain, which helps to model painful disc degeneration as a therapeutic platform and to identify signaling pathways as therapeutic targets for the future treatment of discogenic pain.
Intervertebral disc degeneration (IDD) is an age-dependent progressive spinal disease that causes chronic back or neck pain. Although aging has long been presented as the main risk factor, the exact cause is not fully known. DNA methylation is associated with chronic pain, suggesting that epigenetic modulation may ameliorate disc degeneration. We examined histological changes in the DNA methylation within the discs and their association with pain-related transient receptor potential vanilloid subtype 1 (TrpV1) expression in rats subjected to IDD. Epigenetic markers (5-hydroxymethylcytosine (5hmC), 5-methylcytosine (5Mc)), DNA methyltransferases (DNMTs), and Ten-eleven translocations (Tets) were analyzed using immunohistochemistry, real-time PCR, and DNA dot-blot following IDD. Results revealed high 5mC levels in the annulus fibrosus (AF) region within the disc after IDD and an association with TrpV1 expression. DNMT1 is mainly involved in 5mC conversion in degenerated discs. However, 5hmC levels did not differ between groups. A degenerated disc can lead to locomotor defects as assessed by ladder and tail suspension tests, no pain signals in the von Frey test, upregulated matrix metalloproteinase-3, and downregulated aggrecan levels within the disc. Thus, we found that the DNA methylation status in the AF region of the disc was mainly changed after IDD and associated with aberrant TrpV1 expression in degenerated discs.
Background
To assess the effects of proteoglycan-depleted regions of annular disruptions on nerve ingrowth in the injury site in vivo .
Methods
New Zealand white rabbits ( n = 18) received annular injuries at L3/4, L4/5, and L5/6. The experimental discs were randomly assigned to four groups: (a) an annular defect was created; (b) an annular defect implanted with a poly lactic-co-glycolic acid (PLGA)/fibrin/PBS plug; (c) an annular defect implanted with a PLGA/fibrin/chondroitinase ABC (chABC) plug; and (d) an uninjured L2/3 disc (control). Disc degeneration was evaluated by radiography, MRI, histology, and analysis of the proteoglycan (PG) content. Immunohistochemical detection of nerve fibers and chondroitin sulfate (CS) was performed.
Results
The injured discs produced progressive and reliable disc degeneration. In the defective discs, the lamellated appearance of AF (Annulus fibrosus) was replaced by extensive fibrocartilaginous-like tissue formation outside the injured sites. In contrast, newly formed tissue was distributed along small fissures, and small blood vessels appeared in the outer part of the disrupted area in the PLGA/fibrin/PBS discs. More sprouting nerve fibers grew further into the depleted annulus regions in the PLGA/fibrin/chABC discs than in the control discs and those receiving PLGA/fibrin/PBS. In addition, the innervation scores of the PLGA/fibrin/chABC discs were significantly increased compared with those of the PLGA/fibrin/PBS discs and defected discs.
Conclusion
ChABC-based PLGA/fibrin gel showed promising results by achieving biointegration with native annulus tissue and providing a local source for the sustained release of active chABC. Disc-derived PG-mediated inhibition of nerve and blood vessel ingrowth was abrogated by chABC enzymatic deglycosylation in an annular-injured rabbit disc degeneration model.
Syndecan-1 and syndecan-4 are members of the syndecan family of transmembrane heparan sulfate proteoglycans. Vascular endothelial cells synthesize both species of proteoglycans and use them to regulate the blood coagulation-fibrinolytic system and their proliferation via their heparin-like activity and FGF-2 binding activity, respectively. However, little is known about the crosstalk between the expressions of the proteoglycan species. Previously, we reported that biglycan, a small leucine-rich dermatan sulfate proteoglycan, intensifies ALK5–Smad2/3 signaling by TGF-β1 and downregulates syndecan-4 expression in vascular endothelial cells. In the present study, we investigated the crosstalk between the expressions of syndecan-1 and other proteoglycan species (syndecan-4, perlecan, glypican-1, and biglycan) in bovine aortic endothelial cells in a culture system. These data suggested that syndecan-1 downregulated syndecan-4 expression by suppressing the endogenous FGF-2-dependent ERK1/2 pathway and FGF-2-independent p38 MAPK pathway in the cells. Moreover, this crosstalk was a one-way communication from syndecan-1 to syndecan-4, suggesting that syndecan-4 compensated for the reduced activity in the regulation of vascular endothelial cell functions caused by the decreased expression of syndecan-1 under certain conditions.
Aging, which is accompanied by decreased organ function and increased disease incidence, limits human lifespan and has attracted investigators for thousands of years. In recent decades, with the rapid development of biology, scientists have shown that epigenetic modifications, especially DNA methylation, are key regulators involved in this process. Regular fluctuations in global DNA methylation levels have been shown to accurately estimate biological age and disease prognosis. In this review, we discuss recent findings regarding the relationship between variations in DNA methylation level patterns and aging. In addition, we introduce the known mechanisms by which DNA methylation regulators affect aging and related diseases. As more studies uncover the mechanisms by which DNA methylation regulates aging, antiaging interventions and treatments for related diseases may be developed that enable human life extension.
This review article describes the various image guided interventional techniques used for treating chronic backache attributed to disc related pathologies. With the aim of minimum invasion and maximum relief, these procedures comprise predominantly of annuloplasty and disc decompression via different mechanisms. Newer therapies are discussed in this review article with the objective of restoring disc height and its biomechanical function by substitution of biochemical constituents, regeneration of cartilaginous end plate and finally artificial disc implantation.
Intervertebral disc degeneration (IDD) is the main contributor to low back pain, which is a leading cause of disability worldwide. Although substantial progress has been made in elucidating the molecular mechanisms of IDD, fundamental and long‐lasting treatments for IDD are still lacking. With increased understanding of the complex pathomechanism of IDD, alternative strategies for treating IDD can be discovered. A brief overview of the prevalence and epidemiologic risk factors of IDD is provided in this review, followed by the descriptions of anatomic, cellular, and molecular structure of the intervertebral disc as well as the molecular pathophysiology of IDD. Finally, the recent findings of intervertebral disc progenitors are reviewed and the future perspectives are discussed. Pathomechanism of intervertebral disc degeneration. Several risk factors including genetic factors as well as mechanical stress, trauma and smoking, attributed to the development of intervertebral disc degeneration. These biological and environmental factors induce the reduction of cell numbers and transformation of intervertebral disc cells through several molecular mechanisms, resulting in decreased production of extracellular matrix due to increased catabolic activity and decreased anabolic activities. Thereafter, the structured integrity of intervertebral disc is lost and intervertebral disc degeneration is further accelerated.
Discogenic back pain is multifactorial and physicians often struggle to identify the underlying source of the pain. As a result, discogenic back pain is often hard to treat with clinical treatment strategies of questionable efficacy. The aim of this review paper is to define discogenic back pain into a series of more specific and often interacting pathologies, and to highlight the need to develop novel approaches and treatment strategies for this challenging and unmet clinical need based on a broad literature review. Discogenic pain involves degenerative changes of the intervertebral disc including structural defects that result in biomechanical instability and inflammation. These degenerative changes in intervertebral discs closely intersect with the peripheral and central nervous system at early and late time points to cause nerve sensitization and ingrowth and eventually central sensitization to result in chronic pain conditions. Existing imaging modalities are non‐specific to pain symptoms, whereas discography methods which are more specific have known co‐morbidities due to the intervertebral disc puncture and injection. As a result, alternative non‐invasive and specific diagnostic methods require development in order to better diagnose and identify specific conditions and sources of pain that can be more directly treated. Currently, there are a wide variety of treatments/intervention for discogenic back pain. Many surgical approaches for discogenic pain have limited efficacy thus, accentuating a need to develop novel treatments. Regenerative therapy such as biologics, cell‐based therapy, intervertebral disc repair, and gene‐based therapy offer the most promise and have many advantages over current therapies. This article is protected by copyright. All rights reserved
Background
The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data.
Methods
We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting.
Findings
Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1–4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0–8·4) while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6–9·2) for males and 6·5% (5·4–7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782–3252] per 100 000 in males vs s1400 [1279–1524] per 100 000 in females), transport injuries (3322 [3082–3583] vs 2336 [2154–2535]), and self-harm and interpersonal violence (3265 [2943–3630] vs 5643 [5057–6302]).
Interpretation
Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.
Back pain is a common clinical symptom. Degeneration of intervertebral discs is one of the most important factors leading to back pain, namely, discogenic back pain. However, at present, the understanding of lumbar intervertebral discs causing back pain is confined to biomechanical and histological studies. The neuropathological mechanism related to discogenic back pain is still not well understood. Many studies have found that as an intervertebral disc degenerates, the peripheral nerve tissues have corresponding structural reorganization, and a series of nerve cells become involved in progression of discogenic back pain. Therefore, study of neural mechanisms that are involved in progression of discogenic back pain will provide additional assistance for treatment of its symptoms. We review the anatomical structure of intervertebral discs and the related neural mechanisms involved in discogenic back pain. We also discuss the current view of neural mechanisms underlying discogenic back pain.
Intervertebral disc degeneration is a well-known cause of disability, the result of which includes neck and back pain with associated mobility limitations. The purpose of this article is to provide an overview of the known molecular mechanisms through which intervertebral disc degeneration occurs as a result of complex interactions of exogenous and endogenous stressors. This review will focus on some of the identified molecular changes leading to the deterioration of the extracellular matrix of both the annulus fibrosus and nucleus pulposus. In addition, we will provide a summation of our current knowledge supporting the role of associated DNA and intracellular damage, cellular senescence's catabolic effects, oxidative stress, and the cell's inappropriate response to damage in contributing to intervertebral disc degeneration. Our current understanding of the molecular mechanisms through which intervertebral disc degeneration occurs provides us with abundant insight into how physical and chemical changes exacerbate the degenerative process of the entire spine. Furthermore, we will describe some of the related molecular targets and therapies that may contribute to intervertebral repair and regeneration.
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This is a review paper on the topic of genetic background of degenerative disc diseases in the lumbar spine. Lumbar disc diseases (LDDs), such as lumbar disc degeneration and lumbar disc herniation, are the main cause of low back pain. There are a lot of studies that tried to identify the causes of LDDs. The causes have been categorized into environmental factors and genetic factors. Recent studies revealed that LDDs are mainly caused by genetic factors. Numerous studies have been carried out using the genetic approach for LDDs. The history of these studies is divided into three periods: (1) era of epidemiological research using familial background and twins, (2) era of genomic research using DNA polymorphisms to identify susceptible genes for LDDs, and (3) era of functional research to determine how the genes cause LDDs. This review article was undertaken to present the history of genetic approach to LDDs and to discuss the current issues and future perspectives.
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The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
The nucleus pulposus (NP) of the intervertebral disc (IVD) demonstrates substantial changes in cell and matrix composition with both ageing and degeneration. While recent transcriptomic profiling studies have helped define human NP cell phenotype, it remains unclear how expression of these markers is influenced by ageing or degeneration. Furthermore, cells of the NP are thought to derive from the notochord, although adult NP lacks identifiable notochordal (NC) cells. This study aimed to confirm expression of previously identified NP and NC marker genes in adult human NP cells from a range of ages and degenerate states. Importantly, using gene expression analysis (N = 60) and immunohistochemistry (N = 56) the study demonstrates expression of NP markers FoxF1, Pax-1, keratin-8/18, carbonic anhydrase-12, and NC markers brachyury, galectin-3 and CD24 in cells of the NP irrespective of age or degeneration. Our immunohistochemical data, combined with flow cytometry (N = 5) which identified a small number of CA12⁺Gal3⁺T⁺CD24⁺ cells, suggests the possible presence of a sub-population of cells with an NC-like phenotype in adult NP tissue. These findings suggest that the NP contains a heterogeneous population of cells, which may possess varied phenotypic and functional profiles and thus warrant further investigation to improve our understanding of IVD homeostasis and repair.
Painful intervertebral disc disease is characterised not only by an imbalance between anabolic (i.e., matrix synthesis) and catabolic (i.e., matrix degradation) processes, but also by infl ammatory mechanisms. The increased expression and synthesis of matrix metalloproteinases and infl ammatory factors is mediated by specifi c signal transduction, in particular the nuclear factor-kappaB (NF-B) and mitogen-activated protein kinase (MAPK)-mediated pathways. NF-B and MAPK have been identifi ed as the master regulators of infl ammation and catabolism in several musculoskeletal disorders (e.g., osteoarthritis), and recently growing evidence supports the importance of these signalling pathways in painful disc disease. With continuing research exploiting in vitro and in vivo model systems to elucidate the roles of these pathways in disc degeneration, it may be possible in the near future to specifi cally target these major infl ammatory / catabolic signalling pathways to treat painful degenerative disc disease. In this perspective, we aim to summarise the current state of knowledge concerning the infl ammatory and catabolic molecular pathways of intervertebral disc disease (IDD), with a detailed description of NF-B and MAP kinase-mediated signal transduction in disc cells. Furthermore, we will discuss the emerging novel molecular treatment modalities for IDD using pharmacological inhibitors targeting these pathways.
Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs.
The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis.
A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H 2 O 2 or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H 2 O 2 and BSO-treated AF cells. Conversely, we showed that TNF-α induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model.
A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.
Aged and degenerated intervertebral discs are characterised by a significant increase in the number of senescent cells, which may be associated with the deterioration of this tissue due to their catabolic phenotype. On the other hand, carboxymethyl-lysine has been found to be accumulated with ageing in the proteins of the disc, evidencing the existence of oxidative stress in this tissue. Accordingly, here we investigated the effect of oxidative stress on the physiology of human nucleus pulposus cells. Hydrogen peroxide (H2O2) at subcytotoxic concentrations transiently increased the intracellular levels of reactive oxygen species, activated the p38 MAPK, ERKs, JNKs and Akt signalling pathways and induced the nuclear translocation of NF-κΒ and Nrf2. It also provoked DNA damage and triggered a DNA repair response by activating the ATM-Chk2-p53-p21(WAF1)-pRb pathway, ultimately resulting in a G1 cell cycle delay and the decrease of cells' proliferation. Prolonged exposure to H2O2 led to premature cellular senescence, as characterised by the inhibition of proliferation, the enhanced senescence-associated β galactosidase staining and the over-expression of known molecular markers, without though a significant decrease in the chromosome telomere length. H2O2-senescent cells were found to possess a catabolic phenotype, mainly characterised by the up-regulation of extracellular matrix-degrading enzymes (MMP-1, -2, -9 and ADAMTS-5) and the down-regulation of their inhibitors (TIMPs), as well as of several proteoglycans, including aggrecan, the major component of the nucleus pulposus. The senescent phenotype could be reversed by N-acetyl-L-cysteine, supporting the use of antioxidants for the improvement of disc physiology and the deceleration of disc degeneration.
Using data from 16 published reports, the authors correlated macroscopic disc degeneration grades with age, sex, and spine level In 600 lumbar Intervertebral discs from 273 cadavers (ages: 0-96 years). Male discs were more degenerated than female discs at most ages; significantly so In the second, fifth, sixth, and seventh decades. On average, L4-L5 and L3-L4 level discs showed more degeneration than discs at other lumbar levels. These macroscopic findings corroborate radio-graphic data from epldemlologlc studies. The calculations suggest that higher mechanical stress, perhaps combined with longer nutritional pathways, may be responsible for the earlier degeneration of male discs.
Discogenic low back pain is a serious medical and social problem, and accounts for 26%-42% of the patients with chronic low back pain. Recent studies found that the pathologic features of discs obtained from the patients with discogenic low back pain were the formation of the zones of vascularized granulation tissue, with extensive innervation in fissures extending from the outer part of the annulus into the nucleus pulposus. Studies suggested that the degeneration of the painful disc might originate from the injury and subsequent repair of annulus fibrosus. Growth factors such as basic fibroblast growth factor, transforming growth factor ß1, and connective tissue growth factor, macrophages and mast cells might play a key role in the repair of the injured annulus fibrosus and subsequent disc degeneration. Although there exist controversies about the role of discography as a diagnostic test, provocation discography still is the only available means by which to identify a painful disc. A recent study has classified discogenic low back pain into two types that were annular disruption-induced low back pain and internal endplate disruption-induced low back pain, which have been fully supported by clinical and theoretical bases. Current treatment options for discogenic back pain range from medicinal anti-inflammation strategy to invasive procedures including spine fusion and recently spinal arthroplasty. However, these treatments are limited to relieving symptoms, with no attempt to restore the disc's structure. Recently, there has been a growing interest in developing strategies that aim to repair or regenerate the degenerated disc biologically.
Degenerative changes are commonly found in spine imaging but often occur in pain-free individuals as well as those with back pain. We sought to estimate the prevalence, by age, of common degenerative spine conditions by performing a systematic review studying the prevalence of spine degeneration on imaging in asymptomatic individuals.
We performed a systematic review of articles reporting the prevalence of imaging findings (CT or MR imaging) in asymptomatic individuals from published English literature through April 2014. Two reviewers evaluated each manuscript. We selected age groupings by decade (20, 30, 40, 50, 60, 70, 80 years), determining age-specific prevalence estimates. For each imaging finding, we fit a generalized linear mixed-effects model for the age-specific prevalence estimate clustering in the study, adjusting for the midpoint of the reported age interval.
Thirty-three articles reporting imaging findings for 3110 asymptomatic individuals met our study inclusion criteria. The prevalence of disk degeneration in asymptomatic individuals increased from 37% of 20-year-old individuals to 96% of 80-year-old individuals. Disk bulge prevalence increased from 30% of those 20 years of age to 84% of those 80 years of age. Disk protrusion prevalence increased from 29% of those 20 years of age to 43% of those 80 years of age. The prevalence of annular fissure increased from 19% of those 20 years of age to 29% of those 80 years of age.
Imaging findings of spine degeneration are present in high proportions of asymptomatic individuals, increasing with age. Many imaging-based degenerative features are likely part of normal aging and unassociated with pain. These imaging findings must be interpreted in the context of the patient's clinical condition.
© 2015 American Society of Neuroradiology.
Glucosamine is an endogenous amino monosaccharide naturally occurring in the cartilage. We have recently shown that glucosamine sulfate promotes the biosynthesis of glycosaminoglycans in intervertebral disc cells. Here we assessed the role of glucosamine sulfate in the response of bovine nucleus pulposus cell monolayers to TNFα that constitutes an early signal of disc degeneration. TNFα was not found to affect nucleus pulposus cells' viability, while it resulted in a ∼2.5-fold increase of the intracellular ROS levels, a rapid transient phosphorylation of p38 MAPK and a ROS-dependent activation of JNKs. In addition, TNFα had a prominent inflammatory effect on nucleus pulposus cells by up-regulating MMP-3 expression that was reversed when inhibiting the kinase activity of p38 MAPK. Glucosamine sulfate also diminished the increased by TNFα MMP-3 mRNA levels, but this was unrelated to the p38 MAPK or ROS-mediated JNK activation. Even though the mode of action of glucosamine towards TNFα remains to be elucidated, to the best of our knowledge, this is the first report providing evidence for the protective role of glucosamine against this early mediator of disc degeneration that could support the potential usage of this molecule as a treatment for preventing disc degenerative disorders. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Matrix metalloproteinase-3 (MMP-3) plays an important role in intervertebral disc degeneration, a ubiquitous condition closely linked to low back pain and disability. Elevated expression of syndecan 4, a cell surface heparan sulfate proteoglycan, actively controls disc matrix catabolism. However, the relationship between MMP-3 expression and syndecan 4 in the context of inflammatory disc disease has not been clearly defined. We investigated the mechanisms by which cytokines control MMP-3 expression in rat and human nucleus pulposus cells. Cytokine treatment increased MMP-3 expression and promoter activity. Stable silencing of syndecan 4 blocked cytokine-mediated MMP-3 expression; more important, syndecan 4 did not mediate its effects through NF-κB or mitogen-activated protein kinase (MAPK) pathways. However, treatment with MAPK and NF-κB inhibitors resulted in partial blocking of the inductive effect of cytokines on MMP-3 expression. Loss-of-function studies confirmed that NF-κB, p38α/β2/γ/δ, and extracellular signal-regulated kinase (ERK) 2, but not ERK1, contributed to cytokine-dependent induction of MMP3 promoter activity. Similarly, inhibitor treatments, lentiviral short hairpin-p65, and short hairpin-I κ B kinase β significantly decreased cytokine-dependent up-regulation in MMP-3 expression. Finally, we show that transforming growth factor-β can block the up-regulation of MMP-3 induced by tumor necrosis factor (TNF)-α by counteracting the NF-κB pathway and syndecan 4 expression. Taken together, our results suggest that cooperative signaling through syndecan 4 and the TNF receptor 1-MAPK-NF-κB axis is required for TNF-α-dependent expression of MMP-3 in nucleus pulposus cells. Controlling these pathways may slow the progression of intervertebral disc degeneration and matrix catabolism.
Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1β, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo.
N-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and
oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated
fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence
of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated
under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from
oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose.
Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that
lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
We investigated TNF-α and IL-1β regulation of ADAMTS-4 expression in nucleus pulposus (NP) cells and its role in aggrecan degradation. Real-time quantitative RT-PCR, Western blotting, and transient transfections with rat NP cells and lentiviral silencing with human NP cells were performed to determine the roles of MAPK and NF-κB in cytokine-mediated ADAMTS-4 expression and function. ADAMTS4 expression and promoter activity increased in NP cells after TNF-α and IL-1β treatment. Treatment of cells with MAPK and NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS4 mRNA and protein expression. Although ERK1, p38α, p38β2, and p38γ were involved in induction, ERK2 and p38δ played no role in TNF-α-dependent promoter activity. The inductive effect of p65 on ADAMTS4 promoter was confirmed through gain and loss-of-function studies. Cotransfection of p50 completely blocked p65-mediated induction. Lentiviral transduction with shRNA plasmids shp65, shp52, shIKK-α, and shIKK-β significantly decreased TNF-α-dependent increase in ADAMTS-4 and -5 levels and aggrecan degradation. Silencing of either ADAMTS-4 or -5 resulted in reduction in TNF-α-dependent aggrecan degradation in NP cells. By controlling activation of MAPK and NF-κB signaling, TNF-α and IL-1β modulate expression of ADAMTS-4 in NP cells. To our knowledge, this is the first study to show nonredundant contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells in vitro.
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
We sought to determine the association between radiologic and clinical diagnoses and to measure the impact of more magnetic resonance imaging (MRI) and computed tomography (CT) scans on clinical decision-making in patients referred to a surgical clinic for back pain.
We conducted a 7-week prospective study of patients referred for back pain to spine surgeons in 1 health care centre. Patients were included if they had not previously been seen by a surgeon for their back problems and if their back pain was related to the thoracic or lumbar spine. We collected demographic data, imaging findings, clinical diagnoses as determined by the surgeons and visit outcomes and compared our results with those of a similar study conducted in 1996.
Of 160 patients, 8 (5%) were no-shows and excluded from further analysis owing to incomplete data. There were more MRI scans and fewer plain radiographs ordered in 2009 compared with 1996 (73% v. 11% and 39% v. 68%, respectively). Degenerative disc disease was a more common radiologic diagnosis (n=78, 63%) than clinical diagnosis (n=41, 27%). Disc herniation was a more common radiologic diagnosis (n=69, 56%) than clinical diagnosis (n=25, 16%). With regards to visit outcomes, there were fewer second opinions sought in 2009 compared with 1996 (3% v. 11%). Although not statistically significant, the number of surgical candidates remained relatively stable (19% in 1996 v. 16% in 2009, p=0.44).
The clinical diagnosis had a poor association with radiologic abnormalities. Despite an increase in the number of MRI and CT scans, the number of patients deemed surgical candidates has not changed.
Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
Chronic and debilitating low back pain is a common condition and a huge economic burden. Many cases are attributed to age-related degeneration of the intervertebral disc (IVD); however, age-related degeneration appears to occur at an accelerated rate in some individuals. We have previously demonstrated biomarkers of cellular senescence within the human IVD and suggested a role for senescence in IVD degeneration. Senescence occurs with ageing but can also occur prematurely in response to stress. We hypothesised that stress-induced premature senescence (SIPS) occurs within the IVD and here we have investigated the expression and production of caveolin-1, a protein that has been shown previously to be upregulated in SIPS.
Caveolin-1 gene expression in human nucleus pulposus (NP) cells was assessed by conventional and quantitative real-time polymerase chain reaction (PCR), and caveolin-1 protein expression was examined within human IVDs using immunohistochemistry. The correlation between caveolin-1 and p16INK4a (biomarker of cellular senescence) gene expression was investigated using quantitative real-time PCR.
Caveolin-1 gene expression and protein expression were demonstrated within the human IVD for the first time. NP cells from degenerate discs exhibited elevated levels of caveolin-1 which did not relate to increasing chronological age. A negative correlation was observed between gene expression for caveolin-1 and donor age, and no correlation was found between caveolin-1 protein expression and age. A positive correlation was identified between gene expression of caveolin-1 and p16INK4a.
Our findings are consistent with a role for caveolin-1 in degenerative rather than age-induced changes in the NP. Its expression in IVD tissue and its association with the senescent phenotype suggest that caveolin-1 and SIPS may play a prominent role in the pathogenesis of IVD degeneration.
The prevalence, validity and reliability of high-intensity zones in the annulus fibrosus seen on T2-weighted magnetic resonance images of patients with intractable low-back pain were determined. This sign was readily recognized by two independent observers. It occurred in 28% of 500 patients undergoing magnetic resonance imaging for back pain. The presence of a high-intensity zone correlated significantly with the presence of Grade 4 annular disruption and with reproduction of the patient's pain. Its sensitivity as a sign of either annular disruption or pain was modest but its specificity was high, and its positive predictive value for a severely disrupted, symptomatic disc was 86%. This sign is diagnostic of painful internal disc disruption.
Purpose: Intervertebral disc degeneration (IVDD), Modic changes, and fatty infiltration in the paraspinal muscles are possible causes of low back pain (LBP). Multifidus has been the most commonly blamed paraspinal muscle in the etiology of LBP. However, it contributes to 20% of the extensor moment on the lumbar spine. In the present study, we aimed to identify whether patients with LBP and asymptomatic subjects differed in terms of intervertebral discs, end-plates, and fatty infiltration in their paraspinal muscles.
Methods: Consecutive women and men, who visited the spine outpatient clinics with chronic LBP and had lumbar spine MRI for their LBP without leg pain were included. Asymptomatic subjects without LBP/leg pain for the last year were recruited. Modic changes, IVDD, and fatty infiltration in the paraspinal muscles were evaluated on lumbar spine magnetic resonance imagings of the patients with LBP and age-, gender- and BMI-matched asymptomatic controls.
Results: Low back pain was closely associated with fatty infiltration in the paraspinal muscles at all lumbar levels whereas it had association with severe IVDD and Modic changes at lower lumbar levels. Multifidus at the lower lumbar levels was the fattiest paraspinal muscle in both asymptomatic subjects and patients with LBP. Patients with LBP had severe fatty infiltration in the erector spinae at the upper lumbar levels.
Conclusion: Severe IVDD and Modic changes were more common at lower lumbar levels in patients with LBP. Both asymptomatic subjects and those with LBP had fatty multifidus at lower lumbar levels whereas those with LBP had fatty infiltration in the erector spinae at upper lumbar levels. We suggest that fatty infiltration could have started in the multifidus. The erector spinae had greater contribution to the lumbar extension compared to the multifidus. Thus, LBP could develop when the quality of the erector spinae at the upper lumbar levels impairs due to fatty infiltration.
Objective: Aging is a cause of spinal degeneration. However, the natural history of degeneration process is unclear. We aimed to analyze change of intervertebral disc degeneration (IVDD) and Modic changes in Caucasians with LBP decade by decade. We also aimed to find out breaking points of having severe IVDD and Modic changes throughout human life.
Patients and Methods: We conducted a cross-sectional analysis of a retrospective database in patients aged between 10-100 years. All patients were evaluated in terms of IVDD and Modic changes. Optimal binning was conveyed to group age of the patients in terms of major changes in percentages of severe IVDD and Modic changes.
Results: We evaluated 2434 patients (female: 1328 and male: 1106; mean age: 47.2 ± 17.2 years; age range = 10-98 years). In all patients, 50.5% and 23.6% had severe IVDD and Modic changes at any lumbar level, respectively. Women were significantly more likely to have severe IVDD than men. Frequency of Modic changes at any lumbar level significantly increased in 40s and 60s, whereas frequency of severe IVDD at any lumbar level significantly increased in 20s, 30s, 50s and 70s.
Conclusion: Spinal degeneration had specific gear-up periods in human life. Age groups of future spine studies could be defined according to the new defined change periods of severe IVDD and Modic changes in human life.
Objective: We aimed to develop a new scoring system for spinal degeneration including Modic changes, fatty infiltration (fi) in the paraspinal muscles, and intervertebral disc degeneration (IVDD), briefly Mo-fi-disc, using current radiological classification systems. We also aimed to understand whether Mo-fi-disc could predict patients with more intense low back pain (LBP).
Patients and Methods: We conducted a cross-sectional analysis of a retrospective database between March 2018 and July 2020. We evaluated patients in terms of Modic changes, fatty infiltration in the paraspinal muscles, and IVDD at all lumbar levels on lumbar spine MRI. We grouped patients based on their LBP intensity. Visual analog scales (VAS) scores were used for LBP intensity.
Results: We evaluated 134 patients (female: 66, male: 68; mean age: 35.44 ± 6.5 years). Patients with higher VAS scores had significantly higher ‘Mo-disc’ scores and higher ‘fi’ scores compared to those with lower VAS scores (3.54 ± 2.7 vs. 2.55 ± 2.8, p=0.0075; 6.85 ± 3.2 vs. 5.25 ± 2.9, p=0.0092). Patients with higher VAS scores had significantly higher ‘Mo-fi-disc’ scores compared to those with lower VAS scores (10.4 ± 4.2 vs. 7.94 ± 3.8, p=0.0003). The most significant predictor for patients with higher VAS scores was ‘Mo-fi-disc’ scoring system with an OR of 1.193 (95% CI: 1.055-1.349, p=0.005).
Conclusion: Patients with more intense LBP had higher ‘Mo-fi-disc’ scores. This scoring system suggests an easy and objective classification to evaluate the spinal degeneration.
Background:
A 2007 American College of Physicians guideline addressed nonpharmacologic treatment options for low back pain. New evidence is now available.
Purpose:
To systematically review the current evidence on nonpharmacologic therapies for acute or chronic nonradicular or radicular low back pain.
Data sources:
Ovid MEDLINE (January 2008 through February 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.
Study selection:
Randomized trials of 9 nonpharmacologic options versus sham treatment, wait list, or usual care, or of 1 nonpharmacologic option versus another.
Data extraction:
One investigator abstracted data, and a second checked abstractions for accuracy; 2 investigators independently assessed study quality.
Data synthesis:
The number of trials evaluating nonpharmacologic therapies ranged from 2 (tai chi) to 121 (exercise). New evidence indicates that tai chi (strength of evidence [SOE], low) and mindfulness-based stress reduction (SOE, moderate) are effective for chronic low back pain and strengthens previous findings regarding the effectiveness of yoga (SOE, moderate). Evidence continues to support the effectiveness of exercise, psychological therapies, multidisciplinary rehabilitation, spinal manipulation, massage, and acupuncture for chronic low back pain (SOE, low to moderate). Limited evidence shows that acupuncture is modestly effective for acute low back pain (SOE, low). The magnitude of pain benefits was small to moderate and generally short term; effects on function generally were smaller than effects on pain.
Limitation:
Qualitatively synthesized new trials with prior meta-analyses, restricted to English-language studies; heterogeneity in treatment techniques; and inability to exclude placebo effects.
Conclusion:
Several nonpharmacologic therapies for primarily chronic low back pain are associated with small to moderate, usually short-term effects on pain; findings include new evidence on mind-body interventions.
Primary funding source:
Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).
Muscle relaxants are commonly prescribed for low back pain ( LBP ); however, there is limited evidence of their clinical efficacy and tolerability. This review evaluated the efficacy and tolerability of muscle relaxants in people with LBP . We searched online databases including Medline, EMBASE , CENTRAL and Psyc INFO (inception to end October 2015) and performed citation tracking for eligible randomized controlled trials ( RCT s). Two authors independently extracted data and assessed risk of bias of randomized controlled trials of muscle relaxants. Pain outcomes were converted to a common 0–100 scale. Data were pooled using a random effects model with strength of evidence assessed using GRADE . Fifteen trials (3362 participants) were evaluated in this review. A total of five trials (496 participants) provide high quality evidence that muscle relaxants provide clinically significant pain relief in the short term for acute LBP ; MD −21.3, [−29.0, −13.5]. There was no information on long‐term outcomes. The median adverse event rate in clinical trials for muscle relaxants was similar to placebo 14.1% IQR (7.0–28.7%) and 16.0% (4.1–31.2%); p = 0.5, respectively. There is no evidence for the efficacy of benzodiazepines in LBP . For people with acute LBP , muscle relaxants provide clinically significant short‐term pain relief. For chronic LBP, the efficacy of muscle relaxants is largely unknown. There was no eligible RCT evidence to support the efficacy of benzodiazepines in LBP . Prolonged use of these medicines in LBP cannot be guided by trial evidence.
What does this review add?
Muscle relaxants provide clinically significant pain relief for acute low back pain. Caution must be taken with the interpretation of the findings as the evidence comes from specific muscle relaxant medicines.
Study Design. A review of current knowledge and opinions concerning the biologic changes that take place during development, maturation and degeneration of the intervertebral disc. Objective. To provide an overview of the changes that occur in structure and composition of the extracellular matrix of the intervertebral disc and to explain the origin of such changes and their functional consequences. Summary of Background Data. The structure of the intervertebral disc, and, in particular, the composition of its extracellular matrix, changes throughout life, ultimately resulting in tissue degeneration in the adult. Methods. A review of the published scientific literature. Results. In the young disc, the outer anulus fibrosus and inner nucleus pulposus have clear physical and molecular properties, although these differences become less distinct in the adult. The age changes are due to variations in both the abundance and structure of the macromolecules, particularly aggrecan, and the structural variations may be due to changes in both synthesis and degradation. It is not clear how many of the changes are by design to adapt to the altered environment of the growing spine. However, it is commonly thought that the degradative changes are detrimental to disc function, a property that is exacerbated by the inability of the mature avascular disc to remove and replace accumulated degradation products. The rate at which these detrimental changes occur may vary between individuals because of genetic, biomechanical, and nutritional differences. Such changes are thought to form the basis of tissue loss associated with disc degeneration. Conclusion. Changes in intervertebral disc structure throughout life ultimately result in tissue degeneration and the need for medical intervention. Current research is aimed at trying to restore the integrity of the degenerate disc matrix by biologic means, although at present it is not clear what the structure of the most appropriate repair tissue should be or how it can be achieved.
Study Design. A histologic study on age-related changes of the human lumbar intervertebral disc was conducted. Objectives. To investigate comprehensively age-related temporospatial histologic changes in human lumbar intervertebral disc, and to develop a practicable and reliable classification system for age-related histologic disc alteration. Summary of the Background Data. No comprehensive microscopic analysis of age-related disc changes is available. There is no conceptual morphologic framework for classifying age-related disc changes as a reference basis for more sophisticated molecular biologic analyses of the causative factors of disc aging or premature aging (degeneration). Methods. A total of 180 complete sagittal lumbar motion segment slices obtained from 44 deceased individuals (fetal to 88 years of age) were analyzed with regard to 11 histologic variables for the intervertebral disc and endplate, respectively. In addition, 30 surgical specimens (3 regions each) were investigated with regard to five histologic variables. Based on the semiquantitative analyses of 20,250 histologic variable assessments, a classification system was developed and tested in terms of validity, practicability, and reliability. The classification system was applied to cadaveric and surgical disc specimens not included in the development of the classification system, and the scores were assessed by two additional independent raters. Results. A semiquantitative analyses provided clear histologic evidence for the detrimental effect of a diminished blood supply on the endplate, resulting in the tissue breakdown beginning in the nucleus pulposus and starting in the second life decade. Significant temporospatial variations in the presence and abundance of histologic disc alterations were observed across levels, regions, macroscopic degeneration grades, and age groups. A practicable classification system for age-related histologic disc alterations was developed, resulting in moderate to excellent reliability (κ values, 0.49–0.98) depending on the histologic variable. Application of the classification system to cadaveric and surgical specimens demonstrated a significant correlation with age (P < 0.0001) and macroscopic grade of degeneration (P < 0001). However, substantial data scatter caution against reliance on traditional macroscopic disc grading and favor a histology-based classification system as a reference standard. Conclusions. Histologic disc alterations can reliably be graded based on the proposed classification system providing a morphologic framework for more sophisticated molecular biologic analyses of factors leading to age-related disc changes. Diminished blood supply to the intervertebral disc in the first half of the second life decade appears to initiate tissue breakdown.
Study design:
A prospective consecutive series of 100 patients computer randomized into 2 groups to have treatment by either chemonucleolysis or surgery.
Objective:
To compare the complications and clinical outcome between the groups at 1 year, and at 10 to 13 and 24 to 27 years.
Summary of background data:
Chemonucleolysis was introduced in 1964 and became widely used. Its efficacy was proven by several randomized studies when compared with a placebo and surgery. The manufacturing of Chemonucleolysis was ceased in 2001.
Methods:
One hundred consecutive patients were enrolled for the study and randomized according to age, sex, and disc level. They were followed up at 1 year with self-assessment questionnaires to establish if they were completely better, improved, the same or worse. At 10 to 13 years, 61 patients (32 chemonuceolysis and 29 surgery) and at 24 to 27 years, 45 patients (24 chemonucleolysis and 21 surgery) were self-assessed by questionnaire according to the Macnab criteria.
Results:
Forty-eight patients were treated by chemonucleolysis and 52 by surgery. Ten patients treated by chemonucleolysis underwent surgery within 8 weeks. At 1 year, 10 to 13 years, and 24 to 27 years, 94%, 72%, and 63% of patients treated by chemonucleolysis had good or excellent results compared with 96%, 72%, and 67% of patients who underwent surgery, respectively. There was no difference in the clinical outcome between the treatments at any of the follow-up time points. There were 2 serious complications, 1in each treatment group.
Conclusion:
Chemonucleolysis is as effective as surgery when assessed according to intention-to-treat analysis, with reduced complications, and age has no bearing on the outcome. The authors think that restoration of its availability would be beneficial to patients.
Level of evidence:
1.
Discogenic lower back pain (DLBP) is the most common type of chronic lower back pain (LBP), accounting for 39% of cases, compared to 30% of cases due to disc herniation, and even lower prevalence rates for other causes, such as zygapophysial joint pain. Only a small proportion (approximately 20%) of LBP cases can be attributed with reasonable certainty to a pathologic or anatomical entity. Thus, diagnosing the cause of LBP represents the biggest challenge for doctors in this field. In this review, we summarize the process of obtaining a clinical diagnosis of DLBP and discuss the potential for serum-based diagnosis in the near future. The use of serum biomarkers to diagnose DLBP is likely to increase the ease of diagnosis as well as produce more accurate and reproducible results.
Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan.
Abstract Cell death (apoptosis & necrosis) and extracellular matrix destruction induced by oxidative stress have been suggested to be closely involved in the process of disc degeneration. Glutathione, a natural peptide as a powerful antioxidant in human cytoplasm, plays an important role in protecting living cells. This study is to investigate whether glutathione could retard degenerated phenotypes in cultured disc cells. Human nucleus pulposus cells were isolated and cultured in alginate beads and subsequently treated with a pro-oxidant H2O2 alone or a pro-inflammatory cytokine IL-1β alone or either of them together with glutathione. It was shown that H2O2 dose-dependently promoted nucleus pulposus cell apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and decreased mRNA levels of matrix proteins aggrecan and type II collagen determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR). IL-1β could induce production of nitric oxide and decrease of proteoglycan, detected by the Griess reagent and the dimethylmethylene blue, respectively. The deleterious effects of either H2O2 or IL-1β could be efficiently prevented by glutathione. These results indicated that glutathione might be considered as an option for intervention of disc degeneration.
The purposes of this study were to investigate the prevalence and distribution of intervertebral disc degeneration (DD) over the entire spine using magnetic resonance imaging (MRI), and to examine the factors and symptoms potentially associated with DD.
This study included 975 participants (324 men, mean age of 67.2 years; 651 women, mean age of 66.0 years) with an age range of 21-97 years in the Wakayama Spine Study. DD on MRI was classified into Pfirrmann's system (grades 4 and 5 indicating DD). We assessed the prevalence of DD at each level in the cervical, thoracic, and lumbar regions and the entire spine, and examined DD-associated factors and symptoms.
The prevalence of DD over the entire spine was 71% in men and 77% in women aged <50 years, and >90% in both men and women aged >50 years. The prevalence of an intervertebral space with DD was highest at C5/6 (men: 51.5%, women: 46%), T6/7 (men: 32.4%, women: 37.7%), and L4/5 (men: 69.1%, women: 75.8%). Age and obesity were associated with the presence of DD in all regions. Low back pain was associated with the presence of DD in the lumbar region.
The current study established the baseline data of DD over the entire spine in a large population of elderly individuals. These data provide the foundation for elucidating the causes and mechanisms of DD.
Back pain and intervertebral disc degeneration have a growing socioeconomic healthcare impact. Information on mitochondrial function in human intervertebral disc cells, however, is surprisingly sparse. We assessed mitochondrial bioenergetics, mass, and ultrastructure in annulus cells cultured from human discs of varying degenerative stages. Citrate synthase activity (reflecting mitochondrial mass) declined significantly with increasing Thompson grade (p < 0.0001). Both mitochondrial (p = 0.009) and non-mitochondrial (p = 0.0029) respiration showed significant changes with increasing stages of disc degeneration. No significant relationships were found for the association of respiration data with herniated or non-herniated status, or with subject age. Examination of mitochondrial ultrastructure in cultured annulus cells revealed unusual features which included mitochondrial inclusion bodies, poorly defined cristae and dark staining. Findings reported here are novel and document biochemical, metabolic, and morphologic abnormalities in mitochondria in cells from more degenerated annulus cells. Data suggest that the disc degenerative, not age, is a major factor associated with mitochondrial impairment, and also implicate oxidative stress, driven by mitochondrial dysfunction, as a major component within the degenerating disc. Findings have relevance to advancements in cell-based therapies to treat disc degeneration. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res.
Objective:
To test the null hypotheses that: lumbar intervertebral discs cannot be a source of pain; discs are not a source of pain; painful lumbar discs cannot be diagnosed; and there is no pathology that causes discogenic pain.
Methods:
Philosophical essay and discourse with reference to the literature.
Results:
Anatomic and physiologic evidence denies the proposition that disc cannot be a source of pain. In patients with back pain, discs can be source of pain. No studies have refuted the ability of disc stimulation to diagnose discogenic pain. Studies warn only that disc stimulation may have a false-positive rate of 10% or less. Internal disc disruption is the leading cause of discogenic pain. Discogenic pain correlates with altered morphology on computerized tomography scan, with changes on magnetic resonance imaging, and with internal biophysical features of the disc. The morphological and biophysical features of discogenic pain have been produced in biomechanics studies and in laboratory animals.
Conclusions:
All of the null hypotheses that have been raised against the concept of discogenic pain and its diagnosis have each been refuted by one or more studies. Although studies have raised concerns, none has sustained any null hypothesis. Discogenic pain can occur and can be diagnosed if strict operational criteria are used to reduce the likelihood of false-positive results.
Low back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population. Material and
A cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18-84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition.
The major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (p<0.001) associated with non-specific LBP. The single most important risk factor was the amount of LDD. After adjustment for other risk factors, the individuals who exhibited advanced LDD (90% vs 10%) had 3.2 higher odds of manifesting LBP. The data also showed a significant (p<0.001) genetic correlation between the LBP and LDD measurements, suggesting that approximately 11-13% of the genetic effects are shared by LDD and LBP.
The main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.
Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL-1β, and TNF-α, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in human IVD degeneration. IL-1β and TNF-α stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL-1β and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule-1 (PECAM-1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL-1β is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation.
Prospective, match-cohort study of disc degeneration progression over 10 years with and without baseline discography. Objectives. To compare progression of common degenerative findings between lumbar discs injected 10 years earlier with those same disc levels in matched subjects not exposed to discography. Summary of Background Data. Experimental disc puncture in animal and in vivo studies have demonstrated accelerated disc degeneration. Whether intradiscal diagnostic or treatment procedures used in clinical practice causes any damage to the punctured discs over time is currently unknown.
Seventy-five subjects without serious low back pain illness underwent a protocol MRI and an L3/4, L4/5, and L5/S1 discography examination in 1997. A matched group was enrolled at the same time and underwent the same protocol MRI examination. Subjects were followed for 10 years. At 7 to 10 years after baseline assessment, eligible discography and controlled subjects underwent another protocol MRI examination. MRI graders, blind to group designation, scored both groups for qualitative findings (Pfirrmann grade, herniations, endplate changes, and high intensity zone). Loss of disc height and loss of disc signal were measured by quantitative methods.
Well matched cohorts, including 50 discography subjects and 52 control subjects, were contacted and met eligibility criteria for follow-up evaluation. In all graded or measured parameters, discs that had been exposed to puncture and injection had greater progression of degenerative findings compared to control (noninjected) discs: progression of disc degeneration, 54 discs (35%) in the discography group compared to 21 (14%) in the control group (P = 0.03); 55 new disc herniations in the discography group compared to 22 in the control group (P = 0.0003). New disc herniations were disproportionately found on the side of the anular puncture (P = 0.0006). The quantitative measures of disc height and disc signal also showed significantly greater loss of disc height (P = 0.05) and signal intensity (P = 0.001) in the discography disc compared to the control disc.
Modern discography techniques using small gauge needle and limited pressurization resulted in accelerated disc degeneration, disc herniation, loss of disc height and signal and the development of reactive endplate changes compared to match-controls. Careful consideration of risk and benefit should be used in recommending procedures involving disc injection.
The population of senescent disc cells has been shown to increase in degenerated or herniated discs. However, the mechanism and signaling pathway involved in the senescence of nucleus pulposus (NP) chondrocytes are unknown.
To demonstrate the mechanisms involved in the senescence of NP chondrocytes.
Senescence-related markers were assessed in the surgically obtained human NP specimens.
NP specimens remaining in the central region of the intervertebral disc were obtained from 25 patients (mean: 49 years, range: 20-75 years) undergoing discectomy. Based on the preoperative magnetic resonance images, there were 3 patients with Grade II degeneration, 17 patients with Grade III degeneration, and 5 patients with Grade IV degeneration.
We examined cell senescence markers (senescence-associated beta-galactosidase [SA-beta-gal], telomere length, telomerase activity, p53, p21, pRB, and p16) and the hydrogen peroxide (H(2)O(2)) content as a marker for an oxidative stress in the human NP specimens.
SA-beta-gal expression, telomere length, telomerase activity, and H(2)O(2) content as well as their relationships with age and degeneration grades were analyzed. For the mechanism involved in the senescence of NP chondrocytes, expressions of p53, p21, pRB, and p16 in these cells were assessed with immunohistochemistry and Western blotting.
The percentages of SA-beta-gal-positive NP chondrocytes increased with age (r=.82, p<.001), whereas the telomere length and telomerase activity declined (r=-.41, p=.045; r=-.52, p=.008, respectively) However, there was no significant correlation between age and H(2)O(2) contents (p=.18). The NP specimens with Grade III or Grade IV degeneration showed significantly higher percentages of SA-beta-gal-positive NP chondrocytes than those with Grade II degeneration (p=.01 and p=.025, respectively). Immunohistochemistry showed that the senescent NP chondrocytes in all the specimens expressed p53, p21, and pRB, but a few NP chondrocytes in only two specimens expressed p16. Western blotting showed that the expressions of p53, p21, and pRB displayed a corresponding pattern, that is, a strong p53 expression led to strong p21 and pRB expressions and vice versa.
Our in vivo study demonstrated that senescent NP chondrocytes increased or accumulated in the NP with increasing age and advancing disc degeneration. The NP chondrocytes in the aging discs exhibited characteristic senescent features such as an increased SA-beta-gal expression, shortened telomeres, and decreased telomerase activity. We further demonstrated that the telomere-based p53-p21-pRB pathway, rather than the stress-based p16-pRB pathway, plays a more important role in the senescence of NP chondrocytes in an in vivo condition. Our results suggest that prevention or reversal of the senescence of NP chondrocytes can be a novel therapeutic target for human disc degeneration.
A cross-sectional population study of magnetic resonance imaging (MRI) changes. OBJECTIVE.: To examine the pattern and prevalence of lumbar spine MRI changes within a southern Chinese population and their relationship with back pain.
Previous studies on MRI changes and back pain have used populations of asymptomatic individuals or patients presenting with back pain and sciatica. Thus, the prevalence and pattern of intervertebral disc degeneration within the population is not known.
Lumbar spine MRIs were obtained in 1043 volunteers between 18 to 55 years of age. MRI changes including disc degeneration, herniation, anular tears (HIZ), and Schmorl's nodes were noted by 2 independent observers. Differences were settled by consensus. Disc degeneration was graded using Schneiderman's classification, and a total score (DDD score) was calculated by the summation of the Schneiderman's score for each lumbar level. A K-mean clustering program was used to group individuals into different patterns of degeneration.
Forty percent of individuals under 30 years of age had lumbar intervertebral disc degeneration (LDD), the prevalence of LDD increasing progressively to over 90% by 50 to 55 years of age. There was a positive correlation between the DDD score and low back pain. L5-S1 and L4-L5 were the most commonly affected levels. Apart from the usual patterns of degeneration, some uncommon patterns of degeneration were identified, comprising of subjects with skip level lesions (intervening normal levels) and isolated upper or mid lumbar degeneration.
LDD is common, and its incidence increases with age. In a population setting, there is a significant association of LDD on MRI with back pain.