Molecular therapy for disk degeneration and pain.
Ontology highlight
ABSTRACT:
SUBMITTER: Mwale F
PROVIDER: S-EPMC3854687 | biostudies-other | 2013 Jun
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Intervertebral disks are biologically regulated by the maintenance of a balance between the anabolic and catabolic activities of disk cells. Therapeutic agents, initially evaluated using in vitro studies on disk cells and explants, have been used as intradiscal injections in preclinical settings to test in vivo efficacy. These include anabolic growth factors, other biostimulatory agents, and antagonistic agents against matrix-degrading enzymes and cytokines. Additional work is needed to identify patient populations, using methods such as MRI, and to better understand the mechanism of healing. Clinical trials are underway for a few of these agents and other promising candidates are on the horizon.
| S-EPMC4029337 | biostudies-literature
Project description:Although degeneration of the intervertebral disk has historically been described as a misbalance between anabolic and catabolic factors, the role of inflammatory mediators has long been neglected. However, past research clearly indicates that inflammatory mediators such as interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor-α are expressed at higher levels in "diseased" intervertebral disks. Both disk cells as well as invading macrophages can be the source of the detected cytokines. Importantly, occurrence of inflammatory mediators in the disk can worsen the progress of degeneration by inducing the expression of matrix degrading enzymes as well as by inhibiting extracellular matrix synthesis. In addition, inflammatory mediators play a crucial role in pain development during intervertebral disk herniation (i.e., sciatica) and disk degeneration (i.e., discogenic pain). This review provides information on the most relevant inflammatory mediators during different types of disk diseases and explains how these factors can induce disk degeneration and the development of discogenic and sciatic/radiculopathic pain.
| S-EPMC3854585 | biostudies-other
Project description:Degeneration of the intervertebral disk and its treatments are currently intensely investigated topics. Back pain is a condition whose chronic and debilitating nature combined with its prevalence make it a major health issue of substantial socioeconomic importance. Although researchers, and even sometimes clinicians, focus on the degenerated disk as the problem, to most patients, pain is the factor that limits their function and impacts their well-being. The purpose of this review is to delineate the changes associated with disk degeneration and to outline mechanisms by which they could be the source of back pain. Although the healthy disk is only innervated in the external layer of its annulus fibrosus, adjacent structures are plentiful with nociceptive receptors. Stimulation of such structures as a consequence of processes initiated by disk degeneration is explored. The concept of discogenic pain and possible mechanisms such as neoinnervation and solute transport are discussed. Finally, how such pain mechanisms may relate to current and proposed treatment strategies is discussed.
| S-EPMC3854582 | biostudies-other
Project description:Degeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats.Disk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model.After removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model.Although similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration.
| S-EPMC3308099 | biostudies-literature
Project description:Low back pain (LBP) is the world's most debilitating condition. Disk degeneration has been regarded as a strong determinant associated with LBP. Overweight and obesity are public health concerns that affect every population worldwide and whose prevalence continues to rise. Studies have indicated strong associations between overweight/obesity and disk degeneration as well as with LBP. This broad narrative review article addresses the various mechanisms that may be involved leading to disk degeneration and/or LBP in the setting of overweight/obesity. In particular, our goal is to raise awareness of the role of fat cells and their involvement via altered metabolism or the release of adipokines as well as other pathways that may lead to the development of disk degeneration and LBP. Understanding the role of fat in this process may aid in the development of novel biological therapies and technologies to halt the progression or regenerate the disk. Moreover, with genetic advancements and the appreciation of genetic epidemiology, a more personalized approach to spine care may have to consider the role of fat in any preventative, therapeutic, and/or prognosis modalities toward the disk and LBP.
| S-EPMC3854598 | biostudies-other
Project description:Intervertebral disk (IVD) degeneration is a natural progression of the aging process. Degenerative disk disease (DDD) is a pathologic condition associated with IVD that has been associated with chronic back pain. There are a variety of different mechanisms of DDD (genetic, mechanical, exposure). Each of these pathways leads to a final common result of unbalancing the anabolic and catabolic environment of the extracellular matrix in favor of catabolism. Attempts have been made to gain an understanding of the process of IVD degeneration with in Vitro studies. These models help our understanding of the disease process, but are limited as they do not come close to replicating the complexities that exist with an in Vivo model. Animal models have been developed to help us gain further understanding of the degenerative cascade of IVD degeneration In Vivo and test experimental treatment modalities to either prevent or reverse the process of DDD. Many modalities for treatment of DDD have been developed including therapeutic protein injections, stem cell injections, gene therapy, and tissue engineering. These interventions have had promising outcomes in animal models. Several of these modalities have been attempted in human trials, with early outcomes having promising results. Further, increasing our understanding of the degenerative process is essential to the development of new therapeutic interventions and the optimization of existing treatment protocols. Despite limited data, biological therapies are a promising treatment modality for DDD that could impact our future management of low back pain.
| S-EPMC5585783 | biostudies-other
Project description:Intervertebral disk (IVD) degeneration is a prevalent age-associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age-related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO-deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.
| S-EPMC6156454 | biostudies-literature
Project description:Intervertebral disk degeneration (IVDD) is a leading cause of disability. The degeneration is inevitable, and the mechanisms are complex. Current therapeutic strategies mainly focus on the relief of symptoms, not the intrinsic regeneration of the intervertebral disk (IVD). Tissue engineering is a promising strategy for IVDD due to its ability to restore a healthy microenvironment and promote IVD regeneration. This review briefly summarizes the IVD anatomy and composition and then sets out elements of the microenvironment and the interactions. We rationalized different scaffolds based on tissue engineering strategies used recently. To fulfill the complete restoration of a healthy IVD microenvironment, we propose that various tissue engineering strategies should be combined and customized to create personalized therapeutic strategies for each individual.
| S-EPMC8329559 | biostudies-literature
Project description:Intervertebral disk degeneration (IDD) is strongly associated with genetic predisposition and environmental susceptibility. Several studies been conducted to investigate the potential association between IDD and FokI polymorphism located in the gene encoding the vitamin D receptor (VDR), and inconsistent conclusions had been reached among different ethnic populations. In order to assess the association between the FokI polymorphism and the risk of IDD, we performed a comprehensive and systematic meta-analysis. Candidate articles were retrieved from PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and China Biology Medical (CBM) with strict inclusion criteria in January 2015. Among the 54 articles that were retrieved, only eight studies met the inclusion criteria. The pooled data analysis based on allele contrast, homozygote, heterozygote, dominant, and recessive models revealed no significant correlation between the FokI polymorphism and the risk of IDD. However, when stratified by ethnicity, significant associations were detected for Hispanics based on allele contrast (OR=1.395, 95% CI=1.059-1.836, P=0.018), homozygote (OR=1.849, 95% CI=1.001-3.416, P=0.049), heterozygote (OR=1.254, 95% CI=1.049-1.498, P=0.013), and dominant (OR=1.742, 95% CI=1.174-2.583, P=0.006) models, and for Asians using the dominant model (OR=1.293, 95% CI=1.025-1.632, P=0.030), whereas there is no significant association detected for Caucasians. In conclusion, FokI polymorphism is not generally associated with IDD, but there is increased risk for IDD in Hispanics and Asians carrying FokI allele T.
| S-EPMC4747649 | biostudies-literature
Project description:The intervertebral disk degeneration (IDD) and its associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. IDD progresses with age, leading to spondylosis, spondylarthrosis, intervertebral disk herniation, and spinal stenosis. The purpose of this review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines in IDD and to appreciate the prognostic value of cytokine imbalance as its biomarker. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to the maintenance or alteration of cytokine balance may be a new key to unlocking the mystery of IDD development and new therapeutic strategies for the treatment of IDD in the setting of acute and chronic inflammation. The presented data support the hypothesis that cytokine imbalance is one of the most important biomarkers of IDD.
| S-EPMC9917299 | biostudies-literature