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      An in‐depth analysis of the immunomodulatory mechanisms of intervertebral disc degeneration

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          Abstract

          Intervertebral disc degeneration (IVDD) is the pathological basis of disc herniation, spinal stenosis, and other related diseases, and the lower back pain it produces lays a heavy financial burden on individuals and society. Thus, it is essential to comprehend IVDD's pathophysiology. Numerous factors, such as inflammatory factors, oxidative stress, apoptosis, matrix metalloproteinases, are linked to IVDD pathogenesis. Despite the fact that many researches has provided explanations for the pathophysiology of IVDD, these studies are typically singular, restricted, and isolated, expound only on one or two components, and do not systematically analyze and summarize the numerous influencing elements. In addition, we discovered that the incidence of many chronic diseases in the field of orthopedics may be thoroughly and systematically defined in terms of immunological systems. In order to provide a theoretical foundation for an in‐depth understanding of the pathological process of IVDD and the formulation of more effective prevention and treatment measures, this review provides a comprehensive and systematic account of the pathogenesis of IVDD from the physical to the molecular barriers of the intervertebral disc, from the nucleus pulposus tissue to the cellular to the immune‐molecular level.

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          What low back pain is and why we need to pay attention

          Low back pain is a very common symptom. It occurs in high-income, middle-income, and low-income countries and all age groups from children to the elderly population. Globally, years lived with disability caused by low back pain increased by 54% between 1990 and 2015, mainly because of population increase and ageing, with the biggest increase seen in low-income and middle-income countries. Low back pain is now the leading cause of disability worldwide. For nearly all people with low back pain, it is not possible to identify a specific nociceptive cause. Only a small proportion of people have a well understood pathological cause-eg, a vertebral fracture, malignancy, or infection. People with physically demanding jobs, physical and mental comorbidities, smokers, and obese individuals are at greatest risk of reporting low back pain. Disabling low back pain is over-represented among people with low socioeconomic status. Most people with new episodes of low back pain recover quickly; however, recurrence is common and in a small proportion of people, low back pain becomes persistent and disabling. Initial high pain intensity, psychological distress, and accompanying pain at multiple body sites increases the risk of persistent disabling low back pain. Increasing evidence shows that central pain-modulating mechanisms and pain cognitions have important roles in the development of persistent disabling low back pain. Cost, health-care use, and disability from low back pain vary substantially between countries and are influenced by local culture and social systems, as well as by beliefs about cause and effect. Disability and costs attributed to low back pain are projected to increase in coming decades, in particular in low-income and middle-income countries, where health and other systems are often fragile and not equipped to cope with this growing burden. Intensified research efforts and global initiatives are clearly needed to address the burden of low back pain as a public health problem.
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            Role of cytokines in intervertebral disc degeneration: pain and disc content.

            Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.
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              AP-1 as a regulator of cell life and death.

              The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death. Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these processes were recently identified. Interestingly, the growth-promoting activity of c-Jun is mediated by repression of tumour suppressors, as well as upregulation of positive cell cycle regulators. Mostly, c-Jun is a positive regulator of cell proliferation, whereas JunB has the converse effect. The intricate relationships between the different Jun proteins, their activities and the mechanisms that mediate them will be discussed.
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                Author and article information

                Contributors
                565409672@qq.com
                Journal
                JOR Spine
                JOR Spine
                10.1002/(ISSN)2572-1143
                JSP2
                JOR Spine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2572-1143
                08 December 2022
                December 2022
                : 5
                : 4 ( doiID: 10.1002/jsp2.v5.4 )
                : e1233
                Affiliations
                [ 1 ] Department of Orthopedics and Traumatology (Trauma and Bonesetting) The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University Luzhou China
                Author notes
                [*] [* ] Correspondence

                Zongchao Liu, Department of Orthopedics and Traumatology (Trauma and Bonesetting), No. 182, Chunhui Road, Longmatan District, Luzhou 646000, Sichuan,China.

                Email: 565409672@ 123456qq.com

                Author information
                https://orcid.org/0000-0003-0611-4298
                Article
                JSP21233
                10.1002/jsp2.1233
                9799087
                36601372
                fd0f30e3-907c-4206-8cb9-d5d097931bee
                © 2022 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 September 2022
                : 02 August 2022
                : 20 October 2022
                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 8459
                Funding
                Funded by: Department of Science and Technology of Sichuan Province , doi 10.13039/501100004829;
                Award ID: 22ZDYF0512
                Funded by: The Program for Luzhou Municipal People's Government ‐ Southwest Medical University Science and Technology Strategic Cooperation Climbing Project
                Award ID: 2021LZXNYD‐D02
                Funded by: Sichuan Provincial Administration of Traditional Chinese Medicine Special Project on Traditional Chinese Medicine
                Award ID: 2020LC0228
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                December 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:29.12.2022

                cell death mode,immune regulation,intervertebral disc degeneration,signaling pathway

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