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      Melatonin modulates IL-1β-induced extracellular matrix remodeling in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration and inflammation

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          Abstract

          The inflammatory-associated factors interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are widely reported to be associated with intervertebral disc (IVD) degeneration (IVDD). N-acetyl-5-methoxytryptamine (melatonin) is a natural hormone secreted by the pineal gland which has been shown to participate in several physiological and pathological progresses, such as aging, anti-inflammation, anti-apoptosis and autophagy regulation. However, the effects of melatonin on IVD remain unclear. In the present study, we treated human nucleus pulposus cells (NPCs) with melatonin and discovered that melatonin could modulate extracellular matrix (ECM) remodeling induced by IL-1β by enhancing collagen II and aggrecan expression levels and by downregulating matrix metalloproteinase-3 (MMP-3) levels. These findings were verified by western blot and immunofluorescence assays. Intraperitoneal injection of melatonin mitigated IVDD in the rat tail puncture model. X-ray and magnetic resonance imaging (MRI), as well as hematoxylin-eosin (H&E), Safranine O-Green, Alcian blue and Celium red staining methods were adopted to evaluate IVDD grades, the structural integrity of nucleus pulposus (NP) and annulus fibrosus (AF) and the damage and calcification of the cartilage endplate. Melatonin reduced inflammatory cell aggregation and the release of the inflammatory factors IL-1β, IL-6, TNF-α as determined by immunohistochemistry. In conclusion, the present study demonstrated that melatonin could modulate ECM remodeling by IL-1β in vitro and attenuate the IVDD and induction of inflammation in a rat tail puncture model in vivo. The data demonstrated that melatonin may contribute to the restoration processs of IVD following damage and may be used as a potential novel therapy for IVDD.

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          A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture: correlation between the degree of disc injury and radiological and histological appearances of disc degeneration.

          An in vivo study to radiographically and histologically assess a new method of induction of disc degeneration. OBJECTIVE.: To establish a reproducible rabbit model of disc degeneration by puncturing the anulus with needles of defined gauges and to compare it to the classic stab model. New treatment approaches to disc degeneration are of great interest. Although animal models for disc degenerative disease exist, the quantitative measurement of disease progression remains difficult. A reproducible, progressive disc degeneration model, which can be induced in a reasonable time frame, is essential for development of new therapeutic interventions. The classic anular stab model and the new needle puncture model were used in the rabbit. For the needle puncture model, 3 different gauges of needle (16G, 18G, and 21G) were used to induce an injury to the disc to a depth of 5 mm. Radiographic and histologic analyses were performed; magnetic resonance images were also assessed in the needle puncture model. Significant disc space narrowing was observed as early as 2 weeks after stabbing in the classic stab model; there was no further narrowing of the disc space. In the needle puncture model, all needle sizes tested induced a slower and more progressive decrease in disc height than in the classic stab model. The magnetic resonance imaging supported the results of disc height data. The needle puncture approach, using 16G to 21G needles, resulted in a reproducible decrease of disc height and magnetic resonance imaging grade. The ease of the procedure and transfer of the methodology will benefit researchers studying disc degeneration.
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            Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms.

            The classic theories of aging such as the free radical theory, including its mitochondria-related versions, have largely focused on a few specific processes of senescence. Meanwhile, numerous interconnections have become apparent between age-dependent changes previously thought to proceed more or less independently. Increased damage by free radicals is not only linked to impairments of mitochondrial function, but also to inflammaging as it occurs during immune remodeling and by release of proinflammatory cytokines from mitotically arrested, DNA-damaged cells that exhibit the senescence-associated secretory phenotype (SASP). Among other effects, SASP can cause mutations in stem cells that reduce the capacity for tissue regeneration or, in worst case, lead to cancer stem cells. Oxidative stress has also been shown to promote telomere attrition. Moreover, damage by free radicals is connected to impaired circadian rhythmicity. Another nexus exists between cellular oscillators and metabolic sensing, in particular to the aging-suppressor SIRT1, which acts as an accessory clock protein. Melatonin, being a highly pleiotropic regulator molecule, interacts directly or indirectly with all the processes mentioned. These influences are critically reviewed, with emphasis on data from aged organisms and senescence-accelerated animals. The sometimes-controversial findings obtained either in a nongerontological context or in comparisons of tumor with nontumor cells are discussed in light of evidence obtained in senescent organisms. Although, in mammals, lifetime extension by melatonin has been rarely documented in a fully conclusive way, a support of healthy aging has been observed in rodents and is highly likely in humans. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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              The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration

              Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Methods Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1. Results Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. Conclusions We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                30 November 2019
                26 November 2019
                : 11
                : 22
                : 10499-10512
                Affiliations
                [1 ]Department of Spinal Surgery, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai 200120, China
                [2 ]Department of Spine Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Jun Tan; email: dr_tanjun@tongji.edu.cn
                Correspondence to: Lie Qian; email: qlspine@163.com
                Correspondence to: Yingchao Han; email: hycmed@163.com
                Article
                102472 102472
                10.18632/aging.102472
                6914432
                31772145
                ac56ffb2-57f1-4ab3-812b-94ce8f05a726
                Copyright © 2019 Zhang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 02 August 2019
                : 06 November 2019
                Categories
                Research Paper

                Cell biology
                intervertebral disc degeneration,nucleus pulposus cells,melatonin,inflammation
                Cell biology
                intervertebral disc degeneration, nucleus pulposus cells, melatonin, inflammation

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