Abstract
Cite this article: Bone Joint Res 2023;12(3):199–201.
Chronic back pain is a common reoccurring issue affecting over 570 million people globally.1 It represents the second leading cause of disability worldwide, constituting a major welfare and economic problem.2 Traditionally, the notion that the aetiology of chronic back pain is unknown in the majority of cases has been erroneously perpetuated. More emphasis has been put on identifying the precise pain generator in chronic back pain, with common causes including: radicular pain, facet joint pain, sacroiliac pain, pain related to lumbar stenosis, and discogenic pain.2 Among them, intervertebral disc degeneration is one of the most common identifiable causes of chronic back pain, and previous studies show a clear link between radiological as well as microscopic intervertebral disc (IVD) degeneration and chronic back pain.3 In a healthy adult IVD, homeostasis between extracellular matrix synthesis and degradation is controlled by growth factors and cytokines. An imbalance in the homeostasis trending towards catabolic reactions and inflammatory changes leads to structural degeneration of the IVD, likely contributing to the development of chronic back pain.3,4 In order to overcome the burden of chronic back pain, research efforts have been focused on investigating the molecular aspects of the IVD degeneration pathophysiology along with novel therapeutic approaches, such as Suramin (a medication normally used to treat African sleeping sickness and river blindness).5
In this month’s edition of Bone & Joint Research, two studies present the role of inflammation on human IVD cells. Ruiz-Fernández et al6 demonstrated that monomeric CRP (mCRP) increases nitric oxide synthase 2 (NOS2), cyclooxygenase-2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion protein 1 (VCAM1), interleukin 6 (IL-6), interleukin 8 (IL-8), and lipocalin 2 (LCN2) expression in annulus fibrosus (AF) cells and in the human nucleus pulposus (NP) immortalized cell lines, revealing for the first time functional activity of mCRP in healthy and degenerative human AF and NP disc cells. The authors highlight that mCRP induces sustained multigenic inflammatory responses in healthy tissues without previous exposure to a pro-inflammatory micro-environment. The study by Ruiz-Fernández et al6 shows that the effect of mCRP in healthy and degenerative AF cells is mediated by phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK 1/2), and Nuclear Factor-kappaB (NF-κβ) p65 signalling pathways. Another important aspect of this research is that mCRP has multiple cell targets and that the above mCRP mediators are activated in a similar manner both in healthy and degenerative AF disc cells, confirming that mCRP action does not depend on a previous inflammatory state. Overall, mCRP induces the expression of multiple pro-inflammatory and catabolic factors in human IVD cells. This finding suggests that even in healthy tissues, systemic inflammation can have a molecular influence on IVD tissues and, over the span of a lifetime, it is likely to have a degenerative effect. On the other hand, local mechanical loading from inappropriate posture or body habitus can also contribute to pro-inflammatory processes impacting IVD degeneration.7
In a review by Molinos et al,8 several techniques aimed at decreasing IVD inflammation have been discussed including injectable molecules, such as interleukin 1 (IL-1) inhibitors or tumour necrosis factor alpha (TNF-α) blockers.8,9 Gene therapy based on transforming growth factor beta 1 (TGF-β1) transfection of rabbit IVD cells shows potential to enhance proteoglycan synthesis and, therefore, reverse degenerative processes.10 Nevertheless, both techniques are expensive, and their application in the wider general public to decrease IVD degeneration is unrealistic and still poses many risks associated with side effects of the therapy. In this line of research, the anti-inflammatory and protective properties of melatonin on nucleus pulposus cells (NPCs) were described by Ruiz-Fernández et al6 in this month’s edition of Bone & Joint Research.
Melatonin is secreted principally by the pineal gland at night under normal environmental conditions, controlling the sleep-wake cycle.11 The role of melatonin on human health has been a topic of recent research interest, with studies highlighting that sunlight and melatonin increase health and lifespan.12,13 The study by Bai et al14 is the first to highlight that NPCs derived from patient intervertebral discs express melatonin receptors and their activation decreases cellular pyroptosis, the inflammatory cell death process, induced by reactive oxygen species. Pretreatment with 50 nM of melatonin for 24 hours before treatment of hydrogen peroxide significantly upregulated the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) transcription factor and downregulated the pyroptosis-related protein NLRP3, cleaved casp-1, and cleaved IL-1β. Furthermore, the expression of Nrf2 was altered when the melatonin receptor was activated or inhibited, revealing that Nrf2 was downstream of the melatonin receptor. In this line of research, the study by Bai et al14 demonstrated that the protective effect of melatonin on pyroptosis depends on the Nrf2 upregulation. Importantly, by showing for the first time the presence of melatonin receptors MT-1A-R in human NPCs, Bai et al14 clarified that melatonin functions via the melatonin receptor. Overall, by elucidating melatonin’s significant role in cellular response to inflammation, which contributes to tissue destabilization and back pain, there is a hope to streamline larger future efforts investigating population sunlight-based interventions. The therapeutic and beneficial effect of sunlight and melatonin is widely documented in the literature, such as reducing the risk of dementia as well as reducing postoperative pain and increasing recovery.15,16 Melatonin has even been reported to affect the degree of osseointegration of titanium implants.17 Danilov and Kurganova18 also discuss the involvement of melatonin efficacy in relation to pain syndromes. In a similar vein, other studies have shown that bright light therapy, even in low doses, improves perceived pain intensity in patients who suffer from chronic back pain.19
In conclusion, chronic back pain is a major global problem and inflammation of IVD seems to be at the centre of it, however the pathophysiology of disc degeneration, the epigenetics, and therapeutic approaches remain unclear. Nevertheless, the papers in this month’s edition of Bone & Joint Research show a link between the susceptibility to inflammatory changes, IVD degeneration, and the anti-inflammatory role of melatonin in IVD. Increasing exposure to freely accessible sunlight can potentially be a consistent, cost-effective, and clinically acceptable method in preventing chronic back pain and in increasing quality of life in the ageing population.
References
1. Wu A , March L , Zheng X , et al. Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017 . Ann Transl Med . 2020 ; 8 ( 6 ): 299 . Crossref PubMed Google Scholar
2. Allegri M , Montella S , Salici F , et al. Mechanisms of low back pain: a guide for diagnosis and therapy . F1000Res . 2016 ; 5 : F1000 Faculty Rev-1530 . Crossref PubMed Google Scholar
3. Sampara P , Banala RR , Vemuri SK , Av GR , Gpv S . Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review . Gene Ther . 2018 ; 25 ( 2 ): 67 – 82 . Crossref PubMed Google Scholar
4. Ruiz-Fernández C , Francisco V , Pino J , et al. Molecular relationships among obesity, inflammation and intervertebral disc degeneration: Are adipokines the common link? Int J Mol Sci . 2019 ; 20 ( 8 ): 2030 . Crossref PubMed Google Scholar
5. Liu Z-M , Lu C-C , Shen P-C , et al. Suramin attenuates intervertebral disc degeneration by inhibiting NF-κB signalling pathway . Bone Joint Res . 2021 ; 10 ( 8 ): 498 – 513 . Crossref PubMed Google Scholar
6. Ruiz-Fernández C , Ait Eldjoudi D , González-Rodríguez M , et al. Monomeric CRP regulates inflammatory responses in human intervertebral disc cells . Bone Joint Res . 2023 ; 12 ( 3 ): 189 – 198 . Crossref PubMed Google Scholar
7. Gawri R , Rosenzweig DH , Krock E , et al. High mechanical strain of primary intervertebral disc cells promotes secretion of inflammatory factors associated with disc degeneration and pain . Arthritis Res Ther . 2014 ; 16 ( 1 ): R21 . Crossref PubMed Google Scholar
8. Molinos M , Almeida CR , Caldeira J , Cunha C , Gonçalves RM , Barbosa MA . Inflammation in intervertebral disc degeneration and regeneration . J R Soc Interface . 2015 ; 12 ( 104 ): 20141191 . Crossref PubMed Google Scholar
9. Goupille P , Mulleman D , Paintaud G , Watier H , Valat JP . Can sciatica induced by disc herniation be treated with tumor necrosis factor alpha blockade? Arthritis Rheum . 2007 ; 56 ( 12 ): 3887 – 3895 . Crossref PubMed Google Scholar
10. Nishida K , Kang JD , Gilbertson LG , et al. Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene . Spine (Phila Pa 1976) . 1999 ; 24 ( 23 ): 2419 – 2425 . Crossref PubMed Google Scholar
11. Claustrat B , Brun J , Chazot G . The basic physiology and pathophysiology of melatonin . Sleep Med Rev . 2005 ; 9 ( 1 ): 11 – 24 . Crossref PubMed Google Scholar
12. Karami Z , Golmohammadi R , Heidaripahlavian A , Poorolajal J , Heidarimoghadam R . Effect of daylight on melatonin and subjective general health factors in elderly people . Iran J Public Health . 2016 ; 45 ( 5 ): 636 – 643 . PubMed Google Scholar
13. van der Rhee HJ , de Vries E , Coebergh JW . Regular sun exposure benefits health . Med Hypotheses . 2016 ; 97 : 34 – 37 . Crossref PubMed Google Scholar
14. Bai Z , Shou Z , Hu K , Yu J , Meng H , Chen C . Melatonin protects human nucleus pulposus cells from pyroptosisby regulating Nrf2 via melatonin membrane receptors . Bone Joint Res . 2023 ; 12 ( 3 ): 202 – 211 . Google Scholar
15. Hoel DG , Berwick M , de Gruijl FR , Holick MF . The risks and benefits of sun exposure 2016 . Dermatoendocrinol . 2016 ; 8 ( 1 ): e1248325 . Crossref PubMed Google Scholar
16. Walch JM , Rabin BS , Day R , Williams JN , Choi K , Kang JD . The effect of sunlight on postoperative analgesic medication use: a prospective study of patients undergoing spinal surgery . Psychosom Med . 2005 ; 67 ( 1 ): 156 – 163 . Crossref PubMed Google Scholar
17. Zhou MS , Tao ZS . Systemic administration with melatonin in the daytime has a better effect on promoting osseointegration of titanium rods in ovariectomized rats . Bone Joint Res . 2022 ; 11 ( 11 ): 751 – 762 . Crossref PubMed Google Scholar
18. Danilov A , Kurganova J . Melatonin in chronic pain syndromes . Pain Ther . 2016 ; 5 ( 1 ): 1 – 17 . Crossref PubMed Google Scholar
19. Burns JW , Gerhart J , Rizvydeen M , Kimura M , Burgess HJ . Morning bright light treatment for chronic low back pain: Potential impact on the volatility of pain, mood, function, and sleep . Pain Med . 2020 ; 21 ( 6 ): 1153 – 1161 . Crossref PubMed Google Scholar
Author contributions
J. Brzeszczyńska: Conceptualization, Writing – original draft.
F. Brzeszczyński: Writing – review & editing.
Funding statement
The authors received no financial or material support for the research, authorship, and/or publication of this article.
Follow J. Brzeszczyńska @JBrzeszczynska
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© 2023 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/
