Abstract
Lower back pain (LBP) is a common degenerative musculoskeletal disease that imposes a huge economic burden on both individuals and society. With the aggravation of social aging, the incidence of LBP has increased globally. Intervertebral disc degeneration (IDD) is the primary cause of LBP. Currently, IDD treatment strategies include physiotherapy, medication, and surgery; however, none can address the root cause by ending the degeneration of intervertebral discs (IVDs). However, in recent years, targeted therapy based on specific molecules has brought hope for treating IDD. The tumor suppressor gene p53 produces a transcription factor that regulates cell metabolism and survival. Recently, p53 was shown to play an important role in maintaining IVD microenvironment homeostasis by regulating IVD cell senescence, apoptosis, and metabolism by activating downstream target genes. This study reviews research progress regarding the potential role of p53 in IDD and discusses the challenges of targeting p53 in the treatment of IDD. This review will help to elucidate the pathogenesis of IDD and provide insights for the future development of precision treatments.
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Facts
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IDD is considered to be an IVD cell-mediated degeneration process involving molecules, cells and tissues, which impairs the load-bearing capacity of IVD by affecting its tissue composition and biomechanical properties.
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As a transcription factor, p53 is the central hub of the molecular network that controls cell metabolism and survival, and regulates protein expression in various cellular processes.
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In IDD, p53 is activated by multiple stress signals and exhibits different dynamic characteristics, which can lead to different cell fates.
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p53 is involved in various signal transduction pathways in IVD cells, and participates in the IDD process by influencing IVD cell aging, apoptosis, ECM metabolism, and oxidative stress.
Open questions
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In IDD, what are the changes in the dynamic characteristics of p53 in the face of different stress signals?
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What is the role of p53 in signal transduction and phenotypic changes of IVD cells?
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What are the implications of p53 in the formulation of accurate treatment strategies for IDD?
Introduction
Lower back pain (LBP) is a major musculoskeletal disorder that leads to limited mobility and decreased quality of life in elderly individuals worldwide [1]. With the intensification of aging, the overall disability associated with LBP is on the rise globally [2, 3] and is most pronounced in low- and middle-income countries [4]. According to limited data, the one-year prevalence of LBP among adults in Africa and Latin America is 57% and 67%, respectively [5, 6]. The lifetime prevalence rate can be as high as 93% [7]. LBP seriously affects the quality of life of patients and creates a huge economic burden. In the United States, the total cost associated with LBP exceeds $100 billion annually [8], and the cost of spinal surgery in Brazil increased by 540% between 1995 and 2014 [9]. Intervertebral disc degeneration (IDD) is the primary cause of LBP [10]. However, the specific pathogenic mechanisms underlying IDD remain unclear. Currently, IDD is considered a degenerative process involving molecules, cells, and tissues mediated by intervertebral disc (IVD) cells that can lead to significant changes in IVD tissue composition and biomechanical properties, ultimately impairing the ability of IVDs to withstand loads [11] (Fig. 1). Currently, the treatment options for IDD include drugs and surgery, which relieve symptoms and reduce the incidence of disability; however, both treatment options have the disadvantages of multiple complications, high costs, and unknown efficacy [12] (Fig. 2). Neither approach resolves the underlying pathology by terminating the degenerative process of IVDs, and both are only applicable to end-stage disease. Therefore, it is important to further explore the pathogenic factors and related molecular mechanisms of IDD to guide treatment.
The IVD is a complex avascular connective tissue between the vertebrae, mainly composed of the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate (CEP). Additionally, it connects the spine, cushions spinal pressure, and increases spinal mobility [13,14,15]. As an age-related, multifactorial disease, the etiology of IDD remains unclear. Genetic susceptibility, age, obesity, smoking, occupational exposure, trauma, and abnormal nonphysiological mechanical loads contribute to its occurrence and progress [16,17,18,19,20,21] (Fig. 3). The proper mechanical function of the IVD depends on the quality and composition of the extracellular matrix (ECM) [22]. However, in the process of IVD degeneration, a series of internal, external, physical, or chemical factors promote the death and aging of IVD cells, leading to a decrease in the number of functional and viable cells and, thus, a decline in ECM synthesis [23, 24]. At the same time, dysfunctional IVD cells highly express matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which further promote ECM degradation [ The incidence and burden of IDD, an age-related disease, are increasing annually worldwide [3]. Currently, the treatment of IDD mainly includes conservative and surgical treatments, both aimed at relieving clinical symptoms. Therefore, the further exploration of the pathogenic mechanism of IDD and the adoption of targeted treatment strategies are current research hotspots. Recent studies have shown that p53 plays an important role in the occurrence and progression of IDD, and the inhibition of p53 overactivation in IVD may help delay the progression of IDD. However, extensive p53 inhibition may not be an applicable approach to alleviate IDD because the negative effects of this approach cannot be ignored. Therefore, p53-targeted functional inhibitors in combination with exosomes, biomaterials, and cellular therapies may yield greater benefits (Fig. 8). In 1999, to reduce the serious side effects of p53-mediated chemotherapy and radiotherapy in cancer, Komarov et al. [308] isolated a small fraction of PFT to block the side effects caused by p53-dependent transcriptional activation. PFT protected mice from p53-related cell death induced by radiation and multiple cytotoxic drugs without promoting tumor formation [308]. Studies have confirmed that PFT can alleviate adriamycin-induced apoptosis in human umbilical vein endothelial cells by inhibiting basic and induced levels of the p53 protein [309]. In IDD, compression treatment induces NPC apoptosis by promoting the mitochondrial translocation of p53. In contrast, PFT significantly attenuates compression-induced NPC apoptosis and alleviates IDD progression by inhibiting p53 mitochondrial translocation [109]. These results suggest that PFT may delay the progression of IDD; however, further basic and clinical studies are needed to determine the optimal dose and route of administration. In addition to the typical full-length p53, TP53 produces at least 12 truncated subtypes through the alternative initiation of translation, the use of alternative promoters, and alternative splicing, which can positively or negatively regulate the activity and function of full-length p53 [281, 310]. Among these p53 isoforms, Δ133p53α and p53β are thought to be endogenous regulators of cellular senescence [311]. Under stress conditions, p53β forms a complex with full-length p53, which in turn enhances the transcriptional activities of the Bax and p21 promoters, suggesting that p53β acts synergistically with full-length p53 to induce apoptosis and senescence [281, 311]. ∆133p53α acts in contrast to p53β. ∆133p53α was abundantly expressed in early-passage normal human fibroblasts and was significantly reduced in late-passage and senescent cells, mainly due to excessive autophagic degradation of ∆133p53α in senescent cells [311]. In addition, in Hutchinson–Gilford progeria syndrome (HGPS) fibroblasts, ∆133p53α inhibited cellular senescence by downregulating the p53 senescence-associated genes p21 and miR-34a. ∆133p53α overexpression restored the replicative capacity of HGPS fibroblasts [312]. As mentioned above, the selective, dominant-negative effect of ∆133p53α on full-length p53 suggests that ∆133p53α may be a potent target for the inhibition of cellular senescence. However, the expression and role of 133p53α in IVD cells are unclear, and more studies are needed. Numerous natural compounds have been investigated for their p53-inhibitory activities in the context of IDD. Naringin (Nar) and eupatilin (Eup), the primary flavonoids derived from Citrus and Artemisia, respectively, have been demonstrated to possess diverse biological effects [313, 314]. Both Nar and Eup regulate the expression of Col II, Agg, MMP-3, MMP-13, and ADAMTS-4 to maintain a high-quality ECM [68, 136]. Moreover, Eup suppresses TNF-α-induced senescence of NP cells through the downregulation of p21 and p53 expression [68]. Related mechanistic studies have shown that Nar and Eup can protect NPCs from damage by inhibiting the NF-κB/p53 signaling axis. In addition to Nar and Eup, quercetin (Que) and myricetin (Myr) belong to a family of natural flavonoids found in plants that exhibit anti-inflammatory, anti-aging, and antioxidant properties [315, 316]. Que and Myr can mitigate oxidative stress-induced IVD cell senescence by activating the SIRT1 signaling pathway, thereby inhibiting p53 expression [317, 318]. Morroniside (Mor), which belongs to the class of iridoid glycosides [319], has been reported to effectively attenuate H2O2-induced NP cell senescence by modulating the ROS-Hippo-p53 signaling pathway [101]. In vivo, Mor significantly ameliorated lumbar disc degeneration in rats after an 8-week treatment period. Furthermore, the inhibition of p53 by proanthocyanidins and resveratrol has been documented to effectively impede the progression of IDD [156, 320]. IDD is the initial step in the evolution and progression of a range of degenerative spinal disorders and is a major cause of LBP and disability, the prevalence of which increases with age [321]. Currently, the main treatment for IDD is to control the clinical symptoms through physiotherapy, oral drugs, and surgery; however, it is not to prevent the progression of IDD or reverse its degeneration by treating the causes of degenerative disease [322]. However, these methods lead to a high recurrence rate, treatment cost, and risk of adjacent IVD degeneration [323]. Therefore, the pathogenic mechanisms of IDD and the development of targeted therapeutic approaches are major clinical issues that must be addressed. Transcription factor p53 plays an important role in malignant tumors, cardiovascular diseases, neurodegenerative diseases, and osteoarticular diseases by regulating cell cycle progression, senescence, apoptosis, angiogenesis, DNA repair, and cell metabolism [44, 45, 138, 324]. Recent studies have shown that p53 activation and signal transduction maintain homeostasis in IVD. p53 reduces the number of normal IVD cells by activating intrinsic death mechanisms and senescence-related genes in IVD cells. In contrast, p53 alters the microenvironment where IVD cells survive by promoting the expression of a metabolic phenotype characterized by SASP, leading to an imbalance between anabolic and catabolic cellular metabolism and a decrease in IVD ECM content. The combined action of these two factors promotes abnormal changes in the organizational structure of the IVD, eventually leading to IDD. Current research suggests that inhibiting the activation of p53 and its downstream signaling pathways delays the progression of IDD. However, a few studies have shown that p53 plays an important role in maintaining the activity and functional integrity of NPCs under low-glucose conditions [72]. This suggests that p53 may play different roles at different stages of IDD. Further studies are required to elucidate the role of p53. Studies have shown that p53 responds differently based on the severity and duration of stimulation. Mild and transient stimuli induce the repair of cell damage and transient growth arrest. In contrast, severe and sustained stimuli can lead to cell senescence and apoptosis [325]. Currently, studies on p53 in IDD mainly focus on the dynamic changes and role of p53 in late degeneration and severe stress. However, the dynamic changes and activation of related signaling pathways of p53 in early-stage IVD and sublethal stress have not yet been elucidated. Therefore, future studies should focus on the expression pattern of p53 in the early stages of IDD and its role in related phenotypic changes to explore targeted treatment strategies. In addition, studies on the role of p53 in IDD are still in the exploratory stage, with most studies focusing on rodent models. However, there are still certain species-specific differences in the shape, size, and biochemical composition of the IVDs and the anatomical structure of the spine between rodents and large mammals [326], which makes many current studies inapplicable to human IDD, making it difficult to guide treatment. Therefore, selecting an appropriate animal model is significant for future basic research and clinical applications. Therefore, sheep may be more suitable than rodents for studying human IDD. Sheep IVDs have a shape and size similar to human IVDs and do not exhibit the persistence of notochord cells with age [323]. Additionally, current studies have focused on the NP, and future treatments should focus on the synergistic recovery of the NP, AF, and CEP. Simultaneously, because the progression of IDD is a chronic process, the long-term efficacy of related treatment strategies must be evaluated. In conclusion, the molecular mechanism underlying the potential role of p53 in IDD has not yet been fully elucidated and requires further investigation. Future research should focus on the role of p53 in early IDD, which appears to be crucial for further elucidation of its pathogenesis and the development of targeted therapies.p53-related targeted therapy
p53 inhibitor
p53 homologous sequence
Natural molecules
Conclusions and prospects
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Acknowledgements
This work was supported by the Key Research and Development Program of Shaanxi Province (Program No. 2021SF-237), the Key Research and Development Program of Shaanxi Province (Program No. 2021SF-250) and the Cultivation Project of **’an Health and Construction Commission (Program No.2021ms10).
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Wang, Y., Hu, S., Zhang, W. et al. Emerging role and therapeutic implications of p53 in intervertebral disc degeneration. Cell Death Discov. 9, 433 (2023). https://doi.org/10.1038/s41420-023-01730-5
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DOI: https://doi.org/10.1038/s41420-023-01730-5
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