Cadmium-induced annulus fibrosus cell senescence contributes to intervertebral disc degeneration via the JNK/p53 signaling pathway

Document Type : Original Article

Authors

1 Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China

2 Department of Orthopedics, Dalian Medical University, Dalian 116000, Liaoning, China

Abstract

Objective(s): Investigating the impact of cadmium (Cd) on annulus fibrosus (AF) cells and its potential mechanism was the purpose of the current study.
Materials and Methods: Cd was cultivated in different concentrations (0, 1, 5, 10, and 20 μM) on AF cells and the potential effects of the metal were assessed. Using the CCK-8 method, cell viability and proliferation were identified. Using transcriptome analysis, the annulus fibrosus cells were sequenced both with and without cadmium chloride. The EdU method was used to determine the rate of cell proliferation; senescence-associated β-galactosidase (SA-β-Gal) staining was used to determine the number of positive cells; and western blot, RT-PCR, and immunofluorescence were used to determine the protein and mRNA expression of senescence-associated proteins (p16, p21, and p53) and c-Jun N-terminal kinase (JNK).
Results: According to the findings, Cd has the ability to increase the production of senescence-associated genes (p16 and p21) and senescence-associated secreted phenotype (SASP), which includes IL-1β and IL-6. Through the JNK/p53 signal pathway, Cd exposure simultaneously accelerated AF cell senescence and promoted SASP. Following JNK inhibitor (SP600125) treatment, the expression of p53, JNK, and senescence-associated indices were all down-regulated.
Conclusion: By activating the JNK/p53 signaling pathway, Cd can induce oxidative stress damage and AF cell senescence. These findings could provide a new approach for treating and preventing intervertebral disc degeneration (IVDD) caused by Cd exposure.

Keywords

Main Subjects

References

1. Foster NE, Anema JR, Cherkin D, Chou R, Cohen SP, Gross DP, et al. Prevention and treatment of low back pain: Evidence, challenges, and promising directions. Lancet 2018; 391:2368-2383.
2. Hoy D, March L, Brooks P, Blyth F, Woolf A, Bain C, et al. The global burden of low back pain: Estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014; 73:968-974.
3. Driscoll T, Jacklyn G, Orchard J, Passmore E, Vos T, Freedman G, et al. The global burden of occupationally related low back pain: Estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014; 73:975-981.
4. Zhang S, Hu B, Liu W, Wang P, Lv X, Chen S, et al. The role of structure and function changes of sensory nervous system in intervertebral disc-related low back pain. Osteoarthritis Cartilage 2021; 29:17-27.
5. Cazzanelli P, Wuertz-Kozak K. MicroRNAs in intervertebral disc degeneration, apoptosis, inflammation, and mechanobiology. Int J Mol Sci 2020; 21:3601-3615.
6. Maher C, Underwood M, Buchbinder R. Non-specific low back pain. Lancet 2017; 389:736-747.
7. Elmasry S, Asfour S, de Rivero Vaccari JP, Travascio F. Effects of tobacco smoking on the degeneration of the intervertebral disc: A finite element study. PLoS One 2015; 10:e0136137-136158.
8. Schutte R, Nawrot TS, Richart T, Thijs L, Vanderschueren D, Kuznetsova T, et al. Bone resorption and environmental exposure to cadmium in women: A population study. Environ Health Perspect 2008; 116:777-783.
9. Jarup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 2009; 238:201-208.
10. Bernhard D, Rossmann A, Wick G. Metals in cigarette smoke. IUBMB Life 2005; 57:805-809.
11. Cosselman KE, Navas-Acien A, Kaufman JD. Environmental factors in cardiovascular disease. Nat Rev Cardiol 2015; 12:627-642.
12. Filippini T, Michalke B, Malagoli C, Grill P, Bottecchi I, Malavolti M, et al. Determinants of serum cadmium levels in a Northern Italy community: A cross-sectional study. Environ Res 2016; 150:219-226.
13. Galazyn-Sidorczuk M, Brzoska MM, Moniuszko-Jakoniuk J. Estimation of polish cigarettes contamination with cadmium and lead, and exposure to these metals via smoking. Environ Monit Assess 2008; 137:481-493.
14. Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A. The effects of cadmium toxicity. Int J Environ Res Public Health 2020; 17:3782-3805.
15. Nawrot TS, Martens DS, Hara A, Plusquin M, Vangronsveld J, Roels HA, et al. Association of total cancer and lung cancer with environmental exposure to cadmium: The meta-analytical evidence. Cancer Causes Control 2015; 26:1281-1288.
16. Pi H, Li M, Zou L, Yang M, Deng P, Fan T, et al. AKT inhibition-mediated dephosphorylation of TFE3 promotes overactive autophagy independent of MTORC1 in cadmium-exposed bone mesenchymal stem cells. Autophagy 2019; 15:565-582.
17. Bakulski KM, Seo YA, Hickman RC, Brandt D, Vadari HS, Hu H, et al. Heavy metals exposure and alzheimer’s disease and related dementias. J Alzheimers Dis 2020; 76:1215-1242.
18. Ma Y, Ran D, Zhao H, Song R, Zou H, Gu J, et al. Cadmium exposure triggers osteoporosis in duck via P2X7/PI3K/AKT-mediated osteoblast and osteoclast differentiation. Sci Total Environ 2021; 750:141638.
19. Ou L, Wang H, Wu Z, Wang P, Yang L, Li X, et al. Effects of cadmium on osteoblast cell line: Exportin 1 accumulation, p-JNK activation, DNA damage and cell apoptosis. Ecotoxicol Environ Saf 2021; 208:111668.
20. Wu L, Wei Q, Lv Y, Xue J, Zhang B, Sun Q, et al. Wnt/beta-catenin pathway is involved in cadmium-induced inhibition of osteoblast differentiation of bone marrow mesenchymal stem cells. Int J Mol Sci 2019; 20:1519-1535.
21. Ma Y, Ran D, Shi X, Zhao H, Liu Z. Cadmium toxicity: A role in bone cell function and teeth development. Sci Total Environ 2021; 769:144646.
22. Shukla GS, Singhal RL. The present status of biological effects of toxic metals in the environment: Lead, cadmium, and manganese. Can J Physiol Pharmacol 1984; 62:1015-1031.
23. Bhatnagar A. Environmental determinants of cardiovascular disease. Circ Res 2017; 121:162-180.
24. Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res 2017; 120:472-495.
25. Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 2006; 194:S3-11.
26. Daniell HW. Osteoporosis and smoking. JAMA 1972; 221:509.
27. Wang F, Cai F, Shi R, Wang XH, Wu XT. Aging and age related stresses: A senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage 2016; 24:398-408.
28. Jing D, Wu W, Deng X, Peng Y, Yang W, Huang D, et al. FoxO1a mediated cadmium-induced annulus fibrosus cells apoptosis contributes to intervertebral disc degeneration in smoking. J Cell Physiol 2021; 236:677-687.
29. Jakoniuk M, Kochanowicz J, Lankau A, Wilkiel M, Socha K. Concentration of selected macronutrients and toxic elements in the blood in relation to pain severity and hydrogen magnetic resonance spectroscopy in people with osteoarthritis of the spine. Int J Environ Res Public Health 2022; 19:11377-11391.
30. Chen L, Zhao Y, Liu F, Chen H, Tan T, Yao P, et al. Biological aging mediates the associations between urinary metals and osteoarthritis among U.S. adults. BMC Med 2022; 20:207-218.
31. Aaseth J, Alexander J, Alehagen U, Tinkov A, Skalny A, Larsson A, et al. The aging kidney-as influenced by heavy metal exposure and selenium supplementation. Biomolecules 2021; 11:10708-10718.
32. Luo H, Gu R, Ouyang H, Wang L, Shi S, Ji Y, et al. Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-kappaB pathway and mitochondrial dysfunction. Environ Pollut 2021; 290:118043.
33. Dodig S, Cepelak I, Pavic I. Hallmarks of senescence and aging. Biochem Med  (Zagreb) 2019; 29:030501-030515.
34. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82:47-95.
35. Lin J, Du J, Wu X, Xu C, Liu J, Jiang L, et al. SIRT3 mitigates intervertebral disc degeneration by delaying oxidative stress-induced senescence of nucleus pulposus cells. J Cell Physiol 2021; 236:6441-6456.
36. Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence. IUBMB Life 2005; 57:277-281.
37. Davalli P, Mitic T, Caporali A, Lauriola A, D’Arca D. ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016; 2016:3565127-3565144.
38. Cannino G, Ferruggia E, Luparello C, Rinaldi AM. Cadmium and mitochondria. Mitochondrion 2009; 9:377-384.
39. Koch RE, Josefson CC, Hill GE. Mitochondrial function, ornamentation, and immunocompetence. Biol Rev Camb Philos Soc 2017; 92:1459-1474.
40. Zhu D, Wu X, Zhou J, Li X, Huang X, Li J, et al. NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level. Sci Adv 2020; 6:eabb2529-2540.
41. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol 2018; 28:436-453.
42. Nemmiche S, Chabane-Sari D, Kadri M, Guiraud P. Cadmium-induced apoptosis in the BJAB human B cell line: Involvement of PKC/ERK1/2/JNK signaling pathways in HO-1 expression. Toxicology 2012; 300:103-111.
43. Sugisawa N, Matsuoka M, Okuno T, Igisu H. Suppression of cadmium-induced JNK/p38 activation and HSP70 family gene expression by LL-Z1640-2 in NIH3T3 cells. Toxicol Appl Pharmacol 2004; 196:206-214.
44. Xu C, Wang X, Zhu Y, Dong X, Liu C, Zhang H, et al. Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A. Neuropharmacology 2016; 105:270-284.
45. Yuan Y, Jiang C, Hu F, Wang Q, Zhang K, Wang Y, et al. The role of mitogen-activated protein kinase in cadmium-induced primary rat cerebral cortical neurons apoptosis via a mitochondrial apoptotic pathway. J Trace Elem Med Biol 2015; 29:275-283.
46. Zhang Y, Zhou S, Cai W, Han G, Li J, Chen M, et al. Hypoxia/reoxygenation activates the JNK pathway and accelerates synovial senescence. Mol Med Rep 2020; 22:265-276.
47. Cano M, Guerrero-Castilla A, Nabavi SM, Ayala A, Arguelles S. Targeting pro-senescence mitogen activated protein kinase  (Mapk) enzymes with bioactive natural compounds. Food Chem Toxicol 2019; 131:110544.
48. Nakamura M, Ohsawa S, Igaki T. Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila. Nat Commun 2014; 5:5264.
49. Yang LW, Song M, Li YL, Liu YP, Liu C, Han L, et al. L-Carnitine inhibits the senescence-associated secretory phenotype of aging adipose tissue by JNK/p53 pathway. Biogerontology 2019; 20:203-211.
50. Choudhury C, Mazumder R, Kumar R, Dhar B, Sengupta M. Cadmium induced oxystress alters Nrf2-Keap1 signaling and triggers apoptosis in piscine head kidney macrophages. Aquat Toxicol 2021; 231:105739.
51. Hao R, Song X, Sun-Waterhouse D, Tan X, Li F, Li D. MiR-34a/Sirt1/p53 signaling pathway contributes to cadmium-induced nephrotoxicity: A preclinical study in mice. Environ Pollut 2021; 282:117029.
52. Arbon KS, Christensen CM, Harvey WA, Heggland SJ. Cadmium exposure activates the ERK signaling pathway leading to altered osteoblast gene expression and apoptotic death in Saos-2 cells. Food Chem Toxicol 2012; 50:198-205.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 5
May 2024
Pages 588-595

Files

Share

How to cite

Statistics