Effects of Co-exposure to Fluoride and Arsenic on TRAF-6 Signaling and NF-κB Pathway Of Bone Metabolism

Overview

Journal Biol Trace Elem Res

Date 2022 Dec 1

PMID 36456742

Authors

Chan Nie

Junwei Hu

Bingjie Wang

Hao Li

Xing Yang

Feng Hong

Affiliations

Soon will be listed here.

Abstract

Little is known about the combined effect of fluoride (F) and arsenic (As) on bone metabolism. This study aims to explore the effect of co-exposure to F and As on the expressions of TNF receptor-associated factor 6 (TRAF-6), nuclear factor-kappa B (NF-κB), and the related factors in cell and animal experiments. With the rats exposed to different doses of F, As, and combined F-As, we found that F exposure doses were positively correlated with the protein expression of receptor activator of nuclear factor-kappa B ligand (RANKL), receptor activator of nuclear factor-kappa B (RANK), TRAF-6, NF-κB, and nuclear factor of activated T cells (NFAT-c1) (P < 0.001). As exposure doses were negatively correlated with RANK, TRAF-6, NF-κB, and NFAT-c1 (P < 0.001). The effect of F and As interaction on the protein expression of RANKL, TRAF-6, NF-κB, and NFAT-c1 was significant in bone tissue (P < 0.05). In the cellular experiment, F could promote the mRNA expression of RANK, TRAF-6, and NFAT-c1. A higher concentration of As could inhibit the mRNA expression of Tartrate-resistant acid phosphatase (TRAP), RANK, TRAF-6, and NFAT-c1. The effect of F and As interaction on the mRNA expression of TRAP, RANK, TRAF-6, and NFATc1 in osteoclasts was significant (P < 0.001). In conclusion, the expression of TRAF-6 and NF-κB pathway was affected by F and As co-exposure in osteogenic differentiation, and As could antagonize the promoting effect of F on the expression of TRAF-6, TRAP, RANKL, RANK, NF-κB, and NFAT-c1 in these exposure levels. These results could provide a scientific basis for understanding the interaction of F and As in bone formation.

Citing Articles

TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner.

Kang H, Peng R, Dong Y, Dong Y, Liao F, Zhu M Mol Ther. 2025; 33(3):933-949.

PMID: 39863932 PMC: 11897774. DOI: 10.1016/j.ymthe.2025.01.040.

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Zheng H, Liu Y, Deng Y, Li Y, Liu S, Yang Y Mol Med. 2024; 30(1):20.

PMID: 38310228 PMC: 10838448. DOI: 10.1186/s10020-024-00788-w.

References

Gonzalez-Horta C, Ballinas-Casarrubias L, Sanchez-Ramirez B, Ishida M, Barrera-Hernandez A, Gutierrez-Torres D . A concurrent exposure to arsenic and fluoride from drinking water in Chihuahua, Mexico. Int J Environ Res Public Health. 2015; 12(5):4587-601. PMC: 4454927. DOI: 10.3390/ijerph120504587. View

Podgorski J, Berg M . Global threat of arsenic in groundwater. Science. 2020; 368(6493):845-850. DOI: 10.1126/science.aba1510. View

Yadav A, Kaushik C, Haritash A, Kansal A, Rani N . Defluoridation of groundwater using brick powder as an adsorbent. J Hazard Mater. 2005; 128(2-3):289-93. DOI: 10.1016/j.jhazmat.2005.08.006. View

Wang W, Xu J, Liu K, Liu X, Li C, Cui C . Suppression of Sclerostin and Dickkopf-1 levels in patients with fluorine bone injury. Environ Toxicol Pharmacol. 2013; 35(3):402-7. DOI: 10.1016/j.etap.2013.01.005. View

Nakamoto T, Rawls H . Fluoride Exposure in Early Life as the Possible Root Cause of Disease In Later Life. J Clin Pediatr Dent. 2018; 42(5):325-330. DOI: 10.17796/1053-4625-42.5.1. View

Hu Y, Cheng H, Hsieh B, Huang L, Huang T, Chang K . Arsenic trioxide affects bone remodeling by effects on osteoblast differentiation and function. Bone. 2012; 50(6):1406-15. DOI: 10.1016/j.bone.2012.03.012. View

Wu C, Lu T, Chan D, Tsai K, Yang R, Liu S . Effects of arsenic on osteoblast differentiation in vitro and on bone mineral density and microstructure in rats. Environ Health Perspect. 2014; 122(6):559-65. PMC: 4050517. DOI: 10.1289/ehp.1307832. View

Hong F, Zheng C, Xu D, Qian Y . [Chronic combined effects of fluoride and arsenite on the Runx2 and downstream related factors of bone metabolism in rats]. Zhonghua Yu Fang Yi Xue Za Zhi. 2013; 47(9):794-8. View

Zeng Q, Xu Y, Yu X, Yang J, Hong F, Zhang A . Arsenic may be involved in fluoride-induced bone toxicity through PTH/PKA/AP1 signaling pathway. Environ Toxicol Pharmacol. 2013; 37(1):228-33. DOI: 10.1016/j.etap.2013.11.027. View

10.

Ma Z, Li S, Sun Y . Effect of enhanced masticatory force on OPG, RANKL and MGF in alveolar bone of ovariectomized rats. J Appl Oral Sci. 2020; 28:e20190409. PMC: 7135953. DOI: 10.1590/1678-7757-2019-0409. View

11.

Chung J, Lu M, Yin Q, Lin S, Wu H . Molecular basis for the unique specificity of TRAF6. Adv Exp Med Biol. 2007; 597:122-30. DOI: 10.1007/978-0-387-70630-6_10. View

12.

Lomaga M, Yeh W, Sarosi I, Duncan G, Furlonger C, Ho A . TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999; 13(8):1015-24. PMC: 316636. DOI: 10.1101/gad.13.8.1015. View

13.

Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R . Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med. 1997; 3(11):1285-9. DOI: 10.1038/nm1197-1285. View

14.

van Dam P, Verhoeven Y, Trinh X . The Non-Bone-Related Role of RANK/RANKL Signaling in Cancer. Adv Exp Med Biol. 2020; 1277:53-62. DOI: 10.1007/978-3-030-50224-9_3. View

15.

Li R, Gong Z, Yu Y, Niu R, Bian S, Sun Z . Alleviative Effects of Exercise on Bone Remodeling in Fluorosis Mice. Biol Trace Elem Res. 2021; 200(3):1248-1261. DOI: 10.1007/s12011-021-02741-y. View

16.

Liu X, Song J, Liu K, Wang W, Xu C, Zhang Y . Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro. J Huazhong Univ Sci Technolog Med Sci. 2015; 35(5):712-715. DOI: 10.1007/s11596-015-1495-1. View

17.

Gao M, Sun L, Xu K, Zhang L, Zhang Y, He T . Association between low-to-moderate fluoride exposure and bone mineral density in Chinese adults: Non-negligible role of RUNX2 promoter methylation. Ecotoxicol Environ Saf. 2020; 203:111031. DOI: 10.1016/j.ecoenv.2020.111031. View

18.

Sun R, Zhou G, Liu L, Ren L, Xi Y, Zhu J . Fluoride exposure and CALCA methylation is associated with the bone mineral density of Chinese women. Chemosphere. 2020; 253:126616. DOI: 10.1016/j.chemosphere.2020.126616. View

19.

Jiang N, Guo F, Xu W, Zhang Z, Jin H, Shi L . Effect of fluoride on osteocyte-driven osteoclastic differentiation. Toxicology. 2020; 436:152429. DOI: 10.1016/j.tox.2020.152429. View

20.

Matsuo K, Galson D, Zhao C, Peng L, Laplace C, Wang K . Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem. 2004; 279(25):26475-80. DOI: 10.1074/jbc.M313973200. View