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Aluminum Trichloride Inhibited Osteoblastic Proliferation and Downregulated the Wnt/β-Catenin Pathway

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Abstract

Aluminum (Al) exposure inhibits bone formation. Osteoblastic proliferation promotes bone formation. Therefore, we inferred that Al may inhibit bone formation by the inhibition of osteoblastic proliferation. However, the effects and molecular mechanisms of Al on osteoblastic proliferation are still under investigation. Osteoblastic proliferation can be regulated by Wnt/β-catenin signaling pathway. To investigate the effects of Al on osteoblastic proliferation and whether Wnt/β-catenin signaling pathway is involved in it, osteoblasts from neonatal rats were cultured and exposed to 0, 0.4 mM (1/20 IC50), 0.8 mM (1/10 IC50), and 1.6 mM (1/5 IC50) of aluminum trichloride (AlCl3) for 24 h, respectively. The osteoblastic proliferation rates; Wnt3a, lipoprotein receptor-related protein 5 (LRP-5), T cell factor 1 (TCF-1), cyclin D1, and c-Myc messenger RNA (mRNA) expressions; and p-glycogen synthase kinase 3β (GSK3β), GSK3β, and β-catenin protein expressions indicated that AlCl3 inhibited osteoblastic proliferation and downregulated Wnt/β-catenin signaling pathway. In addition, the AlCl3 concentration was negatively correlated with osteoblastic proliferation rates and the mRNA expressions of Wnt3a, c-Myc, and cyclin D1, while the osteoblastic proliferation rates were positively correlated with mRNA expressions of Wnt3a, c-Myc, and cyclin D1. Taken together, these findings indicated that AlCl3 inhibits osteoblastic proliferation may be associated with the inactivation of Wnt/β-catenin signaling pathway.

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References

  1. Willhite CC, Karyakina NA, Yokel RA, Yenugadhati N, Wisniewski TM, Arnold IM, Momoli F, Krewski D (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Crit Rev Toxicol 44:1–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wesdock JC, Arnold IM (2014) Occupational and environmental health in the aluminum industry: key points for health practitioners. J Occup Environ Med 56:S5–11

    Article  PubMed  PubMed Central  Google Scholar 

  3. Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 88(4):159–167

    Article  CAS  PubMed  Google Scholar 

  4. Priest ND (2004) The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J Environ Monit 6(5):375–403

    Article  CAS  PubMed  Google Scholar 

  5. Li X, Zhang L, Zhu Y, Li Y (2011) Dynamic analysis of exposure to aluminum and an acidic condition on bone formation in young growing rats. Environ Toxicol Pharmacol 31:295–301

    Article  CAS  PubMed  Google Scholar 

  6. Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, Kacew S, Lindsay J, Mahfouz AM, Rondeau V (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 10:1–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kasai K, Hori MT, Goodman WG (1991) Transferrin enhances the antiproliferative effect of aluminum on osteoblast-like cells. Am J Phys 260:E537–E543

    CAS  Google Scholar 

  8. Boyce BF, Byars J, McWilliams S, Mocan MZ, Elder HY, Boyle IT, Junor BJ (1992) Histological and electron microprobe studies of mineralisation in aluminium-related osteomalacia. J Clin Pathol 45:502–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jorgetti V, Soeiro NM, Mendes V, Pereira RC, Crivellari ME, Coutris G, Borelli A, Leite MO, Nussenzweig I, Marcondes M, Drüeke T, Cournot G (1994) Aluminium-related osteodystrophy and desferrioxamine treatment: role of phosphorus. Nephrol Dial Transplant 9:668–674

    Article  CAS  PubMed  Google Scholar 

  10. Aaseth J, Boivin G, Andersen O (2012) Osteoporosis and trace elements—an overview. J Trace Elem Med Biol 26:149–152

    Article  CAS  PubMed  Google Scholar 

  11. Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL (1996) Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney. J Toxicol Environ Health 48:649–665

    Article  CAS  PubMed  Google Scholar 

  12. Willhite CC, Ball GL, McLellan CJ (2012) Total allowable concentrations of monomeric inorganic aluminum and hydrated aluminum silicates in drinking water. Crit Rev Toxicol 42:358–442

    Article  CAS  PubMed  Google Scholar 

  13. Li S, Quarto N, Senarath-Yapa K, Grey N, Bai X, Longaker MT (2015) Enhanced activation of canonical wnt signaling confers mesoderm-derived parietal bone with similar osteogenic and skeletal healing capacity to neural crest-derived frontal bone. PLoS One 10:e0138059

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ducy P, Schinke T, Karsenty G (2000) The osteoblast: a sophisticated fibroblast under central surveillance. Science 289:1501–1504

    Article  CAS  PubMed  Google Scholar 

  15. Cao Z, Fu Y, Sun X, Zhang Q, Xu F, Li Y (2016) Aluminum trichloride inhibits osteoblastic differentiation through inactivation of wnt/β-catenin signaling pathway in rat osteoblasts. Environ Toxicol Pharmacol 42:198–204

    Article  CAS  PubMed  Google Scholar 

  16. Song M, Huo H, Cao Z, Han Y, Gao L (2016) Aluminum trichloride inhibits the rat osteoblasts mineralization in vitro. Biol Trace Elem Res

  17. Chen J, Qiu M, Dou C, Cao Z, Dong S (2015) MicroRNAs in bone balance and osteoporosis. Drug Dev Res 76:235–245

    Article  CAS  PubMed  Google Scholar 

  18. Huang LW, Ren L, Yang PF, Shang P (2015) Response of osteoblasts to the stimulus of fluid flow. Crit Rev Eukaryot Gene Expr 25(2):153–162

    Article  PubMed  Google Scholar 

  19. Marie PJ (1999) Cellular and molecular alterations of osteoblasts in human disorders of bone formation. Histol Histopathol 14(2):525–538

    CAS  PubMed  Google Scholar 

  20. Marie PJ, Kassem M (2011) Osteoblasts in osteoporosis: past emerging and future anabolic targets. Eur J Endocrinol 165(1):1–10

    Article  CAS  PubMed  Google Scholar 

  21. Canalis E (2010) New treatment modalities in osteoporosis. Endocr Pract 16(5):855–863

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bellows CG, Aubin JE, Heersche JN (1995) Aluminum inhibits both initiation and progression of mineralization of osteoid nodules formed in differentiating rat calvaria cell cultures. J Bone Miner Res 10:2011–2016

    Article  CAS  PubMed  Google Scholar 

  23. Lieberherr M, Grosse B, Cournot-Witmer G, Hermann-Erlee MP, Balsan S (1987) Aluminum action on mouse bone cell metabolism and response to PTH and 1,25(OH)2D3. Kidney Int 31:736–743

    Article  CAS  PubMed  Google Scholar 

  24. Lau KH, Yoo A, Wang SP (1991) Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride. Mol Cell Biochem 105:93–105

    CAS  PubMed  Google Scholar 

  25. Zha X, Xu Z, Liu Y, Xu L, Huang H, Zhang J, Cui L, Zhou C, Xu D (2016) Amentoflavone enhances osteogenesis of human mesenchymal stem cells through JNK and p38 MAPK pathways. J Nat Med 70:634–644

    Article  CAS  PubMed  Google Scholar 

  26. Hu H, Chen M, Dai G, Du G, Wang X, He J, Zhao Y, Han D, Cao Y, Zheng Y, Ding D (2016) An inhibitory role of osthole in rat MSCs osteogenic differentiation and proliferation via wnt/β-catenin and Erk1/2-MAPK pathways. Cell Physiol Biochem 38:2375–2388

    Article  CAS  PubMed  Google Scholar 

  27. Hu B, Yu B, Tang D, Li S, Wu Y (2016) Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway. Genet Mol Res 15. doi:10.4238/gmr.15028792

  28. Salazar VS, Zarkadis N, Huang L, Watkins M, Kading J, Bonar S, Norris J, Mbalaviele G, Civitelli R (2013) Postnatal ablation of osteoblast Smad4 enhances proliferative responses to canonical wnt signaling through interactions with β-catenin. J Cell Sci 126:5598–5609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Issack PS, Helfet DL, Lane JM (2008) Role of wnt signaling in bone remodeling and repair. HSS J 4:66–70

    Article  PubMed  Google Scholar 

  30. Zhai M, Jing D, Tong S, Wu Y, Wang P, Zeng Z, Shen G, Wang X, Xu Q, Luo E (2016) Pulsed electromagnetic fields promote in vitro osteoblastogenesis through a wnt/β-catenin signaling-associated mechanism. Bioelectromagnetics 37:152–162

    Article  CAS  Google Scholar 

  31. Espada J, Calvo MB, Díaz-Prado S, Medina V (2009) Wnt signalling and cancer stem cells. Clin Transl Oncol 11:411–427

    Article  CAS  PubMed  Google Scholar 

  32. Chau JF, Leong WF, Li B (2009) Signaling pathways governing osteoblast proliferation, differentiation and function. Histol Histopathol 24:1593–1606

    CAS  PubMed  Google Scholar 

  33. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821

    Article  CAS  PubMed  Google Scholar 

  34. Owen TA, Aronow M, Shalhoub V, Barone LM, Wilming L, Tassinari MS, Kennedy MB, Pockwinse S, Lian JB, Stein GS (1990) Progressive development of the rat osteoblast phenotype in vitro: reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol 143:420–430

    Article  CAS  PubMed  Google Scholar 

  35. Sun X, Cao Z, Zhang Q, Liu S, Xu F, Che J, Zhu Y, Li Y, Pan C, Liang W (2015) Aluminum trichloride impairs bone and downregulates wnt/β-catenin signaling pathway in young growing rats. Food Chem Toxicol 86:154–162

    Article  CAS  PubMed  Google Scholar 

  36. Caverzasio J, Biver E, Thouverey C (2013) Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation. J Bone Miner Res 28:260–270

    Article  CAS  PubMed  Google Scholar 

  37. Zhang J, Shao Y, He D, Zhang L, Xu G, Shen J (2016) Evidence that bone marrow-derived mesenchymal stem cells reduce epithelial permeability following phosgene-induced acute lung injury via activation of wnt3a protein-induced canonical wnt/β-catenin signaling. Inhal Toxicol 19:1–8

    Google Scholar 

  38. Cao Z, Liu D, Zhang Q, Sun X, Li Y (2016) Aluminum chloride induces osteoblasts apoptosis via disrupting calcium homeostasis and activating Ca(2+)/CaMKII signal pathway. Biol Trace Elem Res 169:247–253

    Article  CAS  PubMed  Google Scholar 

  39. Pan L, Shi X, Liu S, Guo X, Zhao M, Cai R, Sun G (2014) Fluoride promotes osteoblastic differentiation through canonical wnt/β-catenin signaling pathway. Toxicol Lett 225:34–42

    Article  CAS  PubMed  Google Scholar 

  40. Li M, Song M, Ren LM, Xiu CY, Liu JY, Zhu YZ, Li YF (2016) AlCl3 induces lymphocyte apoptosis in rats through the mitochondria-caspase dependent pathway. Environ Toxicol 31:385–394

    Article  CAS  PubMed  Google Scholar 

  41. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Goodman WG (1985) Bone disease and aluminum: pathogenic considerations. Am J Kidney Dis 6:330–335

    Article  CAS  PubMed  Google Scholar 

  43. Quarles LD, Wenstrup RJ, Castillo SA, Drezner MK (1991) Aluminum-induced mitogenesis in MC3T3-E1 osteoblasts: potential mechanism underlying neoosteogenesis. Endocrinology 128:3144–3151

    Article  CAS  PubMed  Google Scholar 

  44. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA 2nd, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a wnt coreceptor. J Cell Biol 157:303–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO (2004) Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19(12):2033–2040

    Article  CAS  PubMed  Google Scholar 

  46. Reischmann P, Fiebeck J, von der Weiden N, Müller O (2015) Measured effects of Wnt3a on proliferation of HEK293T cells depend on the applied assay. Int J Cell Biol 2015:928502

    Article  PubMed  PubMed Central  Google Scholar 

  47. Niehrs C, Acebron SP (2012) Mitotic and mitogenic wnt signaling. EMBO J 31:2705–2713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Abrams SL, Montalto G, D’Assoro AB, Libra M, Nicoletti F, Maestro R, Basecke J, Cocco L, Cervello M, Martelli AM (2014) Multifaceted roles of GSK-3 and wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia 28:15–33

    Article  CAS  PubMed  Google Scholar 

  49. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F (1997) The mouse fused locus encodes Axin, an inhibitor of the wnt signaling pathway that regulates embryonic axis formation. Cell 90:181–192

    Article  CAS  PubMed  Google Scholar 

  50. Wang X, Chen J, Li F, Lin Y, Zhang X, Lv Z, Jiang J (2012) MiR-214 inhibits cell growth in hepatocellular carcinoma through suppression of β-catenin. Biochem Biophys Res Commun 28:525–531

    Article  CAS  Google Scholar 

  51. Matsuzaki E, Takahashi-Yanaga F, Miwa Y, Hirata M, Watanabe Y, Sato N, Morimoto S, Hirofuji T, Maeda K, Sasaguri T (2006) Differentiation-inducing factor-1 alters canonical wnt signaling and suppresses alkaline phosphatase expression in osteoblast-like cell lines. J Bone Miner Res 21:1307–1316

    Article  CAS  PubMed  Google Scholar 

  52. Chen JR, Lazarenko OP, Wu X, Kang J, Blackburn ML, Shankar K, Badger TM, Ronis MJ (2010) Dietary-induced serum phenolic acids promote bone growth via p38 MAPK/β-catenin canonical wnt signaling. J Bone Miner Res 25:2399–2411

    Article  CAS  PubMed  Google Scholar 

  53. López-Herradón A, Portal-Núñez S, García-Martín A, Lozano D, Pérez-Martínez FC, Ceña V, Esbrit P (2013) Inhibition of the canonical wnt pathway by high glucose can be reversed by parathyroid hormone-related protein in osteoblastic cells. J Cell Biochem 114:1908–1916

    Article  PubMed  Google Scholar 

  54. Lei B, Chai W, Wang Z, Liu R (2015) Highly expressed UNC119 promotes hepatocellular carcinoma cell proliferation through wnt/β-catenin signaling and predicts a poor prognosis. Am J Cancer Res 5:3123–3134

    PubMed  PubMed Central  Google Scholar 

  55. Chen Y, Jiang T, Shi L, He K (2016) hcrcn81 promotes cell proliferation through wnt signaling pathway in colorectal cancer. Med Oncol 33:3

    Article  PubMed  Google Scholar 

  56. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  CAS  PubMed  Google Scholar 

  57. Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411:342–348

    Article  CAS  PubMed  Google Scholar 

  58. Ruggero D (2009) The role of myc-induced protein synthesis in cancer. Cancer Res 69:8839–8843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cole MD, Cowling VH (2008) Transcription-independent functions of MYC: regulation of translation and DNA replication. Nat Rev Mol Cell Biol 9:810–815

    Article  CAS  PubMed  Google Scholar 

  60. Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn LJ (1994) Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9:3635–3645

    CAS  PubMed  Google Scholar 

  61. Arioka M, Takahashi-Yanaga F, Sasaki M, Yoshihara T, Morimoto S, Takashima A, Mori Y, Sasaguri T (2013) Acceleration of bone development and regeneration through the wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β. Biochem Biophys Res Commun 440:677–682

    Article  CAS  PubMed  Google Scholar 

  62. Liu M, Sun Y, Liu Y, Yuan M, Zhang Z, Hu W (2012) Modulation of the differentiation of dental pulp stem cells by different concentrations of β-glycerophosphate. Molecules 17:1219–1232

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Natural Science Foundation Project (contract grant numbers 31372496 and 31302147) and the National Science Foundation of Fujian Province of China (2013J0102).

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Authors and Affiliations

  1. College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China

    Wanyue Huang, Peiyan Wang, Tongtong Shen, Yanfei Han, Miao Song, Yu Bian & Yanfei Li

  2. College of Animal Science, Fujian Agricultural and Forestry University, Fuzhou, 350002, China

    Chongwei Hu

  3. Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, 130112, China

    Yanzhu Zhu

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  1. Wanyue Huang
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Huang, W., Wang, P., Shen, T. et al. Aluminum Trichloride Inhibited Osteoblastic Proliferation and Downregulated the Wnt/β-Catenin Pathway. Biol Trace Elem Res 177, 323–330 (2017). https://doi.org/10.1007/s12011-016-0880-3

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