Biological Trace Element Research

, Volume 148, Issue 1, pp 117–121

The Influence of Fluoride on the Expression of Inhibitors of Wnt/β-Catenin Signaling Pathway in Rat Skin Fibroblast Cells

  • Xiao-Li Liu
  • Chang-Cheng Li
  • Ke-Jian Liu
  • Cai-Yan Cui
  • Yu-Zeng Zhang
  • Yun Liu
Article

Abstract

The effective therapy of fluoride-induced bone diseases requires an understanding of the mechanism of the disorders. Changes in the inhibitors of the Wnt/β-catenin pathway, Dickkopf-1 (Dkk-1) and Sclerostin (SOST), were studied in supernatants harvested from rat skin fibroblasts cultured with varied doses of fluoride. The contents of SOST and Dkk-1 in fibroblast supernatants were assessed at four exposure time-points and investigated by using the method of ELISA. Compared to the relevant controls (0 mg F/L), a significant decrease of the concentrations of SOST and Dkk-1 was observed as the fluoride concentration increased. Compared to the relevant time controls (24 h), a significant decrease of the concentrations of SOST and Dkk-1 was observed with the extension of time. Our results suggest that the Wnt/β-catenin pathway inhibitors Dkk-1 and SOST play an important role in skeletal fluorosis. They can be used as important indications for diagnosing bone metabolism changes caused by fluoride exposure and therapeutic targets in diseases resulting from fluoride exposure.

Keywords

Fluoride Fibroblast Sclerostin Dickkopf-1 

References

  1. 1.
    Tamer MN, Kale Köroglu B, Arslan C et al (2007) Osteosclerosis due to endemic fluorosis. Sci Total Environ 373(1):43–48PubMedCrossRefGoogle Scholar
  2. 2.
    Day TF, Guo X, Garrett-Beal L et al (2005) Wnt/beta-catenin in mesenchymal progenitor's controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750PubMedCrossRefGoogle Scholar
  3. 3.
    Jian H, Shen X, Liu I et al (2006) Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta 1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20:666–674PubMedCrossRefGoogle Scholar
  4. 4.
    Moon RT, Kohn AD, De Ferrari GV et al (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691–701PubMedCrossRefGoogle Scholar
  5. 5.
    Bennett CN, Ouyang H, Ma YL et al (2007) Wnt10b increase postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22:1924–1932PubMedCrossRefGoogle Scholar
  6. 6.
    Morvan F, Boulukos K, Clement-Lacroix P et al (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945PubMedCrossRefGoogle Scholar
  7. 7.
    Brunkow ME, Gardner JC, Van Ness J et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589PubMedCrossRefGoogle Scholar
  8. 8.
    Balemans W, Ebeling M, Patel N et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543PubMedCrossRefGoogle Scholar
  9. 9.
    Li X, Ominsky MS, Niu QT et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869PubMedCrossRefGoogle Scholar
  10. 10.
    Li X, Zhang Y, Kang H et al (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887PubMedCrossRefGoogle Scholar
  11. 11.
    Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Bilo Chem 280:26770–26775CrossRefGoogle Scholar
  12. 12.
    Brott BK, Sokol SY (2002) Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Mol Cell Biol 22:6100–6110PubMedCrossRefGoogle Scholar
  13. 13.
    Song YE, Tan H, Liu KJ et al (2011) Effect on bone metabolism indicators ALP, BALP and BGP of fluoride exposure. Environ Health and Prev Med 16:158–163CrossRefGoogle Scholar
  14. 14.
    Eric B, Weiru W, Christine T et al (2011) Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6. Cell Res 19(10):1433–1442Google Scholar
  15. 15.
    Dann CE, Hsieh JC, Rattner A et al (2001) Insight into Wnt binding and signaling from the structures of two Frizzled cysteine-rich domains. Nature 412:86–90PubMedCrossRefGoogle Scholar
  16. 16.
    Hoang B, Moos M Jr, Vukicevic S et al (1996) Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. J Biol Chem 271:26131–26137PubMedCrossRefGoogle Scholar
  17. 17.
    Hsieh JC, Kodjabachian L, Rebbert ML et al (1999) A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature 398:431–436PubMedCrossRefGoogle Scholar
  18. 18.
    Glinka A, Wu W, Delius H et al (1998) Dickkopf-1 is member of a new family of secreted protein and functions in head induction. Nature 391:357–362PubMedCrossRefGoogle Scholar
  19. 19.
    Bafico A, Liu G, Yaniv A et al (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3(7):683–686PubMedCrossRefGoogle Scholar
  20. 20.
    Balemans W, Patel N, Ebeling M et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97PubMedCrossRefGoogle Scholar
  21. 21.
    Balemans W, Piters E, Cleiren E et al (2008) The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutation. Calcif Tissue Int 82(6):445–453PubMedCrossRefGoogle Scholar
  22. 22.
    Torra M, Rodamilans M, Corbella J (1998) Normal range in a nonexposed population. Biol Trace Elem Res 63(1):67–71PubMedCrossRefGoogle Scholar
  23. 23.
    Ba Y, Zhu JY, Yang YJ et al (2010) Serum calciotropic hormone levels, and dental fluorisis in children exposed to different concentrations of fluoride and iodine in drinking water. Chin Med J 123(6):675–679PubMedGoogle Scholar
  24. 24.
    Zhou ZR, Zhao MZ, Jin Y et al (1997) The influence of the improvement of water on the biochemical index of the patients of skeletal fluorosis. Chin J of Endemiology 12(1):50, in ChineseGoogle Scholar
  25. 25.
    Hussain I, Arif M, Hussain J (2011) Fluoride contamination in drinking water in rural habitations of Central Rajasthan. India. Environ Monit Assess. doi:10.1007/s10661-011-2329-7
  26. 26.
    Luo K, Liu Y, Li H (2011) Fluoride content and distribution pattern in groundwater of eastern Yunnan and western Guizhou. China. Environ Geochem Health. doi:10.1007/s10653-011-9393-3

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Xiao-Li Liu
    • 1
  • Chang-Cheng Li
    • 1
  • Ke-Jian Liu
    • 1
  • Cai-Yan Cui
    • 1
  • Yu-Zeng Zhang
    • 1
  • Yun Liu
    • 1
  1. 1.Department of Occupational and Environmental Health, School of Public Health, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

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