Journal of Bone and Mineral Metabolism

, Volume 27, Issue 5, pp 555–561

Nicotine modulates bone metabolism-associated gene expression in osteoblast cells

  • David E. Rothem
  • Lilah Rothem
  • Michael Soudry
  • Aviva Dahan
  • Rami Eliakim
Original Article

Abstract

Smoking has a broad range of physiological effects, such as being a risk factor in osteoporosis, bone fracture incidence, and increased nonunion rates. Recent studies showed that nicotine has effects at the cellular level in human osteoblast cells. To identify possible mechanisms underlying nicotine-induced changes in osteogenic metabolism, we defined changes in proliferation and osteocalcin, type I collagen, and alkaline phosphatase gene expression after treating human osteosarcoma cells (MG63), with various concentration of nicotine. Nicotine affects cell proliferation in a biphasic manner, including toxic and antiproliferative effects at high levels of nicotine and stimulatory effects at low levels. Moreover, low levels of nicotine upregulated osteocalcin, type I collagen, and alkaline phosphatase gene expression. The increased cell proliferation and gene upregulation induced by nicotine were inhibited by addition of the nicotinic receptor antagonist d-tubocurarine. High nicotine concentrations downregulated the investigated genes. Our results demonstrate, for the first time, that the addition of nicotine concentrations analogous to those acquired by a light to moderate smoker yields increased osteoblast proliferation and bone metabolism, whereas the addition of nicotine concentrations analogous to heavy smokers leads to the opposite effect. The inhibition of these effects by d-tubocurarine suggests that nicotine acts via the nicotinic acetylcholine receptor (nAChR).

Keywords

Bone metabolism Nicotine Proliferation Gene expression Osteoblast 

References

  1. 1.
    Daniell HW (1976) Osteoporosis of the slender smoker: vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Arch Intern Med 136:298–304PubMedCrossRefGoogle Scholar
  2. 2.
    Dolev E (1997) Cigarette smoking and osteoporosis. Harefuah 132:511–513PubMedGoogle Scholar
  3. 3.
    Grisso JA, Kelsey JL, O’Brien LA, Miles CG, Sidney S, Maislin G, LaPann K, Moritz D, Peters B (1997) Risk factors for hip fractures in men. Am J Epidemiol 145:786–793PubMedGoogle Scholar
  4. 4.
    Krall EA, Dawson HB (1991) Smoking and bone loss among postmenopausal women. J Bone Miner Res 6:331–338PubMedCrossRefGoogle Scholar
  5. 5.
    Krall EA, Dawson HB (1999) Smoking increases bone loss and decreases intestinal calcium absorption. J Bone Miner Res 14:215–220PubMedCrossRefGoogle Scholar
  6. 6.
    Mussolino ME, Looker AC, Madans JH, Langlois JA, Orwoll ES (1998) Risk factors for hip fracture in white men: the NHANES I Epidemiologic Follow-up Study. J Bone Miner Res 13:918–924PubMedCrossRefGoogle Scholar
  7. 7.
    Mazess RB, Barden HS (1991) Bone density in premenopausal women: effects of age dietary intake, physical activity, smoking and birth control pills. Am J Clin Nutr 153:132–142Google Scholar
  8. 8.
    Brown CW, Orme TJ, Richardson HD (1985) The rate of pseudarthrosis (surgical nonunion) in patients who are smokers and patients who are nonsmokers: a comparison study. Spine 11:942–949CrossRefGoogle Scholar
  9. 9.
    Ishikawa SN, Murphy GA, Richardson EG (2002) The effect of cigarette smoking on hindfoot fusions. Foot Ankle Int 23:996–998PubMedGoogle Scholar
  10. 10.
    Kyro A, Usenius JP, Aarnio M, Kunnamo I, Avikainen V (1993) Are smokers a risk group for delayed healing of the tibial shaft fracture? Ann Chir Gynaecol 82:254–262PubMedGoogle Scholar
  11. 11.
    Raikin SM, Landsman JC, Alexander VA, Froimson MI, Plaxton NA (1998) Effect of nicotine on the rate and strength of long bone fracture healing. Clin Orthop 353:231–237PubMedCrossRefGoogle Scholar
  12. 12.
    Syversen U, Nordsletten L, Falch JA, Madsen JE, Nilsen OG, Waldum HL (1999) Effect of lifelong nicotine inhalation on bone mass and mechanical properties in female rat femurs. Calcif Tissue Int 65:246–249PubMedCrossRefGoogle Scholar
  13. 13.
    Kim KS, Yoon ST, Park JS, Li J, Park MS, Hutton WC (2003) Inhibition of proteoglycan and type II collagen synthesis of disc nucleus cells by nicotine. J Neurosurg 99:291–297PubMedCrossRefGoogle Scholar
  14. 14.
    Walker LM, Preston MR, Magnay JL, Thomas PBM, El Haj AJ (2001) Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone (NY) 28:603–608Google Scholar
  15. 15.
    Fang MA, Frost PJ, Iida-Klein A, Hahn TJ (1991) Effects of nicotine on cellular function in UMR 106 osteoblast-like cells. Bone (NY) 12:283–286Google Scholar
  16. 16.
    Tipton DA, Dabbous MK (1995) Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. J Periodontol 66:1056–1064PubMedGoogle Scholar
  17. 17.
    Gotti C, Fornasari D, Clementi F (1997) Human neuronal nicotinic receptors. Prog Neurobiol 53:199–237PubMedCrossRefGoogle Scholar
  18. 18.
    Benowitz NL (1988) Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 319:1318–1330PubMedGoogle Scholar
  19. 19.
    Morris BJ, Hicks AA, Wisden W, Darlison MG, Hunt SP, Barnard EA (1990) Distinct regional expression of nicotinic acetylcholine receptor genes in chick brain. Mol Brain Res 7:305–315PubMedCrossRefGoogle Scholar
  20. 20.
    Villablanca AC (1998) Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro. J Appl Physiol 84:2089–2098PubMedGoogle Scholar
  21. 21.
    Ramp WK, Lenz LG, Galvin RJS (1991) Nicotine inhibits collagen synthesis and alkaline phosphatase activity, but stimulates DNA synthesis in osteoblast-like cells. Proc Soc Exp Biol Med 197:36–43PubMedGoogle Scholar
  22. 22.
    Tanaka H, Tanabe N, Suzuki N, Shoji M, Torigoe H, Sugaya A, Motohashi M, Maeno M (2005) Nicotine affects mineralized nodule formation by human osteosarcoma cell line Saos-2. Life Sci 77:2273–2284PubMedCrossRefGoogle Scholar
  23. 23.
    Kayed H, Bekasi S, Keleg S, Michalski CW, Giese T, Friess H, Kleeff J (2007) BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion. Mol Cancer 6:83–87PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2009

Authors and Affiliations

  • David E. Rothem
    • 1
    • 3
  • Lilah Rothem
    • 2
  • Michael Soudry
    • 1
    • 3
  • Aviva Dahan
    • 2
  • Rami Eliakim
    • 2
    • 3
  1. 1.Department of Orthopaedic Surgery ARambam Health Care CampusHaifaIsrael
  2. 2.Gastroenterology and Nutrition Research LaboratoryRambam Health Care CampusHaifaIsrael
  3. 3.The Bruce & Ruth Rappaport Faculty of Medicine, Technion-Israel Institute of TechnologyHaifaIsrael

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