Skip to main content

Advertisement

Log in

Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Statins are routinely used in the clinic as cholesterol lowering drugs, but recently they were reported to also have anabolic effects on bone tissue. Since regeneration of alveolar bone is one of the primary aims of periodontal treatment, in the present study we investigated the effects of simvastatin, a lipophilic statin, on primary alveolar osteoblasts (AOBs) and periodontal ligament cells (PDLs) in vitro. The effect of simvastatin (1–100 nM) on the cells proliferation/viability after 24, 48, and 72 h stimulation was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT)-assay. The alkaline phosphatase (ALP) activity was measured after stimulation with simvastatin using specific colorimetric assay. Finally, the mRNA expression levels of osteocalcin (OC), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) were measured by real-time PCR. The proliferation/viability of AOBs was significantly decreased by all simvastatin concentrations after 72 h stimulation. The proliferation/viability of PDLs was not influenced by simvastatin. ALP activity of AOBs and PDLs was increased by 1 and 100 nM simvastatin, respectively. Simvastatin induced a dose-dependent increase in OC mRNA expression of AOBs and did not influence that in PDLs. RANKL expression of AOBs was increased at all tested simvastatin concentrations and that in PDLs was increased by higher simvastatin concentrations (10–100 nM). Finally, the expression of OPG in AOBs and PDLs was stimulated by 1–10 and 100 nM simvastatin, respectively. Simvastatin seems to slightly increase the expression of osteogenic markers in AOBs and PDLs, indicating its ability to influence alveolar bone formation and periodontal regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ward S, Lloyd Jones M, Pandor A, et al. A systematic review and economic evaluation of statins for the prevention of coronary events. Health Technol Assess. 2007;11:1–160, iii–iv.

    Google Scholar 

  2. Ogura T, Tanaka Y, Nakata T, Namikawa T, Kataoka H, Ohtsubo Y. Simvastatin reduces insulin-like growth factor-1 signaling in differentiating C2C12 mouse myoblast cells in an HMG-CoA reductase inhibition-independent manner. J Toxicol Sci. 2007;32:57–67.

    Article  PubMed  CAS  Google Scholar 

  3. Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharm Pharmacol. 2006;58:3–18.

    Article  PubMed  CAS  Google Scholar 

  4. Garrett IR, Gutierrez G, Mundy GR. Statins and bone formation. Curr Pharm Des. 2001;7:715–36.

    Article  PubMed  CAS  Google Scholar 

  5. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000;283:3205–10.

    Article  PubMed  CAS  Google Scholar 

  6. Edwards CJ, Hart DJ, Spector TD. Oral statins and increased bone-mineral density in postmenopausal women. Lancet. 2000;355:2218–9.

    Article  PubMed  CAS  Google Scholar 

  7. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–9.

    Article  PubMed  CAS  Google Scholar 

  8. Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3–E1 cells. Biochem Biophys Res Commun. 2001;280:874–7.

    Article  PubMed  CAS  Google Scholar 

  9. Anbinder AL, Junqueira JC, Mancini MN, Balducci I, Rocha RF, Carvalho YR. Influence of simvastatin on bone regeneration of tibial defects and blood cholesterol level in rats. Braz Dent J. 2006;17:267–73.

    Article  PubMed  Google Scholar 

  10. Bjarnason NH, Riis BJ, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int. 2001;12:380–4.

    Article  PubMed  CAS  Google Scholar 

  11. LaCroix AZ, Cauley JA, Pettinger M, et al. Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women’s Health Initiative Observational Study. Ann Intern Med. 2003;139:97–104.

    PubMed  CAS  Google Scholar 

  12. von Stechow D, Fish S, Yahalom D, et al. Does simvastatin stimulate bone formation in vivo? BMC Musculoskelet Disord. 2003;4:8.

    Article  Google Scholar 

  13. Sodek J, McKee MD. Molecular and cellular biology of alveolar bone. Periodontology. 2000;24:99–126.

    Article  CAS  Google Scholar 

  14. Beertsen W, McCulloch CA, Sodek J. The periodontal ligament: a unique, multifunctional connective tissue. Periodontology. 1997;13:20–40.

    Article  CAS  Google Scholar 

  15. McCulloch CA, Bordin S. Role of fibroblast subpopulations in periodontal physiology and pathology. J Periodontal Res. 1991;26:144–54.

    Article  PubMed  CAS  Google Scholar 

  16. Meyer JR. The regenerative potential of the periodontal ligament. J Prosth Dent. 1986;55:260–5.

    Article  CAS  Google Scholar 

  17. Gorustovich AA, Steimetz T, Giglio MJ, Guglielmotti MB. A histomorphometric study of alveolar bone modeling and remodeling under experimental anaemia and polycythaemia in rats. Arch Oral Biol. 2006;51:246–51.

    Article  PubMed  Google Scholar 

  18. Hasegawa T, Yoshimura Y, Kikuiri T, et al. Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells. J Periodontal Res. 2002;37:405–11.

    Article  PubMed  CAS  Google Scholar 

  19. Ozec I, Kilic E, Gumus C, Goze F. Effect of local simvastatin application on mandibular defects. J Craniofac Surg. 2007;18:546–50.

    Article  PubMed  Google Scholar 

  20. Stein D, Lee Y, Schmid MJ, et al. Local simvastatin effects on mandibular bone growth and inflammation. J Periodontol. 2005;76:1861–70.

    Article  PubMed  CAS  Google Scholar 

  21. Yazawa H, Zimmermann B, Asami Y, Bernimoulin JP. Simvastatin promotes cell metabolism, proliferation, and osteoblastic differentiation in human periodontal ligament cells. J Periodontol. 2005;76:295–302.

    Article  PubMed  CAS  Google Scholar 

  22. Qu Z, Rausch-Fan X, Wieland M, Matejka M, Schedle A. The initial attachment and subsequent behavior regulation of osteoblasts by dental implant surface modification. J Biomed Mat Res. 2007;82:658–68.

    Article  Google Scholar 

  23. Rausch-fan X, Qu Z, Wieland M, Matejka M, Schedle A. Differentiation and cytokine synthesis of human alveolar osteoblasts compared to osteoblast-like cells (MG63) in response to titanium surfaces. Dent Mater. 2008;24:102–10.

    Article  PubMed  CAS  Google Scholar 

  24. Qu Z, Laky M, Ulm C, et al. Effect of Emdogain on proliferation and migration of different periodontal tissue-associated cells. Oral Surg Oral Med Oral Path Oral Radiol Endod. 2010;109:924–31.

    Article  Google Scholar 

  25. Zhang Y, Schedle A, Matejka M, Rausch-Fan X, Andrukhov O. The proliferation and differentiation of osteoblasts in co-culture with human umbilical vein endothelial cells: an improved analysis using fluorescence-activated cell sorting. Cell Mol Biol Lett. 2010;15:517–29.

    Article  PubMed  CAS  Google Scholar 

  26. Mundy GR. Statins and their potential for osteoporosis. Bone. 2001;29:495–7.

    Article  PubMed  CAS  Google Scholar 

  27. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007;40:1581–7.

    Article  PubMed  CAS  Google Scholar 

  28. Lindy O, Suomalainen K, Makela M, Lindy S. Statin use is associated with fewer periodontal lesions: a retrospective study. BMC Oral Health. 2008;8:16.

    Article  PubMed  Google Scholar 

  29. Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res. 2006;85:520–3.

    Article  PubMed  CAS  Google Scholar 

  30. Yamashita M, Otsuka F, Mukai T, et al. Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway. J Endocrinol. 2008;196:601–13.

    Article  PubMed  CAS  Google Scholar 

  31. Ruiz-Gaspa S, Nogues X, Enjuanes A, et al. Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cell Biochem. 2007;101:1430–8.

    Article  PubMed  CAS  Google Scholar 

  32. Lima LL, Goncalves PF, Sallum EA, Casati MZ, Nociti FH Jr. Guided tissue regeneration may modulate gene expression in periodontal intrabony defects: a human study. J Periodontal Res. 2008;43:459–64.

    Article  PubMed  CAS  Google Scholar 

  33. Wakabayashi S, Tsutsumimoto T, Kawasaki S, Kinoshita T, Horiuchi H, Takaoka K. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res. 2002;17:249–56.

    Article  PubMed  CAS  Google Scholar 

  34. Lian JB, Stein GS. Concepts of osteoblast growth and differentiation: basis for modulation of bone cell development and tissue formation. Crit Rev Oral Biol Med. 1992;3:269–305.

    PubMed  CAS  Google Scholar 

  35. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5.

    Article  PubMed  CAS  Google Scholar 

  36. Wu B, Elmariah S, Kaplan FS, Cheng G, Mohler ER 3rd. Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol. 2005;25:592–7.

    Article  PubMed  CAS  Google Scholar 

  37. Maeda T, Matsunuma A, Kurahashi I, Yanagawa T, Yoshida H, Horiuchi N. Induction of osteoblast differentiation indices by statins in MC3T3–E1 cells. J Cell Biochem. 2004;92:458–71.

    Article  PubMed  CAS  Google Scholar 

  38. Kim IS, Jeong BC, Kim OS, et al. Lactone form 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) stimulate the osteoblastic differentiation of mouse periodontal ligament cells via the ERK pathway. J Periodontal Res. 2011;46:204–13.

    Article  PubMed  CAS  Google Scholar 

  39. Kaji H, Kanatani M, Sugimoto T, Chihara K. Statins modulate the levels of osteoprotegerin/receptor activator of NFkappaB ligand mRNA in mouse bone-cell cultures. Horm Metab Res. 2005;37:589–92.

    Article  PubMed  CAS  Google Scholar 

  40. Yang H, Feng Y, Luan Y. Determination of simvastatin in human plasma by liquid chromatography-mass spectrometry. J Chromatogr. 2003;785:369–75.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mrs. Nguyen Phuong Quynh, Department of Periodontology, Bernhard Gottlieb Clinic of Dentistry for her fantastic help in preparing and performing the experiments.

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Oleh Andrukhov or Xiaohui Rausch-Fan.

Additional information

S. Liu and K. Bertl contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, S., Bertl, K., Sun, H. et al. Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells. Human Cell 25, 29–35 (2012). https://doi.org/10.1007/s13577-011-0028-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-011-0028-x

Keywords

Navigation