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Simvastatin Induces Osteogenic Differentiation and Suppresses Adipogenic Differentiation in Primarily Cultured Human Adipose-Derived Stem Cells

  • Sun, So-Hyun (Department of Family Medicine, The Catholic University of Korea) ;
  • Lee, Il-Kyu (Department of Family Medicine, The Catholic University of Korea) ;
  • Lee, Jee-Won (Department of Biochemistry, McGill University) ;
  • Shim, In-Sop (Department of Integrative Medicine, The Catholic University of Korea) ;
  • Kim, Se-Hong (Department of Family Medicine, The Catholic University of Korea) ;
  • Kim, Kyung-Soo (Department of Family Medicine, The Catholic University of Korea)
  • Published : 2009.10.31

Abstract

Recent in vitro and in vivo animal studies have reported that statin, a cholesterol-lowering drug, stimulate osteogenic differentiation. In the present study, we investigated the effect of simvastatin on osteogenic and adipogenic differentiation in primarily cultured human adipose-derived stem cells (hADSCs). The simvastatin treatment significantly increased the positive cell numbers in alkaline phosphatase and von Kossa staining, and enhanced the expression levels of bone morphogenic protein (BMP)-2, core binding factor alpha 1 (cbfa1), collgen type I and osteonectin mRNAs. Lastly, hADSCs were cultured in the adipogenic media with or without simvastatin to examine the effect of simvastatin on adipogenic differentiation. In the RT-PCR analysis, there were notable decreases in mRNA expression of aP1, C/EBP-$\alpha$ and PPAR-$\gamma$ in hADSCs cultivated in simvastatin-added medium, compared to those in simvastatin-free medium. It suggests that the adipogenic differentiation was significantly inhibited by simvastatin treatment. These observations indicate that simvastatin induces osteogenic differentiation and suppresses adipogenic differentiation in hADSCs.

Keywords

References

  1. Bauer, D. C., Mundy, G. R., Jamal, S. A., Black, D. M., Cauley, J. A., Ensrud, K., E., van der Klift, M. and Pols, H. A. (2004). Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch. Intern. Med. 164, 146-152. https://doi.org/10.1001/archinte.164.2.146
  2. Blinc, A. and Poredos, P. (2007). Pharmacological prevention of atherothrombotic events in patients with peripheral arterial disease. Eur. J. Clin. Invest. 37, 157-164. https://doi.org/10.1111/j.1365-2362.2007.01767.x
  3. Brasaemle, D. L., Dolios, G., Shapiro, L. and Wang, R. (2004). Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. J. Biol. Chem. 279, 46835-46842. https://doi.org/10.1074/jbc.M409340200
  4. Castro-Malaspina, H., Gay, R. E., Resnick, G., Kapoor, N., Meyers, P., Chiarieri, D., McKenzie, S., Broxmeyer, H. E. and Moore, M. A. (1980). Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood 56, 289-301.
  5. Chen, S. L., Fang, W. W., Ye, F., Liu, Y. H., Qian, J., Shan, S. J., Zhang, J. J., Chunhua, R. Z., Liao, L. M., Lin, S. and Sun, J. P. (2004). Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am. J. Cardiol. 94, 92-95. https://doi.org/10.1016/j.amjcard.2004.03.034
  6. Deans, R. J. and Moseley, A. B. (2000). Mesenchymal stem cells: biology and potential clinical uses. Exp. Hematol. 28, 875-884. https://doi.org/10.1016/S0301-472X(00)00482-3
  7. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D. J. and Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317. https://doi.org/10.1080/14653240600855905
  8. Fibbe, W. E. and Noort, W. A. (2003). Mesenchymal stem cells and hematopoietic stem cell transplantation. Ann. N. Y. Acad. Sci. 996, 235-244. https://doi.org/10.1111/j.1749-6632.2003.tb03252.x
  9. Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., Panasuk, A. F., Rudakowa, S. F., Luria, E. A. and Ruadkow, I. A. (1974). Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 2, 83-92.
  10. Gimble, J. M., Morgan, C., Kelly, K., Wu, X., Dandapani, V., Wang, C. S. and Rosen, V. (1995). Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells. J. Cell Biochem. 58, 393-402. https://doi.org/10.1002/jcb.240580312
  11. Gonyeau, M. J. (2005). Statins and osteoporosis: a clinical review. Pharmacotherapy 25, 228-243. https://doi.org/10.1592/phco.25.2.228.56954
  12. Ho, M. L., Chen, Y. H., Liao, H. J., Chen, C. H., Hung, S. H., Lee, M. J., Fu, Y. C., Wang, Y. H., Wang, G. J. and Chang, J. K. (2009). Simvastatin increases osteoblasts and osteogenic proteins in ovariectomized rats. Eur. J. Clin. Invest. 39, 296-303. https://doi.org/10.1111/j.1365-2362.2009.02092.x
  13. Horwitz, E. M., Prockop, D. J., Fitzpatrick, L. A., Koo, W. W., Gordon, P. L., Neel, M., Sussman, M., Orchard, P., Marx, J. C., Pyeritz, R. E. and Brenner, M. K. (1999). Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 5, 309-313. https://doi.org/10.1038/6529
  14. Im, G. I., Shin, Y. W. and Lee, K. B. (2005). Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrowderived cells? Osteoarthr. Cartil. 13, 845-853. https://doi.org/10.1016/j.joca.2005.05.005
  15. Karpisek, M., Stejskal, D., Kotolova, H., Kollar, P., Janoutova, G., Ochmanova, R., Cizek, L., Horakova, D., Yahia, R. B., Lichnovska, R. and Janout, V. (2007). Treatment with atorvastatin reduces serum adipocyte-fatty acid binding protein value in patients with hyperlipidaemia. Eur. J. Clin. Invest. 37, 637-642. https://doi.org/10.1111/j.1365-2362.2007.01835.x
  16. Koc, O. N., Gerson, S. L., Cooper, B. W., Dyhouse, S. M., Haynesworth, S. E., Caplan, A. I. and Lazarusm, H. M. (2000). Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J. Clin. Oncol. 18, 307-316. https://doi.org/10.1200/JCO.2000.18.2.307
  17. Kopen, G. C., Prockop, D. J. and Phinney, D. G. (1999). Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc. Natl. Acad. Sci. U.S.A. 96, 10711-10716. https://doi.org/10.1073/pnas.96.19.10711
  18. Lange, C., Togel, F., Ittrich, H., Clayton, F., Nolte-Ernsting, C., Zander, A. R. and Westenfelder, C. (2005). Administered mesenchymal stem cells enhance recovery from ischemia/- reperfusion-induced acute renal failure in rats. Kidney Int. 68, 1613-1617. https://doi.org/10.1111/j.1523-1755.2005.00573.x
  19. Le Blanc, K., Rasmusson, I., Sundberg, B., Götherström, C., Hassan, M., Uzunel, M. and Ringdén, O. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439-1441. https://doi.org/10.1016/S0140-6736(04)16104-7
  20. Li, X., Cui, Q., Kao, C., Wang, G. J. and Balian, G. (2003). Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARgamma2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures. Bone 33, 652-659. https://doi.org/10.1016/S8756-3282(03)00239-4
  21. Lin, C. P., Chen, Y. H., Lin, W. T., Leu, H. B., Liu, T. Z., Huang, S. L. and Chen, J. W. (2008). Direct effect of statins on homocysteine-induced endothelial adhesiveness: potential impact to human atherosclerosis. Eur. J. Clin. Invest. 38, 106-116. https://doi.org/10.1111/j.1365-2362.2007.01911.x
  22. Lips, P. (2002). Statins and bone turnover. Eur. J. Clin. Invest. 32, 543-544. https://doi.org/10.1046/j.1365-2362.2002.01025.x
  23. Mahmood, A., Lu, D. and Chopp, M. (2004). Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery 55, 1185-1193. https://doi.org/10.1227/01.NEU.0000141042.14476.3C
  24. Mundy, G., Garrett, R., Harris, S., Chan, J., Chen, D., Rossini, G., Boyce, B., Zhao, M. and Gutierrez, G. (1999). Stimulation of bone formation in vitro and in rodents by statins. Science 286, 1946-1949. https://doi.org/10.1126/science.286.5446.1946
  25. Ohnaka, K., Shimoda, S., Nawata, H., Shimokawa, H., Kaibuchi, K., Iwamoto, Y. and Takayanagi, R. (2001). Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem. Biophys. Res. Commun. 287, 337-342. https://doi.org/10.1006/bbrc.2001.5597
  26. Pedersen, T. R. and Kjekshus, J. (2000). Statin drugs and the risk of fracture. 4S Study Group. JAMA 284, 1921-1922. https://doi.org/10.1001/jama.284.15.1921
  27. Petite, H., Viateau, V., Bensaïd, W., Meunier, A., de Pollak, C., Bourguignon, M., Oudina, K., Sedel, L. and Guillemin, G. (2000). Tissue-engineered bone regeneration. Nat. Biotechnol. 18, 959-963. https://doi.org/10.1038/79449
  28. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S. and Marshak, D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147. https://doi.org/10.1126/science.284.5411.143
  29. Reid, I. R., Hague, W., Emberson, J., Baker, J., Tonkin, A., Hunt, D., MacMahon, S. and Sharpe, N. (2001). Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischaemic Disease. Lancet 357, 509-512. https://doi.org/10.1016/S0140-6736(00)04042-3
  30. Shepherd, J., Cobbe, S. M., Ford, I., Isles, C. G., Lorimer, A. R., MacFarlane, P. W., McKillop, J. H. and Packard, C. J. (1995). Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301-1307. https://doi.org/10.1056/NEJM199511163332001
  31. Solomon, D. H., Avorn, J., Canning, C. F. and Wang, P. S. (2005). Lipid levels and bone mineral density. Am. J. Med. 118, 1414. https://doi.org/10.1016/j.amjmed.2005.07.031
  32. Song, C., Guo, Z., Ma, Q., Chen, Z., Liu, Z., Jia, H. and Dang, G. (2003). Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. Biochem. Biophys. Res. Commun. 308, 458-462. https://doi.org/10.1016/S0006-291X(03)01408-6
  33. Vaughan, C. J., Gotto, A. M. and Jr. Basson, C. T. (2000). The evolving role of statins in the management of atherosclerosis. J. Am. Coll Cardiol. 35, 1-10. https://doi.org/10.1016/S0735-1097(99)00525-2

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