Browse > Article
http://dx.doi.org/10.4062/biomolther.2009.17.4.353

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)
Publication Information
Biomolecules & Therapeutics / v.17, no.4, 2009 , pp. 353-361 More about this Journal
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
Simvastatin; Human adipose-derived stem cells; Osteogenic differentiation; Adipogenic differentiation;
Citations & Related Records

Times Cited By Web Of Science : 0  (Related Records In Web of Science)
Times Cited By SCOPUS : 0
연도 인용수 순위
  • Reference
1 Solomon, D. H., Avorn, J., Canning, C. F. and Wang, P. S. (2005). Lipid levels and bone mineral density. Am. J. Med. 118, 1414.   DOI   ScienceOn
2 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.   DOI   ScienceOn
3 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.   DOI   ScienceOn
4 Lips, P. (2002). Statins and bone turnover. Eur. J. Clin. Invest. 32, 543-544.   DOI   ScienceOn
5 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.   DOI
6 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.   DOI   ScienceOn
7 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.   DOI   ScienceOn
8 Pedersen, T. R. and Kjekshus, J. (2000). Statin drugs and the risk of fracture. 4S Study Group. JAMA 284, 1921-1922.   DOI   ScienceOn
9 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.   DOI   ScienceOn
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.   DOI   ScienceOn
11 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.   DOI   ScienceOn
12 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.   DOI   ScienceOn
13 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.   DOI   ScienceOn
14 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.   DOI   ScienceOn
15 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.   DOI
16 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.   DOI
17 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.   DOI   ScienceOn
18 Blinc, A. and Poredos, P. (2007). Pharmacological prevention of atherothrombotic events in patients with peripheral arterial disease. Eur. J. Clin. Invest. 37, 157-164.   DOI   ScienceOn
19 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.   DOI   ScienceOn
20 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.
21 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.   DOI   ScienceOn
22 Deans, R. J. and Moseley, A. B. (2000). Mesenchymal stem cells: biology and potential clinical uses. Exp. Hematol. 28, 875-884.   DOI   ScienceOn
23 Fibbe, W. E. and Noort, W. A. (2003). Mesenchymal stem cells and hematopoietic stem cell transplantation. Ann. N. Y. Acad. Sci. 996, 235-244.   DOI   ScienceOn
24 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.
25 Gonyeau, M. J. (2005). Statins and osteoporosis: a clinical review. Pharmacotherapy 25, 228-243.   DOI   ScienceOn
26 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.   DOI   ScienceOn
27 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.   DOI   ScienceOn
28 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.   DOI   ScienceOn
29 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.   DOI   ScienceOn
30 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.   DOI   ScienceOn
31 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.   DOI   ScienceOn
32 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.   DOI   ScienceOn
33 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.   DOI   ScienceOn