Statins, hydroxymethylglutaryl-coenzyme-A reductase inhibitors (HMG-Co-A), are known to reduce plasma cholesterol levels. However, the biocompatibility of Simvastatin with human bone tissue has not been studied thoroughly. The purpose of this study was to further investigate the effectiveness of different concentrations of simvastatin on the attachment, proliferation, toxicity, cell cycle, and apoptosis of normal human osteoblasts. Osteoblasts derived from normal human alveolar bone chips were cultured with simvastatin at concentrations of 1, 10, 25, 50, 75, 100 mol/L, and 0 mol/L as a control. The cell attachment was evaluated at 9 hours. The proliferation rate and cytotoxicity were investigated at 7, 14, and 21 days. Cell cycle and apoptosis were assessed at 1 and 3 days. Statistical analysis was performed using ANOVA. P-values ≤0.05 were considered statistically significant. The results showed that there was no statistical significance (P>0.05) amongst the groups in the cell attachment efficiency. All tested concentrations of Simvastatin showed a significant decrease in the proliferation rate (P<0.001) and an increase in cytotoxicity (P<0.001). Cell cycle and apoptosis significantly increased as time increased (P<0.001). In conclusion, the present findings showed that Simvastatin adversely affects human osteoblasts' proliferation and cell viability by inducing apoptosis.
Published in | International Journal of Materials Science and Applications (Volume 12, Issue 2) |
DOI | 10.11648/j.ijmsa.20231202.12 |
Page(s) | 26-35 |
Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
Copyright |
Copyright © The Author(s), 2023. Published by Science Publishing Group |
Simvastatin, Osteoblasts, Toxicity
[1] | Kwak B, Mulhaupt F, Veillard N, Pelli G, Mach F. The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells. Swiss Med Wkly 2001; 31 (3-4): 41-46. |
[2] | Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 63 (9421): 1607-1608. |
[3] | Hatzigeorgiou C, Jackson JL. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int 2005; 6 (8): 990-998. |
[4] | Oxlund H, Dalstra M, Andreassen TT. Statin given perorally to adult rats increases cancellous bone mass and compressive strength. Calcif Tissue Int 2001; 9 (5): 299-304. |
[5] | Oxlund H, Andreassen TT. Simvastatin treatment partially prevents ovariectomy-induced bone loss while increasing cortical bone formation. Bone 2004; 4 (4): 609-618. |
[6] | Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999; 286 (5446): 1946-1949. |
[7] | Skoglund B, Forslund C, Aspenberg P. Simvastatin improves fracture healing in mice. J Bone Miner Res 2002; 17 (11): 2004-2008. |
[8] | Gutierrez G, Lalka D, Garrett I, Rossini G, Mundy G. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporosis international 2006; 7: 1033-1042. |
[9] | Liu C, Wu Z, Sun HC. The effect of simvastatin on mRNA expression of transforming growth factor-beta1, bone morphogenetic protein-2 and vascular endothelial growth factor in tooth extraction socket. Int J Oral Sci 2009; 1 (2): 90-98. |
[10] | Liu M, Wang K, Tang T, Dai K, Zhu Z. The effect of simvastatin on the differentiation of marrow stromal cells from aging rats. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2009; 64 (1): 43-48. |
[11] | 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 (2): 295-302. |
[12] | Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochemical and biophysical research communications 2001; 280 (3): 874-877. |
[13] | Sugiyama M, Kodama T, Konishi K, Abe K, Asami S, Oikawa S. Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun 2000; 271 (3): 688-692. |
[14] | Du Z, Chen J, Yan F, Xiao Y. Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Implants Res 2009; 20 (2): 145-150. |
[15] | Sallam MM. The influence of oral administration of simvastatin on delayed non-union facial fractures—clinical study. J Am Sci 2011; 7 (5): 812-818. |
[16] | Lin LD, Lin SK, Chao YL, Kok SH, Hong CY, Hou KL, et al. Simvastatin suppresses osteoblastic expression of Cyr61 and progression of apical periodontitis through enhancement of the transcription factor Forkhead/winged helix box protein O3a. J Endod 2013; 39 (5): 619-625. |
[17] | Lin SK, Kok SH, Lee YL, Hou KL, Lin YT, Chen MH, et al. Simvastatin as a novel strategy to alleviate periapical lesions. J Endod 2009; 35 (5): 657-662. |
[18] | Lai EH, Hong CY, Kok SH, Hou KL, Chao LH, Lin LD, et al. Simvastatin alleviates the progression of periapical lesions by modulating autophagy and apoptosis in osteoblasts. J Endod 2012; 38 (6): 757-763. |
[19] | Kok SH, Hou KL, Hong CY, Wang JS, Liang PC, Chang CC, et al. Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis. Arthritis Rheum 2011; 63 (4): 1010-1020. |
[20] | Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences 2000; 97 (25): 13625-13630. |
[21] | Suchanek J, Soukup T, Ivancakova R, Karbanova J, Hubkova V, Pytlik R, et al. Human dental pulp stem cells--isolation and long term cultivation. Acta Medica (Hradec Kralove) 2007; 50 (3): 195-201. |
[22] | Hilkens P, Gervois P, Fanton Y, Vanormelingen J, Martens W, Struys T, et al. Effect of isolation methodology on stem cell properties and multilineage differentiation potential of human dental pulp stem cells. Cell and tissue research 2013; 53 (1): 65-78. |
[23] | Raoof M, Yaghoobi MM, Derakhshani A, Kamal-Abadi AM, Ebrahimi B, Abbasnejad M, et al. A modified efficient method for dental pulp stem cell isolation. Dental Research Journal 2014; 1 (2): 244. |
[24] | Samiei M, Aghazadeh M, Alizadeh E, Aslaminabadi N, Davaran S, Shirazi S, et al. Osteogenic/Odontogenic Bioengineering with co-Administration of Simvastatin and Hydroxyapatite on Poly Caprolactone Based Nanofibrous Scaffold. Adv Pharm Bull 2016; (3): 353-365. |
[25] | Garrett IR, Mundy GR. The role of statins as potential targets for bone formation. Arthritis research & therapy 2002; (4): 1-4. |
[26] | Edwards C, Russell R, Spector T. Statins and bone: myth or reality? Calcified tissue international 2001; 9: 63-66. |
[27] | Moshiri A, Shahrezaee M, Shekarchi B, Oryan A, Azma K. Three-dimensional porous gelapin–simvastatin scaffolds promoted bone defect healing in rabbits. Calcified tissue international 2015; 6: 552-564. |
[28] | Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S. Effect of statins on bone mineral density and bone histomorphometry in rodents. Arteriosclerosis, thrombosis, and vascular biology 2001; 1 (10): 1636-1641. |
[29] | Junqueira JC, Mancini MN, Carvalho YR, Anbinder AL, Balducci I, Rocha RF. Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels. Journal of oral science 2002; 4 (3-4): 117-124. |
[30] | Thylin MR, McConnell JC, Schmid MJ, Reckling RR, Ojha J, Bhattacharyya I, et al. Effects of simvastatin gels on murine calvarial bone. J Periodontol 2002; 3 (10): 1141-1148. |
[31] | Wong R, Rabie A. Statin collagen grafts used to repair defects in the parietal bone of rabbits. British Journal of Oral and Maxillofacial Surgery 2003; 1 (4): 244-248. |
[32] | Saraf S, Singh A, Garbyal R, Singh V. Effect of simvastatin on fracture healing—an experimental study. 2007. |
[33] | Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Koyano K. Topical application of statin affects bone healing around implants. Clinical oral implants research 2008; 9 (6): 600-605. |
[34] | Pauly S, Back DA, Kaeppler K, Haas NP, Schmidmaier G, Wildemann B. Influence of statins locally applied from orthopedic implants on osseous integration. BMC musculoskeletal disorders 2012; 3 (1): 1-8. |
[35] | Ayukawa Y, Ogino Y, Moriyama Y, Atsuta I, Jinno Y, Kihara M, et al. Simvastatin enhances bone formation around titanium implants in rat tibiae. Journal of oral rehabilitation 2010; 7 (2): 123-130. |
[36] | Goes P, Lima APS, Melo IM, Rêgo ROCC, Lima V. Effect of Atorvastatin in radiographic density on alveolar bone loss in wistar rats. Brazilian Dental Journal 2010; 1: 193-198. |
[37] | Yoshii T, Hafeman AE, Nyman JS, Esparza JM, Shinomiya K, Spengler DM, et al. A sustained release of lovastatin from biodegradable, elastomeric polyurethane scaffolds for enhanced bone regeneration. Tissue Engineering Part A 2010; 6 (7): 2369-2379. |
[38] | Edwards C, Hart D, Spector T. Oral statins and increased bone-mineral density in postmenopausal women. The Lancet 2000; 55 (9222): 2218-2219. |
[39] | Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. Statin Drugs and the Risk of Fracture—Reply. Jama 2000; 284 (15): 1921-1922. |
[40] | Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, et al. Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. The Lancet 2000; 55 (9222): 2185-2188. |
[41] | van Staa T-P, Wegman S, de Vries F, Leufkens B, Cooper C. Use of statins and risk of fractures. Jama 2001; 85 (14): 1850-1855. |
[42] | Bjarnason N, Riis B, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporosis International 2001; 2: 380-384. |
[43] | Sirola J, Sirola J, Honkanen R, Kröger H, Jurvelin J, Mäenpää P, et al. Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women. Osteoporosis International 2002; 3: 537-541. |
[44] | Rejnmark L, Buus HN, Vestergaard P, Heickendorff L, Andreasen F, Larsen LM, et al. Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women. Journal of Bone and Mineral Research 2004; 9 (5): 737-744. |
[45] | Staal A, Frith JC, French MH, Swartz J, Güngör T, Harrity TW, et al. The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. Journal of Bone and Mineral Research 2003; 8 (1): 88-96. |
[46] | Von Stechow D, Fish S, Yahalom D, Bab I, Chorev M, Müller R, et al. Does simvastatin stimulate bone formation in vivo? BMC musculoskeletal disorders 2003; : 1-10. |
[47] | Murray MM, Spindler KP, Devin C, Snyder BS, Muller J, Takahashi M, et al. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL. Journal of Orthopaedic Research 2006; 4 (4): 820-830. |
[48] | Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH. Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial. Archives of internal medicine 2008; 68 (7): 721-727. |
[49] | Mammen AL, Amato AA. Statin myopathy: a review of recent progress. Current opinion in rheumatology 2010; 2 (6): 644-650. |
[50] | Godlee F. Adverse effects of statins. In.: British Medical Journal Publishing Group; 2014. |
[51] | Oryan A, Kamali A, Moshiri A. Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions. Journal of controlled release 2015; 15: 12-24. |
[52] | Tomlinson SS, Mangione KK. Potential adverse effects of statins on muscle. Physical therapy 2005; 5 (5): 459-465. |
[53] | Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA internal medicine 2013; 73 (14): 1318-1326. |
[54] | Peeters G, Tett SE, Conaghan PG, Mishra GD, Dobson AJ. Is statin use associated with new joint-related symptoms, physical function, and quality of life? Results from two population-based cohorts of women. Arthritis care & research 2015; 7 (1): 13-20. |
[55] | Min KS, Lee YM, Hong SO, Kim EC. Simvastatin promotes odontoblastic differentiation and expression of angiogenic factors via heme oxygenase-1 in primary cultured human dental pulp cells. J Endod 2010; 6 (3): 447-452. |
[56] | Baek KH, Lee WY, Oh KW, Tae HJ, Lee JM, Lee EJ, et al. The effect of simvastatin on the proliferation and differentiation of human bone marrow stromal cells. Journal of Korean medical science 2005; 0 (3): 438-444. |
[57] | Okamoto Y, Sonoyama W, Ono M, Akiyama K, Fujisawa T, Oshima M, et al. Simvastatin induces the odontogenic differentiation of human dental pulp stem cells in vitro and in vivo. J Endod 2009; 5 (3): 367-372. |
[58] | Nath SD, Linh NT, Sadiasa A, Lee BT. Encapsulation of simvastatin in PLGA microspheres loaded into hydrogel loaded BCP porous spongy scaffold as a controlled drug delivery system for bone tissue regeneration. Journal of Biomaterials Applications 2014; 8 (8): 1151-1163. |
[59] | Liu S, Bertl K, Sun H, Liu Z-H, Andrukhov O, Rausch-Fan X. Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells. Human Cell 2012; 5: 29-35. |
[60] | van Vliet AK, Nègre-Aminou P, van Thiel GCF, Bolhuis PA, Cohen LH. Action of lovastatin, simvastatin, and pravastatin on sterol synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle. Biochemical pharmacology 1996; 2 (9): 1387-1392. |
[61] | Nègre-Aminou P, van Vliet AK, van Erck M, van Thiel GCF, van Leeuwen RE, Cohen LH. Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types. Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism 1997; 345 (3): 259-268. |
[62] | Chen P-Y, Sun J-S, Tsuang Y-H, Chen M-H, Weng P-W, Lin F-H. Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway. Nutrition research 2010; 0 (3): 191-199. |
[63] | Yang Y-m, Huang W-d, Xie Q-m, Xu Z-r, Zhao Q-j, Wu X-m, et al. Simvastatin attenuates TNF-α-induced growth inhibition and apoptosis in murine osteoblastic MC3T3-E1 cells. Inflammation research 2010; 9: 151-157. |
[64] | Feng X, Yue X, Niu M. Simvastatin-Loaded Nanomicelles Enhance the Osteogenic Effect of Simvastatin. Journal of Nanomaterials 2020; 020: 1-14. |
[65] | Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circulation research 1998; 3 (5): 490-500. |
[66] | Yao W, Farmer R, Cooper R, Chmielewski P, Tian X, Setterberg R, et al. Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats. JOURNAL OF MUSCULOSKELETAL AND NEURONAL INTERACTIONS 2006; (3): 277. |
APA Style
Kanwal Maheshwari, Laisheng Chou. (2023). Cytotoxic Effects of Simvastatin on Normal Human Osteoblasts. International Journal of Materials Science and Applications, 12(2), 26-35. https://doi.org/10.11648/j.ijmsa.20231202.12
ACS Style
Kanwal Maheshwari; Laisheng Chou. Cytotoxic Effects of Simvastatin on Normal Human Osteoblasts. Int. J. Mater. Sci. Appl. 2023, 12(2), 26-35. doi: 10.11648/j.ijmsa.20231202.12
AMA Style
Kanwal Maheshwari, Laisheng Chou. Cytotoxic Effects of Simvastatin on Normal Human Osteoblasts. Int J Mater Sci Appl. 2023;12(2):26-35. doi: 10.11648/j.ijmsa.20231202.12
@article{10.11648/j.ijmsa.20231202.12, author = {Kanwal Maheshwari and Laisheng Chou}, title = {Cytotoxic Effects of Simvastatin on Normal Human Osteoblasts}, journal = {International Journal of Materials Science and Applications}, volume = {12}, number = {2}, pages = {26-35}, doi = {10.11648/j.ijmsa.20231202.12}, url = {https://doi.org/10.11648/j.ijmsa.20231202.12}, eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijmsa.20231202.12}, abstract = {Statins, hydroxymethylglutaryl-coenzyme-A reductase inhibitors (HMG-Co-A), are known to reduce plasma cholesterol levels. However, the biocompatibility of Simvastatin with human bone tissue has not been studied thoroughly. The purpose of this study was to further investigate the effectiveness of different concentrations of simvastatin on the attachment, proliferation, toxicity, cell cycle, and apoptosis of normal human osteoblasts. Osteoblasts derived from normal human alveolar bone chips were cultured with simvastatin at concentrations of 1, 10, 25, 50, 75, 100 mol/L, and 0 mol/L as a control. The cell attachment was evaluated at 9 hours. The proliferation rate and cytotoxicity were investigated at 7, 14, and 21 days. Cell cycle and apoptosis were assessed at 1 and 3 days. Statistical analysis was performed using ANOVA. P-values ≤0.05 were considered statistically significant. The results showed that there was no statistical significance (P>0.05) amongst the groups in the cell attachment efficiency. All tested concentrations of Simvastatin showed a significant decrease in the proliferation rate (P<0.001) and an increase in cytotoxicity (P<0.001). Cell cycle and apoptosis significantly increased as time increased (P<0.001). In conclusion, the present findings showed that Simvastatin adversely affects human osteoblasts' proliferation and cell viability by inducing apoptosis.}, year = {2023} }
TY - JOUR T1 - Cytotoxic Effects of Simvastatin on Normal Human Osteoblasts AU - Kanwal Maheshwari AU - Laisheng Chou Y1 - 2023/07/21 PY - 2023 N1 - https://doi.org/10.11648/j.ijmsa.20231202.12 DO - 10.11648/j.ijmsa.20231202.12 T2 - International Journal of Materials Science and Applications JF - International Journal of Materials Science and Applications JO - International Journal of Materials Science and Applications SP - 26 EP - 35 PB - Science Publishing Group SN - 2327-2643 UR - https://doi.org/10.11648/j.ijmsa.20231202.12 AB - Statins, hydroxymethylglutaryl-coenzyme-A reductase inhibitors (HMG-Co-A), are known to reduce plasma cholesterol levels. However, the biocompatibility of Simvastatin with human bone tissue has not been studied thoroughly. The purpose of this study was to further investigate the effectiveness of different concentrations of simvastatin on the attachment, proliferation, toxicity, cell cycle, and apoptosis of normal human osteoblasts. Osteoblasts derived from normal human alveolar bone chips were cultured with simvastatin at concentrations of 1, 10, 25, 50, 75, 100 mol/L, and 0 mol/L as a control. The cell attachment was evaluated at 9 hours. The proliferation rate and cytotoxicity were investigated at 7, 14, and 21 days. Cell cycle and apoptosis were assessed at 1 and 3 days. Statistical analysis was performed using ANOVA. P-values ≤0.05 were considered statistically significant. The results showed that there was no statistical significance (P>0.05) amongst the groups in the cell attachment efficiency. All tested concentrations of Simvastatin showed a significant decrease in the proliferation rate (P<0.001) and an increase in cytotoxicity (P<0.001). Cell cycle and apoptosis significantly increased as time increased (P<0.001). In conclusion, the present findings showed that Simvastatin adversely affects human osteoblasts' proliferation and cell viability by inducing apoptosis. VL - 12 IS - 2 ER -