Statin-induced calcification in human mesenchymal stem cells is cell death related.
Statins are widely used in clinics to lower cholesterol levels. Recently, they have been shown to positively affect bone formation and bone mass in a rat model. The aim of this study was to investigate the effect of pravastatin, simvastatin and lovastatin on the osteoblastic differentiation of human mesenchymal stem cells (MSCs) in vitro. Cell number, alkaline phosphatase (ALP) activity, matrix mineralization and gene expression pattern were determined. Pravastatin did not affect cell differentiation. Simvastatin and lovastatin enhanced bone morphogenetic protein 2 (BMP-2) mRNA levels. In contrast, ALP activity and mRNA levels were suppressed by statins, as well as the DNA content and cell activity (MTT). An increase in apoptotic events was observed at high concentrations of statins, along with high Ca-45 incorporation. Lower concentrations of statins did not increase apoptotic staining, but also failed to induce calcification. When statin-induced calcification did occur, the morphology of the deposits was very different from the conventional nodule formation; the calcium was laid down along the membranes of the rounded cells suggesting it was as a result of cell death. Our results indicate that statins are not able to differentiate human MSCs into osteoblasts and that high concentrations of statins (>1 microM) have a cytotoxic effect.
Kupcsik
Laszlo
L
Biomaterials and Tissue Engineering Program, AO Research Institute, Davos, Switzerland.
Meurya
Thomas
T
Flury
Matthias
M
Stoddart
Martin
M
Alini
Mauro
M
D000469:Alkaline Phosphatase / Q000378:metabolism; D001681:Biological Assay; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013194:Staining and Labeling
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D004247:DNA; D000469:Alkaline Phosphatase; D002118:Calcium