Rosuvastatin promotes osteoblast differentiation and regulates SLCO1A1 transporter gene expression in MC3T3-E1 cells.
Rosuvastatin (RSV) is a synthetic statin with favourable pharmacologic properties including minimal metabolism, hepatic selectivity and enhanced inhibition of HMG-CoA reductase. An induction of osteoblast differentiation has been reported in vitro with lipophilic statins but not with RSV, which, like pravastatin, is relatively hydrophilic compared with other statins. To mediate its action, an active transport mechanism via solute carrier (SLC) transporters from the SLC16, SLC21/SLCO and SLC22 gene family - specifically Slc16a1, Slco1a1, Slco2b1 and Slc22a8 - may be present to allow effective entry in osteoblastic cells. In this study, we demonstrate that RSV induced osteoblast differentiation, as measured by increased BMP-2 gene expression and secretion, and ALP activity in MC3T3-E1 osteoblast cells, without significantly affecting cell proliferation within the concentration range of 0.001-10 μM. Low concentrations of RSV (0.001-0.01 μM) were protective against cell death whereas higher concentrations (10-100 μM) showed cytotoxicity. Moreover, MC3T3-E1 osteoblasts expressed high levels of Slco1a1 and Slc16a1 mRNA and low levels of Slco2b1 and Slc22a8 mRNA, when compared with kidney and liver tissues from mice. Slco1a1 gene expression increased 12-fold during osteoblast differentiation and was further regulated after RSV treatment. In conclusion, as for other statins, RSV promotes osteoblast differentiation, and also, demonstrated for the first time, regulates the expression of Slco1a1, which may constitute the transport system for RSV across the cell membrane in mature osteoblasts.
Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Oslo, Norway.
Marta
M
Monjo
Marina
M
Rubert
Jan Eirik
JE
Ellingsen
S Petter
SP
Lyngstadaas
D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D027701:Organic Cation Transport Proteins
D000469:Alkaline Phosphatase; D055396:Bone Morphogenetic Protein 2; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D011743:Pyrimidines; D012333:RNA, Messenger; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C572127:SLCO1A1 protein, mouse; D027701:Organic Cation Transport Proteins