The effect of simvastatin on the differentiation of marrow stromal cells from aging rats.

Simvastatin is a pro-drug of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Simvastatin inhibits cholesterol synthesis in humans and animals. Antecedent studies reported that statins could increase bone formation in vitro in cell lineages and primary cultured marrow stromal cells (MSCs) from juvenile mice. MSCs maintain the ability to differentiate into multiple lineages in adult life, but a decline in the stemness potential with aging has been recognized, which results in reduced osteogenesis and increased adipogenesis in the bone marrow. Thus, we assessed the effect of simvastatin on osteoblastic and adipocytic differentiation of MSCs from aging rats, 18 months of age. Simvastatin, added into culture medium with a low dose of dexamethasone, enhanced alkaline phosphatase (ALP) activity and staining, increased the gene expression of ALP and osteocalcin (OC), and promoted mineralization in a dose-dependent fashion. Simultaneously, simvastatin also decreased Oil Red O staining and inhibited the gene expression of lipoprotein lipase (LPL) and peroxisome proliferator activated receptor (PPAR gamma 2) in a dose-dependent fashion. Significant effects were observed at 10(-6) M and 10(-7) M simvastatin (p < 0.05). These results indicate that simvastatin has anabolic effects on bone through the inhibition of adipocytic differentiation and the modest promotion of osteoblastic differentiation, suggesting that it could be used for the treatment of common metabolic bone diseases, such as aged osteoporosis.