The Effect of Simvastatin on the Proliferation and Differentiation of Human Bone Marrow Stromal Cells

Abstract

Statins have been postulated to affect the bone metabolism. Recent experimental and epidemiologic studies have suggested that statins may also have bone protective effects. This study assessed the effects of simvastatin on the proliferation and differentiation of human bone marrow stromal cells (BMSCs) in an ex vivo culture. The bone marrow was obtained from healthy donors. Mononuclear cells were isolated and cultured to osteoblastic lineage. In the primary culture, 10-6 M simvastatin diminished the mean size of the colony forming units-fibroblastic (CFU-Fs) and enhanced matrix calcification. At near confluence, the cells were sub-cultured. Thereafter, the alkaline phosphatase (ALP) activities of each group were measured by the time course of the secondary culture. Simvastatin increased the ALP activity in a dose dependent manner, and this stimulatory effect was more evident during the early period of culture. A 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay was performed during the secondary culture in order to estimate the effect of simvastatin on the proliferation of human BMSCs. When compared to the control group, simvastatin significantly decreased the proliferation of cells of each culture well. 10-6 M of simvastatin also significantly enhanced the osteocalcin mRNA expression level. This study shows that simvastatin has a stimulatory effect on bone formation through osteoblastic differentiation, and has an inhibitory effect on the proliferative potential of human BMSCs

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

“…0.5 g) would be diluted by 54 -153 ml of fluid after 24h. This would give rise to a dynamic concentration of simvastatin within the micromolar range, which could be expected to stimulate osteoblastic cells [27,[33][34][35]. The incorporation of simvastatin in brushite cement can therefore be expected to increase the effectiveness of the non-invasive treatment, this remaining to be evaluated in future studies.…”

“…The concentration of the simvastatin solution was selected with three considerations in mind: 1) a simvastatin concentration between 0.01 and 1 µM has been shown to promote osteoblastic differentiation in vitro [27,[33][34][35], 2) there is a dynamic exchange of interstitial fluids in vivo, flow rate in pig bones was estimated to be 7.5-21.3 ml/min/100g [36] and, 3) 1h-set cement released almost half of the dosage in 1 day (preliminary study using a simvastatin solution of 2 mM).…”

Behavioural and cognitive effects of simvastatin dose used in stimulation of bone regeneration in rats

“…The latter, in turn, are widely used to lower blood cholesterol level and can stimulate bone formation, as observed by the increasing activity of the alkaline phosphatase, osteocalcin expression levels and mineral deposits, suggesting an anabolic effect on bone tissue by increasing osteoblast differentiation 6 . Some studies suggest that simvastatin (SVT) enhances differentiation of osteoblasts in humans, measured by increased alkaline phosphatase activity and the expression of osteoblast-related genes 7 .…”

“…The materials available for bone regeneration are still expensive and unaffordable to many patients, and therefore, there is a tireless search by the scientific community for a biomaterial that is efficient and, at the same time, accessible to the majority of the population 6,8 .…”

Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair

“…[10][11][12][13][14][15] Previous in vivo studies showed that oral administration of a high dose of simvastatin (20 mg/kg/day) enhances trabecular bone volume in ovariectomized rats. 9, 16 Skoglund et al also reported that systemic administration of an extremely high dose of simvastatin (120 mg/kg/day) in mice increases bone healing.…”