Simvastatin Promotes Osteoblast Differentiation and Mineralization in MC3T3-E1 Cells

Maeda, Toshio; Matsunuma, Ayako; Kawane, Tetsuya; Horiuchi, Noboru

doi:10.1006/bbrc.2000.4232

Cited by 330 publications

(260 citation statements)

References 19 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Cement Preparationmentioning

confidence: 99%

“…It stimulates the expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts [26] and enhances alkaline phosphatase (ALP) activity and mineralization [27]. The drug release was monitored and modeled through Korsmeyer-Peppas (KP) equation.…”

Section: Introductionmentioning

confidence: 99%

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

Mestres

Kugiejko

Pastorino

et al. 2016

Materials Science and Engineering: C

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Calcium phosphate cements are synthetic bone graft substitutes able to set at physiological conditions. They can be applied by minimally invasive surgery and can also be used as drug delivery systems.Consequently, the drug release pattern from the cement paste (fresh cement) is of high clinical interest.However, previous studies have commonly evaluated the drug release using pre-set cements only.Therefore, the aim of this work was to determine if the time elapsed from cement preparation until immersion in the solution (3 min for fresh cements, and 1 h and 15 h for pre-set cements) had an influence on its physical properties, and correlating these to the drug release profile. Simvastatin was selected as a model drug, while brushite cement was used as drug carrier. This study quantified how the setting of a material reduces the accessibility of the release media to the material, thus preventing drug release. A shift in the drug release pattern was observed, from a burst-release for fresh cements to a sustained release for pre-set cements.

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Section: Discussionmentioning

confidence: 99%

Section: Cement Preparationmentioning

confidence: 99%

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

Mestres

Kugiejko

Pastorino

et al. 2016

Materials Science and Engineering: C

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“…The continued inhibition of HMG-CoA reductase activity and therefore of cholesterol synthesis resulting from high, sustained concentrations of simvastatin acid appear to have adversely affected the cells and prevented growth and activity. After Mundy and colleagues (1999) reported that simvastatin induced expression of BMP-2 in a model reporter system, Maeda et al (2001) showed that continuous low doses of simvastatin enhanced AP activity and mineralization and increased BMP-2 production in MC3T3E-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Most relevant to the present work, Mundy's group originally demonstrated that statins induce expression of bone morphogenetic protein 2 (BMP-2) and that they stimulate bone formation on the calvaria of mice following daily subcutaneous injections (Mundy et al, 1999). Subsequent studies have shown that oral dosing with simvastatin increases cancellous bone volume in rats (Maeda et al, 2001), and it also increases transverse area of fracture callus as well as mechanical properties compared to controls (Skoglund et al, 2002).…”

Section: Introductionmentioning

confidence: 93%

Bioerodible devices for intermittent release of simvastatin acid

Jeon

Thomas

Puleo

2007

International Journal of Pharmaceutics

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The association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used to create intermittent release devices for mimicking the daily injection of simvastatin that has been reported to stimulate bone formation. To enhance solubility in water, prodrug simvastatin was modified by lactone ring opening, which converts the molecule to its hydroxyacid form. CAP/ PF-127 microspheres incorporating simvastatin acid were prepared by a water-acetone-oil-water (W/ A/O/W) triple emulsion process. Devices were then fabricated by pressure-sintering UV-treated blank and drug-loaded microspheres. Using a multilayered fabrication approach, pulsatile release profiles were obtained. Delivery was varied by changing loading, number of layers, blend ratio, and incubation conditions. To determine the cellular effects of intermittent exposure to simvastatin acid, MC3T3-E1 cells were cultured with either alternating or sustained concentrations of simvastatin acid in the medium, and DNA content, alkaline phosphatase activity, and osteocalcin secretion were measured. For all three cell responses, cultures exposed to simvastatin acid showed higher activity than did control cultures. Furthermore, cell activity was greater for cells cultured with intermittent concentrations of simvastatin acid compared to cells that were constantly treated. These results imply that devices intermittently releasing simvastatin acid warrant further study for locally promoting osteogenesis.

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