Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells

Song, Chunli; Guo, Zhixin; Ma, Qilong; Chen, Zhongqiang; Liu, Zhongjun; Jia, Hong-Ti; Dang, Gengting

doi:10.1016/s0006-291x(03)01408-6

Cited by 170 publications

(141 citation statements)

References 23 publications

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“…Statins stimulate increased expression of the BMP-2 gene in osteoblasts, and simvastatin has been suggested to activate the protein kinase pathway and resist the inhibitory action of TNF-α on BMP-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho mitosis (25,26). Statins are associated with a variety of other activities including induction of osteoblast differentiation (27), resistance of the inhibitory effects on osteoblast growth and enhancement of osteoclast activity induced by IL-1, IL-6, TNF-α and other inflammatory factors (28), inhibition of matrix metalloproteinase activity (29), upregulation of vascular endothelial growth factor (VEGF) (30), enhanced activity of endothelial nitric oxide synthase (eNOS) (31) and inhibition of differentiation of adipose cells from multipotential stem cells (32).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Zhao

Zhang

et al. 2011

Mol Med Report

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Abstract. Apoptosis of osteoblasts has been proposed as the common basis of osteoporosis, with oxidative stress as the major cause. This study was performed to investigate the protective effect of simvastatin (0.001-0.1 µM) on 100 µM hydrogen peroxide (H 2 O 2 )-mediated oxidative stress-induced apoptosis in human osteosarcoma (MG63) cells and the molecular mechanisms involved. Cell apoptosis was evaluated by observation of morphological changes and Annexin V-propidium iodide double staining followed by flow cytometric analysis. MTS assays were used to evaluate cell viability. To investigate the underlying molecular mechanisms, the expression of caspase-3, caspase-9 and Bcl-2 were analyzed by Western blotting. Following stimulation with H 2 O 2 for 24 h, a high proportion of MG63 cells underwent apoptosis, while a dosedependent inhibition of apoptosis was observed in the presence of simvastatin. A significant, dose-dependent reduction in the expression of caspase-3 and caspase-9 protein induced by H 2 O 2 in MG63 cells was observed in response to simvastatin and the Bcl-2 levels were increased. In conclusion, simvastatin protects MG63 cells from oxidative stress-induced apoptosis through downregulation of caspase-3 and caspase-9 activation and upregulation of Bcl-2 expression, suggesting a protective effect in osteoporosis. IntroductionOsteoporosis has been defined as a systemic skeletal disease characterized by gradual loss and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture (1). Osteoblasts are responsible for bone formation while osteoclasts are involved in bone resorption. Conditions such as postmenopausal osteoporosis are associated with significant changes in bone turnover; bone formation decreases and bone resorption increases or remains the same, resulting in net bone loss (2,3).Oxidative stress, resulting from excessive levels of reactive oxygen species (ROS), represents a major cause of cellular damage and death in a plethora of pathological conditions, including osteoporosis. This is associated with distinct increases in blood levels of oxidative stress markers (4-6). The main oxygen species responsible for oxidative stress are hydrogen peroxide (H 2 O 2 ), the free radical superoxide anion (O 2 -) and the hydroxyl radical (OH -). Osteoblasts produce antioxidants such as glutathione peroxidase that protect against ROS (7) and osteoclast-generated superoxide contributes to bone degradation (8). In ovariectomized rats, a model of postmenopausal osteoporosis, increased levels of lipid peroxidation and H 2 O 2 and decreased levels of enzymatic antioxidants were detected in tissue homogenates from the femora (9). Furthermore, antioxidant enzyme GPX1 gene polymorphisms are associated with low bone mineral density (BMD) and increased bone turnover markers (10).The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA) reductase inhibitor, simvastatin, is a widely used cholesterollowering drug that inhibits hepatic cholesterol biosynthesis. Recent...

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Section: Discussionmentioning

confidence: 99%

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Zhao

Zhang

et al. 2011

Mol Med Report

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“…Since locally applied statins were found to be potent stimulators of bone formation 5) , the possibility of using these compounds as practical bone anabolic agents has been postulated. Song et al reported that statins promote osteoblast differentiation and expression of BMPs in mouse bone marrow stromal cells 6) .…”

Section: Introductionmentioning

confidence: 99%

Osteogenic Effect of Local Administration of Fluvastatin using a Fluvastatin-gelatin Complex in Senile Osteoporosis Model Rat

Yasuda

Koji

Satô

et al. 2014

J. Hard Tissue Biology.

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Statins, inhibitors of 3-hydroxy-2-methyl-glutaryl coenzyme A reductase, were recently reported to promote the differentiation of osteoblasts produced by the stimulation of bone morphogenetic protein-2 (BMP-2). The aim of this study was to investigate the osteogenic effect of a local administration of fluvastatin in senile osteoporosis model rats using a fluvastatin-gelatin complex. The gelatin-hydrogel was put into cylindrical titanium tubes 1.5 mm in diameter and 2.2 mm high. It was then crosslinked by ultraviolet irradiation, after which it was lyophilized. Subsequently, the carriers were placed in the fluvastatin solution (300 μM) for one day to bind the alkaline gelatin and acidic statin electrostatically (fluvastatin-gelatin complex; statin group). A control group consisted of the carriers immersed in sterilized water. Specimens of both the statin group and the control group were implanted into the femur of 15-week-old male senile osteoporosis model rats (SHRSP). Radiographic analysis, histologic examination, and immunohistochemical staining (BMP-2 and Runx2) were then performed. At 14 and 21 days, the bone volumes of the newly formed bone in the statin group was significantly higher compared to those of the control group (P<0.05). Histological observation showed that a high level of new bone formation was present in the statin group compared to that of the control group during all time periods. At 7 days, positive immune reactions with BMP-2 and Runx2 were seen in the statin group. The local administration of the fluvastatin-gelatin complex facilitated bone formation in senile osteoporosis model rats.

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“…Previous in vitro studies have indicated that statins in the dose range of 0.01-5 µM increase expression of osteogenic marker genes, such as RUNX-2, BMP-2, osteocalcin, osteopontin, and alkaline phosphatase, in cultured osteoblastic cells and bone marrow-derived cells. [9][10][11][12][13][14][15] In this study, the amount of simvastatin released daily was within the concentrations range of 0.02-0.53 µg/day (0.1-5 µM/day), which significantly stimulated osteogenic gene expression of RUNX-2, BMP-2, alkaline phosphatase, and osteocalcin ( Figure 3A-D) and final mineralization ( Figure 3E) in cultured D1 cells. This result indicates that this newly developed SIM/PLGA/HAp system releases a nontoxic therapeutic dose of simvastatin for osteogenesis in bone marrow stromal cells.…”

Section: Discussionmentioning

confidence: 53%

“…[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.…”

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confidence: 99%

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

Tai¹,

Fu²,

Wang³

et al. 2013

IJN

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Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells

Cited by 170 publications

References 23 publications

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Osteogenic Effect of Local Administration of Fluvastatin using a Fluvastatin-gelatin Complex in Senile Osteoporosis Model Rat

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

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