Compactin and Simvastatin, but Not Pravastatin, Induce Bone Morphogenetic Protein-2 in Human Osteosarcoma Cells

Sugiyama, Masako; Kodama, Tohru; Konishi, Kyoko; Abe, Keiichi; Asami, Sumio; Oikawa, Shinzo

doi:10.1006/bbrc.2000.2697

Cited by 253 publications

(204 citation statements)

References 28 publications

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“…The main mechanism of action of the statins is to increase bone formation through stimulation of bone morphogenetic protein (BMP), which is important in the differentiation and induction of osteoblasts (6,33). Sugiyama et al (33) proved that the effect of simvastatin on BMP-2 is the result of inhibition of HMG-CoA reductase and that this enzyme is a regulator of bone morphogenetic protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…Sugiyama et al (33) proved that the effect of simvastatin on BMP-2 is the result of inhibition of HMG-CoA reductase and that this enzyme is a regulator of bone morphogenetic protein expression. Moreover, the statins inhibit the bone reabsorption process because they induce osteoclast apoptosis by the same mechanism as biphosphonates containing nitrogen (34).…”

Section: Discussionmentioning

confidence: 99%

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Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels.

Junqueira

Mancini

Carvalho

et al. 2002

Journal of Oral Science

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Abstract:The purpose of this study was to evaluate the effects of simvastatin on guided bone regeneration in the mandibles of ovariectomized rats, and to observe their blood cholesterol levels. Seventy female rats were divided into two groups: control and treated, both groups containing normal and ovariectomized rats. A month after ovariectomy a bone defect was created in the mandible, and was covered by a polytetrafluoroethylene membrane. The treated groups received simvastatin orally for 15 or 30 days. The rats were sacrificed 15, 30 or 60 days after surgery, at which time a blood sample was extracted for blood cholesterol level analysis and the mandible was extracted for densitometric, histological and morphometric analysis. All specimens underwent analysis of variance. The ovariectomized animals had higher cholesterol levels than the treated normal animals, and no significant difference was found between the different treatment periods and the sacrifice times. The densitometric, histological and morphometric analysis showed that the treated ovariectomized animals developed more new bone than the control ovariectomized rats, but no significant difference was observed between the treatment periods. It can be concluded that the deficiency of estrogen increased the level of blood cholesterol and that the simvastatin aided new bone formation in the ovariectomized animals. (J. Oral Sci. 44, 117-124, 2002)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels.

Junqueira

Mancini

Carvalho

et al. 2002

Journal of Oral Science

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“…19,20 As we previously showed that BMP-2 promotes human osteosarcoma cell apoptosis through BMPR-IB signaling, 18 we tested the hypothesis that statins may induce osteosarcoma cell apoptosis by increasing BMP-2 production. To this goal, we compared the effects of statins in SaOS 2 cells that express BMP-RIB and OHS 4 cells that do not express this receptor.…”

Section: Statin-induced Osteosarcoma Cell Apoptosis Occurs Independenmentioning

confidence: 99%

“…18 Some statins are known to activate the BMP-2 promoter, 19,20 resulting in increased Runx2 expression and osteoprogenitor cell commitment to osteoblasts. 21 These studies raise the question of whether statins may promote apoptosis in osteosarcoma cells through induction of BMP-2.…”

Section: Introductionmentioning

confidence: 99%

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation. Although statins increased BMP-2 expression, the proapoptotic effect of statins was not prevented by the BMP antagonist noggin, and was abolished by mevalonate and geranylgeranylpyrophosphate, suggesting the involvement of defective protein geranylgeranylation. Consistently, lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44-mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statininduced apoptosis. Thus, lipophilic statins induce caspasedependent osteosarcoma cell apoptosis by a RhoA-p42/p44 MAPKs-Bcl-2-mediated mechanism, independently of BMP-2 signaling and cell differentiation.

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“…Statins are potent pro-drugs of hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors that block conversion of HMG-CoA to mevalonic acid, which is needed for cholesterol biosynthesis (Sugiyama et al, 2000). Simvastatin occupies a portion of the binding site for HMG-CoA, thus blocking access of substrate to the active site (Istvan and Deisenhofer, 2001).…”

Section: Introductionmentioning

confidence: 99%

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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Compactin and Simvastatin, but Not Pravastatin, Induce Bone Morphogenetic Protein-2 in Human Osteosarcoma Cells

Cited by 253 publications

References 28 publications

Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels.

Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels.

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

Bioerodible devices for intermittent release of simvastatin acid

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