Simvastatin attenuates TNF-α-induced growth inhibition and apoptosis in murine osteoblastic MC3T3-E1 cells

Yang, Yunmei; Huang, Weidong; Xie, Qiang-min; Xu, Zhe-rong; Zhao, Qiu; Wu, Ximei; Li, Fenfen; Dong, Xiaopeng

doi:10.1007/s00011-009-0082-y

Cited by 6 publications

(1 citation statement)

References 34 publications

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“…The critically suppressed osterix expression and dramatically elevated apoptotic cell proportion strongly suggested that both differentiation suppression and apoptosis induction contributed to the compromised mineralization ability of cementoblasts. An inhibitory effect on the proliferation of cementoblasts was also observed by MTS assay, although no obvious change in the short exposure period groups was observed, similar to the results obtained on MC3T3-E1 cells (Yang et al 2010). This result may be caused by the time-dependent effect of TNF-α on proliferation, and the short exposure period groups demonstrated effects that were too marginal for detection.…”

Section: Discussionsupporting

confidence: 80%

Effects of TNF-α on Cementoblast Differentiation, Mineralization, and Apoptosis

Wang

Liu

et al. 2015

J Dent Res

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Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown. In this study, we found that TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis. Various signaling pathways, such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways. Taken together, these results suggested that the differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway.

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Section: Discussionsupporting

confidence: 80%

Effects of TNF-α on Cementoblast Differentiation, Mineralization, and Apoptosis

Wang

Liu

et al. 2015

J Dent Res

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Simvastatin protects osteoblast against H2O2-induced oxidative damage via inhibiting the upregulation of Nox4

Huang

Shang

et al. 2011

Mol Cell Biochem

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Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been used clinically as a cholesterol-lowering drug to treat hyperlipidemia. In recent years, accumulating evidence indicates the possible beneficial effect of statins on osteoporosis. However, the underlying molecular mechanism remains to be elucidated. In the present study, we investigated the therapeutic effects of simvastatin on cell viability, apoptosis, and alkaline phosphatase activity in murine osteoblastic MC3T3-E1 cells treated by hydrogen peroxide (H(2)O(2), 100 μM). It was shown that simvastatin suppressed H(2)O(2)-induced oxidative stress and attenuated H(2)O(2)-induced cell injury including increasing osteoblastic viability, inhibiting apoptosis, and promoting differentiation. Then, we examined the effects of simvastatin (10(-7) M) on Nox1, Nox2, and Nox4 expressions in osteoblastic cells treated by H(2)O(2) (100 μM). We found that in MC3T3-E1 cells, H(2)O(2)-induced upregulation of Nox4 expression was inhibited by simvastatin, which was restored by farnesyl pyrophosphate (5 μM) as well as geranylgeranyl pyrophosphate (5 μM). RNAi approach was used to reduce Nox4 protein levels in osteoblastic cells to explore its biological effects against H(2)O(2)-induced oxidative damage. When Nox4 expression was reduced in osteoblastic cells, H(2)O(2)-induced cell injury was attenuated markedly. We concluded that simvastatin protected osteoblast against H(2)O(2)-induced oxidative damage, at least in part, via inhibiting the upregulation of Nox4.

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