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

Abstract

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.

Simvastatin rescues homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by decreasing the expressions of NADPH oxidase 1 and 2

“…[25] and MG-63 cells [26]. In addition, in their studies, treatment with simvastatin significantly prevented the apoptotic effects of H 2 O 2 in the cells [25,26]. In the present study, we demonstrated the protective effect of simvastatin against Hcy-induced increases in Nox1 and Nox2 expressions and apoptosis of osteocytic cells, suggesting that simvastatin has anti-apoptotic effects on not only osteoblasts but also osteocytes by reducing oxidative stress.…”

“…In addition, we showed for the first time that simvastatin ameliorated the Hcy-induced apoptosis and the upregulation of Nox1 and Nox2 in MLO-Y4 cells. [25] and MG-63 cells [26]. In addition, in their studies, treatment with simvastatin significantly prevented the apoptotic effects of H 2 O 2 in the cells [25,26].…”

“…Statistical evaluations for differences between groups were performed using one-way ANOVA foland/or activity in various cell types [21][22][23][24], including osteoblasts [25,26]. Therefore, we hypothesized that statins might prevent Hcy-induced apoptosis.…”

Nrf2 Inhibits Periodontal Ligament Stem Cell Apoptosis under Excessive Oxidative Stress

“…In recent years, accumulating evidence has indicated that many drugs suppressed H 2 O 2 -induced oxidative stress and attenuated its induced cell injury via the expression of Nrf2 [43]. Research has also confirmed that Nrf2 itself influences the intrinsic and extrinsic apoptosis pathways at different levels [19].…”

Oxidative actions of hydrogen peroxide in human gingival and oral periosteal fibroblasts: Responses to glutathione and nicotine, relevant to healing in a redox environment

“…It is relevant that in our investigation, glutathione was effective in overcoming the oxidative effects of nicotine and H 2 O 2 , using steroid biomarkers which are mediated by the functions of androgen receptor, including modulation of AP activity and matrix synthesis. Therapeutic effects of simvastatin on cell viability, apoptosis, and alkaline phosphatase activity in murine osteoblastic cells have been demonstrated in response to H 2 O 2 [39]. Simvastatin suppressed H 2 O 2 -induced oxidative stress and attenuated H 2 O 2 -induced cell injury including increased osteoblastic viability, inhibition of apoptosis, and enhanced cell- differentiation.…”