title: Tanshinone IIA blocks dexamethasone-induced apoptosis in osteoblasts through inhibiting Nox4-derived ROS production.
abstract: Apoptosis of osteoblasts caused by glucocorticoids has been identified as an important contributor to the development of osteoporosis. Tanshinone IIA (Tan), an active ingredient extracted from the rhizome of the Salvia miltiorrhiza Bunge (Danshen), has been reported to cast positive effects on osteoporosis. However, the precise mechanisms accounting this action remain elusive. In this study, by using osteoblastic MC3T3-E1 cells as a model, we confirmed the protective effects of Tan against dexamethasone (Dex)-induced cell apoptosis and further clarified its molecular mechanism of action. Our results showed that treatment with Dex caused cell injury, increased cytosol cytochrome c level and Nox expression, induced apoptosis in caspase-9-dependent manner, and enhanced reactive oxygen species (ROS) production. Tan attenuated these deleterious consequence triggered by Dex. Moreover, Dex-induced ROS production and cell injury were inhibited by antioxidant, NADPH oxidases inhibitors, Nox4 inhibitor, and Nox4 small interfering RNA (siRNA). Overexpression of Nox4 almost abolished the inhibitory effect of Tan on Dex-induced cell injury and apoptosis. The results also demonstrated significant involvement of Nox4 in the Dex-induced apoptosis. Nox4-derived ROS led to apoptosis through activation of intrinsic mitochondrial pathway. Additionally, we evidenced that Tan reversed Dex-induced apoptosis via inactivation of Nox4. The present findings suggest that inhibition of Nox4 may be a novel therapeutic approach of Tan to prevent against glucocorticoids-induced osteoblasts apoptosis and osteoporosis.
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Chongru
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tong
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Dahe
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Changhai Hospital, Second Military Medical University Shanghai 200433, P. R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Xu
mesh_terms: D016475:3T3 Cells; D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000009:adverse effects*; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000517:prevention & control*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D045784:Abietanes; D000975:Antioxidants; D005938:Glucocorticoids; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C021751:tanshinone; D003907:Dexamethasone; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D053453:Caspase 9
keywords: Nox4; Tanshinone IIA; apoptosis; glucocorticoids; osteoporosis