The New Synthetic H2S-Releasing SDSS Protects MC3T3-E1 Osteoblasts against H2O2-Induced Apoptosis by Suppressing Oxidative Stress, Inhibiting MAPKs, and Activating the PI3K/Akt Pathway.
Reactive oxygen species (ROS) are important in osteoporosis development. Oxidative stress induces apoptosis of osteoblasts and arrest of their differentiation. Both Danshensu (DSS) and hydrogen sulfide (H2S) produce significant antioxidant effect in various systems. In this study, we synthesized SDSS, a novel H2S-releasing compound derived from DSS, and studied its antioxidant effect in an H2O2-induced MC3T3-E1 osteoblastic cell injury model. We first characterized the H2S releasing property of SDSS in bothin vivoandin vitromodels. HPLC chromatogram showed that intravenous injection of SDSS in adult rats released ADT-OH, a well proved H2S sustained-release moiety, within several minutes in the rat plasma. Using an H2S selective fluorescent probe, we further confirmed that SDSS released H2S in MC3T3-E1 osteoblastic cells. Biological studies revealed that SDSS had no significant toxic effect but produced protective effects against H2O2-induced MC3T3-E1 cell apoptosis. SDSS also reversed the arrest of cell differentiation caused by H2O2treatment. This was caused by the stimulatory effect of SDSS on bone sialoprotein, runt-related transcription factor 2, collagen expression, alkaline phosphatase activity, and bone nodule formation. Further studies revealed that SDSS reversed the reduced superoxide dismutase activity and glutathione content, and the increased ROS production in H2O2treated cells. In addition, SDSS significantly attenuated H2O2-induced activation of p38-, ERK1/2-, and JNK-MAPKs. SDSS also stimulated phosphatidylinositol 3-kinase/Akt signaling pathway. Blockade of this pathway attenuated the cytoprotective effect of SDSS. In conclusion, SDSS protects MC3T3-E1 cells against H2O2-induced apoptosis by suppressing oxidative stress, inhibiting MAPKs, and activating the phosphatidylinositol 3-kinase/Akt pathway.
Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong UniversityXi'an, China; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.
Xiaofei
X
Yan
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore; Department of Food Science, Faculty of Science, National University of SingaporeSingapore, Singapore.
Haixia
H
Wu
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
Zhiyuan
Z
Wu
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
Fei
F
Hua
Department of Food Science, Faculty of Science, National University of Singapore Singapore, Singapore.
Dong
D
Liang
Department of Physiology, Xuzhou Medical University Xuzhou, China.
Hong
H
Sun
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University Nanjing, China.
Yong
Y
Yang
Department of Food Science, Faculty of Science, National University of Singapore Singapore, Singapore.
Dejian
D
Huang
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
Jin-Song
JS
Bian
MAPK signaling; PI3K/AKT; hydrogen sulfide donating drugs; osteoblast; reactive oxygen species