AUTHOR=Yan Xiaofei , Wu Haixia , Wu Zhiyuan , Hua Fei , Liang Dong , Sun Hong , Yang Yong , Huang Dejian , Bian Jin-Song 

TITLE=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

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00007

DOI=10.3389/fphar.2017.00007

ISSN=1663-9812

ABSTRACT=<p>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 (H<sub>2</sub>S) produce significant antioxidant effect in various systems. In this study, we synthesized SDSS, a novel H<sub>2</sub>S-releasing compound derived from DSS, and studied its antioxidant effect in an H<sub>2</sub>O<sub>2</sub>-induced MC3T3-E1 osteoblastic cell injury model. We first characterized the H<sub>2</sub>S releasing property of SDSS in both <italic>in vivo</italic> and <italic>in vitro</italic> models. HPLC chromatogram showed that intravenous injection of SDSS in adult rats released ADT-OH, a well proved H<sub>2</sub>S sustained-release moiety, within several minutes in the rat plasma. Using an H<sub>2</sub>S selective fluorescent probe, we further confirmed that SDSS released H<sub>2</sub>S in MC3T3-E1 osteoblastic cells. Biological studies revealed that SDSS had no significant toxic effect but produced protective effects against H<sub>2</sub>O<sub>2</sub>-induced MC3T3-E1 cell apoptosis. SDSS also reversed the arrest of cell differentiation caused by H<sub>2</sub>O<sub>2</sub> treatment. 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 H<sub>2</sub>O<sub>2</sub> treated cells. In addition, SDSS significantly attenuated H<sub>2</sub>O<sub>2</sub>-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 H<sub>2</sub>O<sub>2</sub>-induced apoptosis by suppressing oxidative stress, inhibiting MAPKs, and activating the phosphatidylinositol 3-kinase/Akt pathway.</p>