Abstract
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 both in vivo and in vitro models. 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 H2O2 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 H2O2 treated 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.
Highlights
Osteoporosis is a disease in which bones become fragile, leading to increased bone fracture risk
Primary antibodies against phosphorylated extracellular- signal-regulated kinase 1/2 (ERK1/2), phosphorylated p38, phosphorylated c-Jun N-terminal kinase (JNK), phosphorylated Akt, and total ERK1/2, p38, JNK and Akt were purchased from Cell Signaling Technology (Beverly, MA, USA)
The metabolism of the deacetylation and de-esterification products was completed within 5 min as evidenced by the rapid disappearance of these products accompanied by the appearance of anethole dithiolethione sulphoraphane (ADT)-OH and its metabolites
Summary
Osteoporosis is a disease in which bones become fragile, leading to increased bone fracture risk. The pathogenesis of osteoporosis is still not fully understood, recent findings support that reactive oxygen species (ROS) are important in the development of osteoporosis (Basu et al, 2001; Isomura et al, 2004; Manolagas, 2010). In all cases of osteoporosis, there is an imbalance between bone resorption and bone formation. Osteoblasts are responsible for bone formation and osteoclasts are associated with bone degradation. Osteoporosis can occur when bone formation decreases and bone resorption increases or remains unchanged, leading to a net bone loss (Isomura et al, 2004). ROS accelerate apoptosis of osteoblasts, inhibit their differentiation, and impair bone formation (Bai et al, 2004; She et al, 2014; Li et al, 2015)
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