MiR-455-3p activates Nrf2/ARE signaling via HDAC2 and protects osteoblasts from oxidative stress

• Published in: International journal of biological macromolecules 2018-02, Vol.107 (Pt B), p.2094-2101
• Main Authors: Zhang, Shijun, Wu, Wenliang, Jiao, Guangjun, Li, Ci, Liu, Haichun
• Format: Article
• Language: English
• Subjects: Animals; Antioxidant Response Elements - genetics; Apoptosis; Base Sequence; Cell Differentiation; Cell Line; Cytoprotection; HDAC2; Histone Deacetylase 2 - metabolism; Iron - metabolism; Kelch-Like ECH-Associated Protein 1; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-455-3p; NF-E2-Related Factor 2 - metabolism; Osteoblasts; Osteoblasts - metabolism; Osteoblasts - pathology; Osteoporosis; Osteoporosis - pathology; Oxidative Stress; Signal Transduction
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2017.10.080

The important role of miR-455-3p in the pathogenesis of bone metabolism associated diseases is gradually emerging. This study aims to ascertain the involvement of miR-455-3p and its underlying mechanisms in osteoporosis. The osteoblast cell lines MC3T3-E1 was treated with ferric ammonium citrate (FAC) to mimic a pathological environment for osteoporosis. The cytotoxic effect of iron overload was assessed by proliferation, apoptosis and oxidative stress of osteoblasts using commercial kits. Molecular biological methods, including qRT-PCR analysis, cell transfection and luciferase reporter assays were used to explain the role of miR-455-3p and its potential mechanisms in osteoblast apoptosis. FAC dramatically inhibited the proliferation of osteoblast cells MC3T3-E1 but increased the apoptosis. We also observed that FAC significantly down-regulated miR-455-3p in MC3T3-E1 cells but enhanced HDAC2 protein level. Moreover, miR-455-3p overexpression eliminated the effects of iron overload on osteoblast cell proliferation, apoptosis and oxidative stress. In addition, miR-455-3p regulated osteoblast cell proliferation, apoptosis and oxidative stress through regulating HDAC2-Nrf2/ARE signaling pathway. MiR-455-3p overexpression alleviated the oxidative stress injury in osteoporosis mice. Our results demonstrated that miR-455-3p activated Nrf2/ARE signal pathway through suppressing Keap1 via negative regulating HDAC2 protein level, thereby suppressing oxidative stress and promoting osteoblasts growth.