Abstract
Over-production of hydrogen peroxide (H2O2) will lead to human osteoblast dysfunction and apoptosis, causing progression of osteoporosis and osteonecrosis. NF-E2-related factor 2 (Nrf2) is a well-characterized anti-oxidant signaling. Cullin 3 (Cul3) ubiquitin E3 ligase dictates Nrf2 degradation. We demonstrate that microRNA-455 (“miR-455”) is a putative Cul3-targeting microRNA. Forced-expression of miR-455 in both hFOB1. 19 osteoblast cell line and primary human osteoblasts induced Cul3 degradation and Nrf2 protein stabilization, which led to subsequent transcription of ARE (anti-oxidant response element)-dependent genes (NQO1, HO1 and GCLC). Cul3 silencing, by expressing miR-455 or targeted-shRNA, protected human osteoblasts from H2O2. Reversely, miR-455 anti-sense caused Cul3 accumulation and Nrf2 degradation, which exacerbated H2O2 damages in hFOB1. 19 cells. Moreover, forced over-expression of Cul3 in hFOB1. 19 cells silenced Nrf2 and sensitized H2O2. Together, we propose that miR-455 activated Nrf2 signaling and protected human osteoblasts from oxidative stress possibly via targeting Cul3.
Highlights
Over-production of reactive oxygen species (ROS) shall cause oxidative damages to human osteoblasts
We discovered that miR-455 (“-3p.1”) putatively targets the 3-untranslated region (UTR) of Cullin 3 (Cul3) mRNA at position 28-34 (Figure 1A)
Thereafter, a miR-455-expressing vector was constructed (See Method), which was introduced to hFOB1. 19 human osteoblastic cells
Summary
Over-production of reactive oxygen species (ROS) shall cause oxidative damages to human osteoblasts. It is the key contributor of osteoporosis or even osteonecrosis [1,2,3,4]. In vitro studies have been adding H2O2 to the cultured human osteoblasts to establish a cellular model of osteoporosis/ osteonecrosis [7,8,9,10] This model would help to understand the pathological mechanisms of ROS-induced osteoblast injuries, and to develop possible intervention strategies [11,12,13,14,15,16]
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