Glucose oxidase facilitates osteogenic differentiation and mineralization of embryonic stem cells through the activation of Nrf2 and ERK signal transduction pathways

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signal is known to play important roles in controlling bone homeostasis. This study examined how oxidative stress affects the mineralization of embryonic stem (ES) cells by exposing them to glucose oxidase (GO), which continuously generates H2O2 at low concentrations. The roles of Nrf2/HO-1 and mitogen-activated protein kinases on osteogenesis in GO-exposed ES cells were also investigated. GO treatment at relatively low concentrations did not change the viability of ES cells, whereas it enhanced osteogenic differentiation and mineralization in the cells. GO treatment (1 mU/ml) augmented the induction of runt-related transcription factor 2 (Runx2), Nrf2, and HO-1 in ES cells. GO-mediated acceleration of Runx2 expression and mineralization was inhibited either by Nrf2 knockdown or by treating with 5 μM PD98059, an inhibitor of phospho-extracellular signal-regulated kinase (p-ERK). The GO-stimulated mineralization was also suppressed by treating the cells with reduced glutathione or catalase, but not by superoxide dismutase or N-acetyl-cysteine. Collectively, our results demonstrate that a mild oxidative stress activates Nrf2/HO-1 signaling and an ERK-mediated pathway, and facilitates the mineralization of ES cells with a corresponding increase in Runx2.

Curcumin Protects Osteoblasts From Oxidative Stress-Induced Dysfunction via GSK3β-Nrf2 Signaling Pathway

“…It is well recognized that Runx2 plays a key role in osteoblastic differentiation and bone formation. Nrf2 is reported to positively regulate the expression of Runx2 (Sim et al, 2016). Therefore, our finding suggested that Nrf2 stabilization and activation mediated the protective effects of Cur on the viability and differentiation of osteoblasts.…”

Activation of KEAP1/NRF2/P62 signaling alleviates high phosphate-induced calcification of vascular smooth muscle cells by suppressing reactive oxygen species production

“…However, mild oxidative stress can activate a protective mechanism via the NRF2 signaling pathway, while high ROS accumulation activates a stress signal related to cell death rather than survival 42 . Additionally, according to the previous report 43 , NRF2 signaling is activated in response to ROS and regulates bone metabolism positively or negatively depending on the degree of oxidative stress. NRF2 signaling positively controls bone homeostasis by maintaining an intracellular redox balance, whereas NRF2 may negatively regulate cellular differentiation to osteoblasts through inhibition of the Runx2-dependent transcriptional activity.…”

The Role of Nrf2 in Cardiovascular Function and Disease

“…For example, studies in vitro using rodent vascular smooth muscle cells show that dimethyfumarate or resveratrol could attenuate the deposition of a mineralised matrix and suggest protection against oxidative stress-induced mitochondrial damage, via activation of Nrf2 and SIRT1 signaling and downregulation of osteogenic transcription factors [ 126 , 127 ]. In contrast, glucose-induced oxidative stress enhances the osteogenic differentiation and mineralisation of human embryonic stem (ES) cells, by the upregulation of runt-related transcription factor 2 (Runx2), Nrf2, and HMOX1, which was inhibited by Nrf2 knockdown [ 128 ] highlighting a context-specific regulation of the calcification process. Given the links between Nrf2 and bone homeostasis, it is not surprising to have an association between Nrf2 signaling and vascular calcification.…”