Abstract
Accumulation of reactive oxygen species (ROS), which can be induced by inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), can significantly inhibit the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). This process can contribute to the imbalance of bone remodeling, which ultimately leads to osteoporosis. Therefore, reducing the ROS generation during osteogenesis of BMSCs may be an effective way to reverse the impairment of osteogenesis. Melatonin (MLT) has been reported to act as an antioxidant during cell proliferation and differentiation, but its antioxidant effect and mechanism of action during osteogenesis of MSCs in the inflammatory microenvironment, especially in the presence of TNF-α, remain unknown and need further study. In our study, we demonstrate that melatonin can counteract the generation of ROS and the inhibitory osteogenesis of BMSCs induced by TNF-α, by upregulating the expression of antioxidases and downregulating the expression of oxidases. Meanwhile, MLT can inhibit the phosphorylation of p65 protein and block the degradation of IκBα protein, thus decreasing the activity of the NF-κB pathway. This study confirmed that melatonin can inhibit the generation of ROS during osteogenic differentiation of BMSCs and reverse the inhibition of osteogenic differentiation of BMSCs in vitro, suggesting that melatonin can antagonize TNF-α-induced ROS generation and promote the great effect of osteogenic differentiation of BMSCs. Accordingly, these findings provide more evidence that melatonin can be used as a candidate drug for the treatment of osteoporosis.
Highlights
Reactive oxygen species (ROS) are oxygen-containing chemically active substances
These results showed that melatonin can reduce the generation of ROS induced by TNF-α during osteogenic differentiation
We induced bone marrow mesenchymal stem cells (BMSCs), which have a stronger osteogenesis potential than other sources of MSCs, to undergo osteogenic differentiation, and we found that melatonin can decrease the generation of ROS—which had been significantly increased by TNF-α supplementation—to a remarkable degree (Figure 1), through downregulating the expression of NADPH oxidase1 (NOX1) and NADPH oxidase2 (NOX2) (Figure 3) and upregulating the expression of SOD1 and CAT (Figure 4)
Summary
Reactive oxygen species (ROS) are oxygen-containing chemically active substances. They include the hydroxyl radical (OH), hydroxyl ion (OH-) hydrogen peroxide (H2O2), and superoxide anion (O2-). ROS can be formed as a natural byproduct of cellular oxygen metabolism, mainly in the mitochondria. It can be derived from nicotinamide adenine dinucleotide phosphate oxidase (NAPDH oxidase/NOX), peroxisome, xanthine oxidase, and lipolytic enzyme [1]. There are antioxidant systems that can antagonize ROS production, such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), to maintain a normal level of ROS. ROS remain at low levels with no obvious cytotoxicity and they can play an important role in
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