Chrysophanol (Chrysophanic acid; CA) is a natural anthraquinone found in Senna tora and rhubarb that has various characteristic features, including the ability to suppress adipogenesis. However, its effects on osteoblast differentiation have not been investigated. Herein, this study aimed to demonstrate the mechanism by which CA induces the osteoblast differentiation. CA increased the expression of osteogenic genes. The staining levels Alkaline phosphatase (ALP) and Alizarin Red S (ARS) were increased by chrysophanol. CA induced osteoblast differentiation through AMP‐activated protein kinase (AMPK)/Small mothers against decapentaplegic (Smad1/5/9) activation in MC3T3‐E1 cells. In addition, compound C, AMPK inhibitor (Comp. C)‐induced cells suppressed osteogenic genes expression and AMPK/Smad1/5/9 activation. Interestingly, AMPK in the CA‐induced AMPK/Smad1/5/9 signalling pathway was an upstream regulator of Smad1/5/9. In order to further dissect in bone development, we used a zebrafish model to investigate the effect of CA on bone development. These results suggest that CA stimulated bone development via AMPK/Smad1/5/9. Overall, our results demonstrate that CA promotes osteoblast differentiation via AMPK/Smad1/5/9 expression in vitro and in vivo.
Controlling the level of intracellular reactive oxygen species (ROS) is important for the survival and differentiation of osteoblasts. Intracellular ROS levels are controlled by antioxidant enzymes that modulate the redox state of the cell. Nucleoredoxin-like 1 (NXNL1) is an antioxidant enzyme that increases the viability of rod and cone cells by protecting them from oxidative stress, and is a potential pharmacological target for the treatment of retinitis pigmentosa. The present study investigated the role of NXNL on osteoblast differentiation of MC3T3-E1 preosteoblast cells. Results from qPCR experiments demonstrated that growth differentiation factor 15 (GDF15) increased NXNL1 expression, and that GDF15-induced NXNL1 decreased the expression of osteogenic genes such as distal-less homeobox 5 (Dlx5) and Runt-related transcription factor 2. Furthermore, NXNL1 also inhibits bone morphogenetic protein 2-induced phosphorylation of Smad1/5/9 and alkaline phosphatase activity. The inhibitory effects of NXNL1 on osteoblast differentiation were mediated by protein phosphatase 2A Cα (PP2A Cα). The expression of PP2A Cα was regulated by GDF15, and overexpression of PP2A Cα increased the expression of NXNL1.Taken together, our results demonstrate that NXNL1 inhibits osteoblast differentiation of MC3T3-E1 due to GDF15-induced expression of PP2A Cα.
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