Kaempferol Ameliorates the Inhibitory Activity of Dexamethasone in the Osteogenesis of MC3T3-E1 Cells by JNK and p38-MAPK Pathways

Baocheng Xie,Zhanwei Zeng,Chenhui Zhou,Daohua Xu,Longhuo Wu,Shiyi Liao

doi:10.3389/fphar.2021.739326

Abstract

Kaempferol has been reported to exhibit beneficial effect on the osteogenic differentiation in mesenchymal stem cells (MSC) and osteoblasts. In our previous study, dexamethasone (DEX) demonstrated inhibitory effect on MC3T3-E1 cells differentiation. In this study, we mainly explored the protective effect of kaempferol on the inhibitory activity of DEX in the osteogenesis of MC3T3-E1 cells. We found that kaempferol ameliorated the proliferation inhibition, cell cycle arrest, and cell apoptosis and increased the activity of alkaline phosphatase (ALP) and the mineralization in DEX-treated MC3T3-E1 cells. Kaempferol also significantly enhanced the expression of osterix (Osx) and runt-related transcription factor 2 (Runx2) in MC3T3-E1 cells treated with DEX. In addition, kaempferol attenuated DEX-induced reduction of cyclin D1 and Bcl-2 expression and elevation of p53 and Bax expression. Kaempferol also activated JNK and p38-MAPK pathways in DEX-treated MC3T3-E1 cells. Furthermore, kaempferol improved bone mineralization in DEX-induced bone damage in a zebrafish larvae model. These data suggested that kaempferol ameliorated the inhibitory activity of DEX in the osteogenesis of MC3T3-E1 cells by activating JNK and p38-MAPK signaling pathways. Kaempferol exhibited great potentials in developing new drugs for treating glucocorticoid-induced osteoporosis.

Highlights

Glucocorticoids are widely used in the anti-inflammatory treatment of various immune-mediated diseases, such as rheumatic arthritis and inflammatory bowel disease (Güler-Yüksel et al, 2018; Vandewalle et al, 2018)
We explored the roles of kaempferol on the suppression of osteogenesis induced by dexamethasone (DEX) in MC3T3-E1 cells and zebrafish
The EdU assay demonstrated that DEX significantly inhibited cell proliferation (p < 0.01), and the kaempferol (5 and 10 μM) ameliorated the inhibition of cell proliferation caused by DEX (p < 0.05) (Figures 1C,D)

Summary

Introduction

Glucocorticoids are widely used in the anti-inflammatory treatment of various immune-mediated diseases, such as rheumatic arthritis and inflammatory bowel disease (Güler-Yüksel et al, 2018; Vandewalle et al, 2018). Long-term use of glucocorticoids could cause a variety of serious adverse effects. Glucocorticoids inhibited cellular proliferation, osteoblast differentiation, and mineralization of osteoblasts and induced cell apoptosis in vivo and in vitro (Yoon et al, 2012; Chen et al, 2016). Glucocorticoid-induced osteoporosis (GIOP), a secondary iatrogenic osteoporosis, is one of the most common clinical complications (Buehring et al, 2013). A research indicated that 30–50% patients with GIOP would have the risk of fractures if they were. Kaempferol Protects Against GIOP treated with long-term glucocorticoids and that the risk would never return to the baseline after discontinuing administration of glucocorticoids (Buehring et al, 2013). Fracture is a significant cause of increased mortality and reduced quality of life. It is critical to discover new drugs to counteract GIOP

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Results

Conclusion