Effects of Bakuchiol on chondrocyte proliferation via the PI3K-Akt and ERK1/2 pathways mediated by the estrogen receptor for promotion of the regeneration of knee articular cartilage defects.

Kang Xu,Yongqiang Sha,Li Yang,Chunli Wang,Sixiang Wang,Yanju Liu,Qingjia Chi

doi:10.1111/cpr.12666

Abstract

ObjectivesCartilaginous tissue degradation occurs because of the lack of survival of chondrocytes. Here, we ascertained whether bakuchiol (BAK) has the capability of activating chondrocyte proliferation.Materials and methodsThe effect of BAK on the proliferation of rat chondrocytes at a concentration of 10 and 20 µmol/L was investigated. The molecular mechanisms involving target binding and signalling pathways were elucidated by RNA‐sequencing, qPCR, molecular docking and Western blotting. Matrigel mixed with bakuchiol was implanted locally into rat knee articular cartilage defects to verify the activation of chondrocytes due to bakuchiol in vivo.ResultsBakuchiol implantation resulted in the activation of rat chondrocyte proliferation in a dose‐dependent manner. RNA‐sequencing revealed 107 differentially expressed genes (DEGs) with 75 that were up‐regulated and 32 that were down‐regulated, indicating increased activation of the PI3K‐Akt and cell cycle pathways. Activation of the phosphorylation of Akt, ERK1/2 and their inhibitors blocked the proliferative effect of bakuchiol treatment, confirming its direct involvement in these signal transduction pathways. Molecular docking and siRNA silencing revealed that estrogen receptor‐α (ERα) was the target of bakuchiol in terms of its cell proliferative effect via PI3K activation. Two weeks after implantation of bakuchiol, the appearance and physiological structure of the articular cartilage was more integrated with abundant chondrocytes and cartilage matrix compared to that of the control.ConclusionsBakuchiol demonstrated significant bioactivity towards chondrocyte proliferation via the PI3K‐Akt and ERK1/2 pathways mediated by estrogen receptor activation and exhibited enhanced promotion of the remodelling of injured cartilage.

Highlights

Dietary supplements and traditional herbal medicines are consid‐ ered to be forms of complementary and alternative medicine that are extensively used globally and widely used for the prevention of cartilage degeneration in Asia and other developed countries
In this study and in accordance with our initial hypotheses and experimental results, we have demonstrated that bakuchiol, a bioactive natural product, caused significant stimula‐ tion of chondrocyte proliferation via the PI3K‐Akt and ERK1/2 sig‐ nal transduction pathways mediated by estrogen receptors
We demonstrated that components in extracts of fructus psoraleae demonstrated the potential to treat cartilage degeneration induced by chondrocyte apoptosis

Summary

Introduction

Dietary supplements and traditional herbal medicines are consid‐ ered to be forms of complementary and alternative medicine that are extensively used globally and widely used for the prevention of cartilage degeneration in Asia and other developed countries. (Leguminosae), exhibits powerful effects against dis‐ eases of the skeletal system.[1-3]. It has been established that baku‐ chiol, a natural meroterpenoid compound extracted from Fructus psoraleae, exhibits antioxidant,[4] antitumour,[5] antimicrobial[6] and anti‐inflammatory activity.[7]. We have previously demonstrated that components of extracts of fructus psoraleae demonstrate the potential to treat cartilage de‐ generation induced by chondrocyte death.[8]. We found that bakuchiol was present at a concentration as high as 84.5% of the active extract and that it was the principal cartilage protective component within the extract. This discovery has motivated us to continue to explore the therapeutic possibilities of bakuchiol against cartilage diseases

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Conclusion