Fumitremorgin C Attenuates Osteoclast Formation and Function via Suppressing RANKL-Induced Signaling Pathways.

Yu Yuan,Chao Wang,Jun Zou,Jennifer Tickner,Zhen Cao,Xi Chen,Heng Qiu,Dezhi Song,Jiake Xu,Youqiang Sun,Jianmin Guo,Kai Chen

doi:10.3389/fphar.2020.00238

Abstract

Excessive bone resorption conducted by osteoclasts is considered as the main cause of osteoclast-related bone diseases such as osteoporosis. Therefore, the suppression of excessive osteoclast formation and function is one of the strategies to treat osteoclast-related bone diseases. Fumitremorgin C (Fum) is a mycotoxin extracted from Aspergillus fumigatus. It has been shown to have extensive pharmacological properties, but its role in the treatment of osteoclast-related bone diseases remains unclear. In this study, we aim to find out whether Fum can inhibit the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and function. The results showed that Fum could significantly attenuate osteoclast formation and function at concentrations from 2.5 to 10 µM. The protein expression of bone resorption factors such as NFATc1, cathepsin K, V-ATPase-d2, and c-Fos was suppressed with the treatment of Fum at a concentration of 10 µM. In addition, Fum was also shown to suppress the activity of NF-κB, intracellular reactive oxygen species level, and MAPK pathway. Taken together, the present study showed that Fum could attenuate the formation and function of osteoclast via suppressing RANKL-induced signaling pathways, suggesting that Fum might be a potential novel drug in the treatment of osteoclast-related bone diseases.

Highlights

Bone is a dynamic organ keeping constant remodeling throughout life
All of these results suggest that Fumitremorgin C (Fum) is capable of inhibiting receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis without obvious cytotoxicity on Bone marrow-derived macrophages (BMMs)
Osteoclasts play an essential role in regulating bone remodeling, and excessive bone resorption regulated by osteoclasts is considered as the main cause of osteoclast-related bone diseases (Sun et al, 2019)

Summary

Introduction

The dynamic balance of bone remodeling depends on the osteoblast-induced bone formation and the osteoclast-regulated bone resorption (He et al, 2013). During osteoclastogenesis and bone resorption, both receptor activator of nuclear factor-kB ligand (RANKL) and M-CSF are the necessary cytokines for osteoclast formation and function (Karst et al, 2004). M-CSF plays an indispensable role in the survival, formation, and function of osteoclast (De Vries et al, 2015). RANKL, a TNF ligand superfamily member, is an essential cytokine during osteoclastogenesis and bone resorption via interacting with RANK (Kreja et al, 2007). RANK is essential for osteoclast survival, formation, and activation as well (Dougall, 2012). The interaction between RANKL and RANK leads to the activation of NF-kB, MAPK, and NFATc1 signaling (Song et al, 2016)

Objectives

Methods

Results

Conclusion