Administration of SB239063 Ameliorates Ovariectomy-Induced Bone Loss via Suppressing Osteoclastogenesis in Mice.

Bao Huang,Ziang Xie,Jiasheng Wang,Shunwu Fan,Fengdong Zhao,Hao Wu,An Qin,Jian Chen,Junhui Liu,Xiangde Zhao,Xuyang Zhang,Zhiwei Jie

doi:10.3389/fphar.2019.00900

Abstract

Activation of osteoclast formation and function is crucial for the development of osteolytic diseases such as osteoporosis. RANKL (receptor activator of nuclear factor-κB ligand) activates NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) signaling pathways to induce osteoclastogenesis. In this study, we demonstrated that SB239063, a p38-specific inhibitor, suppressed osteoclastogenesis and bone resorption via inhibiting phosphorylation of MEF2C (myocyte enhancer factor 2C) and subsequently leading to MEF2C degradation by ubiquitination. Knockdown of MEF2C impaired osteoclast formation due to decreased c-Fos expression. Furthermore, MEF2C can directly bind to the promoter region of c-Fos to initiate its transcription. Interestingly, overexpression of either MEF2C or c-Fos can partially rescue the inhibitory effect of SB239063 on osteoclastogenesis. In addition, in vivo data proved that SB239063 also played a preventive role in both LPS (lipopolysaccharide)- and OVX (ovariectomy)-induced bone loss in mice. In conclusion, our results show that SB239063 can be a potential therapy for osteolytic diseases, and a novel p38/MEF2C/c-Fos axis is essential for osteoclastogenesis.

Highlights

Bone is a highly dynamic tissue that undergoes consistent remodeling, which relies on the balance between bone-resorbing osteoclasts and bone-forming osteoblasts
In view of the reports that myocytespecific enhancer factor 2C (MEF2C) has been revealed to be a phosphorylation-dependent transcription factor mainly activated by p38/mitogen-activated protein kinase (MAPK) (Han et al, 1997; Zhang et al, 2014; Brown et al, 2018), we investigated whether SB239063 can suppress the nuclear translocation of MEF2C and subsequently influence c-Fos expression
We demonstrated that MEF2C mainly phosphorylated by p38 played a crucial role in osteoclastogenesis by promoting the translational activation of c-Fos

Summary

Introduction

Bone is a highly dynamic tissue that undergoes consistent remodeling, which relies on the balance between bone-resorbing osteoclasts and bone-forming osteoblasts. The receptor activator of nuclear factor-κ B ligand (RANKL) and its receptor [receptor activator of nuclear factor κ B (RANK)] are vital regulators in the formation and function of multinucleated osteoclasts (Arai et al, 1999), which are derived from the monocyte/. RANKL binding to RANK can lead to the activation of many molecules such as TRAF6 (TNF receptor-associated factor 6) (Darnay et al, 1999), following the activation of downstream signaling mechanisms including NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) pathways (Pearson et al, 2001; Xie et al, 2018). The multinucleated osteoclasts are gradually induced after upregulation and activation of downstream molecules, such as NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) (Takayanagi et al, 2002a) and c-Fos (Monje et al, 2005). Key molecules of the RANKL-induced signaling pathways could be therapeutic targets when treating osteoclastic diseases

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