TNF-α inhibits SATB2 expression and osteoblast differentiation through NF-κB and MAPK pathways.

Chijian Zuo,Yu Shi,Guoli Hu,Xiaoying Zhao,Xiaoling Zhang,Chuandong Wang,Ning Zhang,Jiake Xu,Wen Wu

doi:10.18632/oncotarget.23373

Abstract

Although the mechanisms of Tumor necrosis factor alpha (TNF-α) on facilitating osteoclast differentiation and bone resorption is well known, the mechanisms behind the suppression of the osteoblast differentiation from mesenchymal stem cells (MSCs) are still poorly understood. In this study, we observed a negative correlation between TNF-α levels and the expression of special AT-rich sequence-binding protein 2 (SATB2), a critical osteoblastogenesis transcription factor, in ovariectomy (OVX)-induced bone loss and IL-1-induced arthritis animal model. We found that TNF-α treatment inhibited mesenchymal cell line C2C12 osteoblast differentiation and sharply decreased BMP2-induced SATB2 expression. Upon TNF-α treatment, the activity of smad1/5/8 was inhibited, by contrast, extracellular signal-regulated kinase-1/2 (ERK1/2) and P38 was increased in C2C12 cells, the inhibitor of ERK1/2 (U0126) was found to abrogate the TNF-α inhibition of SATB2 expression. Furthermore, the NF-κB signaling pathway in C2C12 cells was significantly activated by the treatment of TNF-α, and TNF-α induced NF-κB directly binds to SATB2 promoter to suppress its expression. These results suggest that TNF-α suppresses SATB2 expression through activating NF-κB and MAPK signaling and depressing smad1/5/8 signaling, which contributes to the inhibition of osteoblast differentiation and might be potential therapeutic targets for inflammation-induced bone loss.

Highlights

Pathological status such as high inflammatory responses often leads to an imbalance of bone remodeling which usually results in bone loss such as osteoporosis and arthritis [1,2,3]
To proof the models are successful, the Bone Mineral Density (BMD) and BMC of the OVX- and shamoperated mice were examined using micro-CT (Figure 1A) and the bone mass were shown by H & E staining (Figure 1B) and the levels of TNF-α and IL-1β in the synovia in the IL-1β-induced arthritis mice and PBS-induced control mice were detected by ELISA (Figure 1F) and the bone mass were shown by H & E
TNF-α is a critical inflammatory cytokine that induces bone loss in osteoporosis, rheumatoid arthritis [29], prosthetic loosening and other osteolytic diseases based on its osteoblastic differentiation inhibition and osteoclastic bone resorption stimulation, which leads to an ultimate imbalance in bone remodeling

Summary

Introduction

Pathological status such as high inflammatory responses often leads to an imbalance of bone remodeling which usually results in bone loss such as osteoporosis and arthritis [1,2,3]. Tumor necrosis factor alpha (TNF-α) is critical for the pathogenesis of bone loss as it stimulates osteoclastic bone resorption and suppresses osteoblastic bone formation. The mechanisms of TNF-α in facilitating osteoclast differentiation and bone resorption is well known, the mechanisms behind the suppression of the osteoblast differentiation from mesenchymal stem cells (MSCs) are still poorly understood. TNF-α stimulates Wwp expression and facilitates the transcription factor JunB degradation, which in turn, attenuates MSCs osteoblast differentiation [7]. Due to the complexity of the transcriptional network of osteoblast differentiation and the complex signaling of TNF-α and osteoblastregulating factors, the above findings can only partially explain the molecular mechanisms of the inhibition of osteoblastogenesis by TNF-α

Methods

Results

Conclusion