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Updated: Feb 1, 2026
Reconstitution Of β-catenin Degradation In Xenopus Egg Extract
Published on: June 17, 2014
Activating β-catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of
Zhiwei Jie1,2, Shuying Shen1,2, Xiangde Zhao1,2
1Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Balance of osteoclast formation is regulated by the receptor activator of NF-κB ligand and extracellular negative regulators such as IFN-γ and IFN-β. However, very little is known about the intrinsic negative regulatory factors of osteoclast differentiation. Recently, the paired-box homeodomain transcription factor Pax6 was shown to negatively regulate receptor activator of NF-κB ligand-mediated osteoclast differentiation. However, the mechanism underlying this regulation is still unclear. In this study, we show that a p38 inhibitor (VX-745) up-regulates the expression of Pax6 during osteoclast differentiation. Subsequently, we found that β-catenin could bind to the proximal region of Pax6 promoter to induce its expression, and this action could be impaired by p38-induced ubiquitin-mediated degradation of β-catenin. Our results suggest that Pax6 is regulated by a novel p38/β-catenin pathway. Pax6 can further regulate the nuclear translocation of NF of activated T cells, cytoplasmic 1. Our study indicates that this novel p38/β-catenin/Pax6 axis contributes to negative regulation of osteoclastogenesis. In addition, our study proposes a novel approach to treat osteoclast-related diseases through the use of VX-745 complemented with the β-catenin activator SKL2001.-Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang, B., Tang, P., Qin, A., Fan, S., Xie, Z. Activating β-catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK.
Insights
A novel p38/β-catenin/Pax6 pathway negatively regulates osteoclast formation. Activating this axis, particularly with VX-745 and SKL2001, offers a new therapeutic strategy for osteoclast-related diseases.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Osteoclast formation is crucial for bone remodeling and is tightly regulated.
- While extracellular factors are known regulators, intrinsic negative regulators of osteoclast differentiation remain less understood.
- The transcription factor Pax6 has been identified as a negative regulator, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which Pax6 negatively regulates osteoclast differentiation.
- To identify the signaling pathways involved in the regulation of Pax6 during osteoclastogenesis.
- To explore potential therapeutic strategies for osteoclast-related diseases.
Main Methods:
- Utilized a p38 inhibitor (VX-745) to study its effect on Pax6 expression.
- Investigated the interaction between β-catenin and the Pax6 promoter.
- Examined the role of p38 in β-catenin degradation.
- Assessed the impact of the identified pathway on NFATc1 nuclear translocation.
Main Results:
- VX-745 treatment up-regulated Pax6 expression during osteoclast differentiation.
- β-catenin binds to the Pax6 promoter, inducing its expression.
- p38 signaling mediates β-catenin degradation, which can be inhibited by VX-745.
- The p38/β-catenin/Pax6 pathway negatively regulates osteoclastogenesis by affecting NFATc1 nuclear translocation.
Conclusions:
- A novel signaling axis involving p38, β-catenin, and Pax6 negatively regulates osteoclastogenesis.
- Pax6 plays a key role in this negative feedback loop.
- Targeting the p38/β-catenin/Pax6 pathway, using agents like VX-745 and SKL2001, presents a promising therapeutic approach for bone diseases characterized by excessive osteoclast activity.
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