Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK
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. FASEB J. 33, 4236–4247 (2019). www.fasebj.org
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A few studies have revealed that homeobox genes, such as Lhx2, Dlx5, and Pax6, affect osteoclast formation.
“A few studies have revealed that homeobox genes, such as Lhx2, Dlx5, and Pax6, affect osteoclast formation44–46”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [46]
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Ma, Q., Wang, S., Xue, H., Ni, L., Yuan, P., Shen, Y., Zheng, B., Wang, Q., Zhang, J., Wang, H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61938-0 · Cited by 15 · see citing works
“A few studies have revealed that homeobox genes, such as Lhx2, Dlx5 , and Pax6 , affect osteoclast formation 44 – 46 ; however, these minority studies are fragmented and unsystematic.”
Self-citation
- Authors
- Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang, B., Tang, P., Qin, A., Fan, S., & Xie, Z.
- Affiliations
- Sir Run Run Shaw Hospital (CN)
- Zhejiang University (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Fan, Shunwu
- Xie, Ziang
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2018-12-07
- Volume
- 33
- Issue
- 3
- Pages
- 4236-4247
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2904782810
- Cited by
- 22
- References
- 45
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 1
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Basic Research Program of China (2018YFC1105200)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- osteoclastogenesis, β-catenin, Pax6, p38 MAPK, RANKL, ubiquitin-mediated proteolysis, NF-κB, SKL2001, transcriptional regulation, bone resorption
- MeSH terms
- PAX6 Transcription Factor, Animals, Bone Resorption, Cell Differentiation, Female, Male, Mice, Inbred C57BL, Osteoclasts, Osteogenesis, Phosphorylation, Up-Regulation, NF-kappa B, p38 Mitogen-Activated Protein Kinases, beta Catenin, Mice, RANK Ligand
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