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VGLL3 Regulates DAPK2-Mediated Autophagy During Osteoblast Differentiation
Yuhan He1, Ziyi Wang2, Yao Weng1
1Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Biofactors (Oxford, England)
|April 29, 2026
Summary
Vestigial-like family member 3 (VGLL3) regulates osteoblast differentiation by controlling autophagy through death-associated protein kinase 2 (DAPK2). Restoring autophagy partially rescues VGLL3
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Vestigial-like family member 3 (VGLL3) is a known regulator of osteoblast differentiation.
- VGLL3 is a transcriptional cofactor of the TEA domain family.
Purpose of the Study:
- To investigate VGLL3 function in MC3T3-E1 osteoblasts.
- To identify VGLL3 downstream effectors and explore associated autophagy mechanisms.
Main Methods:
- Transcriptomic analysis (RNA-seq) of Vgll3-knockdown cells.
- Functional assays including transmission electron microscopy, western blotting (LC3-II, p62), qPCR, and staining (alkaline phosphatase, Alizarin Red).
- Pharmacologic manipulation using rapamycin and genetic manipulation (knockdown and overexpression).
Main Results:
- Death-associated protein kinase 2 (DAPK2) was identified as a downstream effector of VGLL3.
- VGLL3 knockdown suppressed autophagic flux, decreased LC3-II, and increased p62.
- DAPK2 knockdown impaired osteoblast differentiation, similar to VGLL3 knockdown.
- Rapamycin treatment partially restored autophagy and osteogenic differentiation in Vgll3-deficient cells.
- DAPK2 overexpression partially rescued autophagy and differentiation in Vgll3-deficient cells.
Conclusions:
- VGLL3 influences osteogenic differentiation in osteoblasts through DAPK2-associated autophagy.
- DAPK2 is a key downstream functional effector of VGLL3 in this process.
- FOXM1 may act as a transcriptional regulator of DAPK2.
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