TET2 regulates osteoclastogenesis by modulating autophagy in OVX-induced bone loss

Increased bone resorption by osteoclasts after estrogen deficiency is the main cause of postmenopausal osteoporosis. TET2 (tet methylcytosine dioxygenase 2) is a DNA demethylase that regulates cellular function and differentiation potential. Macroautophagy/autophagy maintains cellular homeostasis by...

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Bibliographic Details
Published in:Autophagy 2022-12, Vol.18 (12), p.2817-2829
Main Authors: Yang, Chen, Tao, Huaqiang, Zhang, Haifeng, Xia, Yu, Bai, Jiaxiang, Ge, Gaoran, Li, Wenming, Zhang, Wei, Xiao, Long, Xu, Yaozeng, Wang, Zhirong, Gu, Ye, Yang, Huilin, Liu, Yu, Geng, Dechun
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - physiology
BCL2
Bone Resorption - pathology
Cell Differentiation
Dioxygenases - metabolism
DNA-Binding Proteins - metabolism
Mice
osteoclast
Osteoclasts - metabolism
Osteogenesis - genetics
osteoporosis
Proto-Oncogene Proteins c-bcl-2 - metabolism
Research Paper
TET2
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Summary:Increased bone resorption by osteoclasts after estrogen deficiency is the main cause of postmenopausal osteoporosis. TET2 (tet methylcytosine dioxygenase 2) is a DNA demethylase that regulates cellular function and differentiation potential. Macroautophagy/autophagy maintains cellular homeostasis by recycling unnecessary and damaged organelles. This study revealed that TET2 promoted bone loss in oophorectomized (OVX) mice and that TET2 promoted osteoclast differentiation by regulating autophagy. Tet2 knockdown inhibited autophagy and osteoclast differentiation in vitro. Mechanistically, Tet2 knockdown increased BCL2 (B cell leukemia/lymphoma 2) expression and BCL2 exhibited increased binding to BECN1 and negatively regulated autophagy. Small interfering RNA specific to Bcl2 interfered with BCL2 expression in Tet2-knockdown bone marrow cells/precursors, partially reversing autophagy dysregulation and promoting osteoclast differentiation. Moreover, the LV-shTet2 lentivirus prevented bone loss in OVX mice. In summary, our findings provide evidence that TET2 promotes osteoclast differentiation by inhibiting BCL2 expression and positively regulating BECN1-dependent autophagy. Abbreviations: ACP5/TRAP: acid phosphatase 5, tartrate resistant; ATP6V0D2: ATPase, H+ transporting, lysosomal V0 subunit D2; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BMs: bone marrow cells; CTSK: cathepsin K; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MMP9: matrix metallopeptidase 9; OVX: oophorectomy; RUNX1: runt related transcription factor 1; SOCS3: suppressor of cytokine signaling 3; SPI1/PU.1: Spi-1 proto-oncogene; TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11; TET2: tet methylcytosine dioxygenase 2.
ISSN:1554-8627
1554-8635
DOI:10.1080/15548627.2022.2048432