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Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

Authors
 Sue Young Oh  ;  Namju Kang  ;  Jung Yun Kang  ;  Ki Woo Kim  ;  Jong-Hoon Choi  ;  Yu-Mi Yang  ;  Dong Min Shin 
Citation
 FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, Vol.9 : 646,803, 2021-03 
Journal Title
 FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 
Issue Date
2021-03
Keywords
antioxidant proteins ; autophagy inducer ; bone homeostasis ; osteoclast differentiation ; reactive oxygen species
Abstract
The receptor activator of nuclear factor-kappa B ligand (RANKL) mediates osteoclast differentiation and functions by inducing Ca2+ oscillations, activating mitogen-activated protein kinases (MAPKs), and activating nuclear factor of activated T-cells type c1 (NFATc1) via the RANK and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interaction. Reactive oxygen species (ROS) also plays an important role during osteoclastogenesis and Sestrin2, an antioxidant, maintains cellular homeostasis upon stress injury via regulation of ROS, autophagy, and inflammation. However, the role of Sestrin2 in osteoclastogenesis remains unknown. In this study, we investigated the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation. Deletion of Sestrin2 (Sesn2) increased bone mass and reduced the number of multinucleated osteoclasts on bone surfaces. RANKL-induced osteoclast differentiation and function decreased in Sesn2 knockout (KO) bone marrow-derived monocytes/macrophages (BMMs) due to inhibition of NFATc1 expression, but osteoblastogenesis was not affected. mRNA expression of RANKL-induced specific osteoclastogenic genes and MAPK protein expression were lower in Sesn2 KO BMMs than wild-type (WT) BMMs after RANKL treatment. However, the Sesn2 deletion did not affect ROS generation or intracellular Ca2+ oscillations during osteoclastogenesis. In contrast, the interaction between TRAF6 and p62 was reduced during osteoclasts differentiation in Sesn2 KO BMMs. The reduction in the TRAF6/p62 interaction and TRAP activity in osteoclastogenesis in Sesn2 KO BMMs was recovered to the WT level upon expression of Flag-Sesn2 in Sesn2 KO BMMs. These results suggest that Sestrin2 has a novel role in bone homeostasis and osteoclasts differentiation through regulation of NFATc1 and the TRAF6/p62 interaction.
Files in This Item:
T202101061.pdf Download
DOI
10.3389/fcell.2021.646803
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Orofacial Pain and Oral Medicine (구강내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ki Woo(김기우) ORCID logo https://orcid.org/0000-0002-7790-1515
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Yang, Yu Mi(양유미)
Choi, Jong Hoon(최종훈) ORCID logo https://orcid.org/0000-0003-3211-3619
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/182362
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