Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts.

Abstract

Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodeling. However, their underlying mechanism of action is not fully understood. Herein, we report the identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signaling. RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhances osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 mediated by 14-3-3γ, whereas its deficiency suppresses osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibit high bone mass phenotype and osteoporosis, respectively. Ectopic SELENOW expression stimulates cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW regulates osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.

• Authors: Hyunsoo Kim, Kyunghee Lee, Jin Man Kim, Mi Yeong Kim, Jae-Ryong Kim, Han-Woong Lee, Youn Wook Chung, Hong-In Shin, Taesoo Kim, Eui-Soon Park, Jaerang Rho, Seoung Hoon Lee, Nacksung Kim, Soo Young Lee, Yongwon Choi, Daewon Jeong
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2258 (04 15 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33859201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• NFATC Transcription Factors
• Nfatc1 protein, mouse
• RANK Ligand
• Selenoprotein W
• TNF Receptor-Associated Factor 6
• TRAF6 protein, mouse
• Tnfsf11 protein, mouse

Topics

• 14-3-3 Proteins (metabolism)
• Animals
• Bone Remodeling (genetics)
• Cell Differentiation (genetics)
• Disease Models, Animal
• Gene Expression Regulation (physiology)
• Humans
• Male
• Mice
• Mice, Knockout
• NFATC Transcription Factors (metabolism)
• Osteoclasts (physiology)
• Osteogenesis (genetics)
• Osteoporosis (genetics, pathology)
• RANK Ligand (metabolism)
• RNA-Seq
• Selenoprotein W (genetics, metabolism)
• Signal Transduction (physiology)
• TNF Receptor-Associated Factor 6 (metabolism)