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.

Cytokine-scavenging nanodecoys reconstruct osteoclast/osteoblast balance toward the treatment of postmenopausal osteoporosis

“…Then, the femurs were embedded in paraffin, cross-sectioned at 8 μm in thickness, and stained using a TRAP staining kit. The number of osteoclasts per bone surface (N.Oc/BS) was calculated ( 35 ).…”

“…Moreover, leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), which can compete with RANK in binding with RANKL, and TNF- antagonist etanercept, which can inhibit TNF- function, are considered beneficial for the treatment of osteoporosis (9,32). However, these RANKL/TNF- inhibitors, mostly protein drugs, often suffer from shortcomings such as short blood circulation time, suboptimal biodistribution, complex manufacturing processes, and resistance of antibodies (33)(34)(35). In addition, the pathological background of osteoporosis is often related to multiple targets, and thus, a single-target therapeutic modality may be suboptimal (36).…”

Recent Advances in Osteoclast Biological Behavior

“…Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts. Study identifies selenoprotein W (SELENOW) as a protein down-regulated through RANKL/RANK/tumor necrosis factor receptor-associated factor 6/p38 signaling by large-scale mRNA analysis of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoblast differentiation ( Kim et al, 2021 ). RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes.…”

“…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 ( Kim et al, 2021 ). Major vault protein (MVP) (also known as lung resistance-related protein, LRP), is the main component of cellular ribonucleoprotein particles called vaults.…”

The Effects of Selenium on Bone Health: From Element to Therapeutics

“…A crucial component of the intracellular Recently, Kim et al demonstrated that SELENOW contributes to osteoclastogenesis, but is downregulated via RANKL/RANK/tumor-necrosis-factor-receptor-associated factor 6/p38 signaling. They suggested that this RANK-dependent inhibition of SELENOW blocks overactive osteoclasts to prevent osteoporosis [178]. SELENOP is a major selenium transporter in plasma that is produced and released by hepatocytes and resorbed by bone cells via apolipoprotein receptor 2(ApoER2) [179][180][181].…”