Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization

A mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis

Eiko Sakai, Masanobu Morita, Masahiro Ohuchi, Mizuho A. Kido, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Ken Itoh, Masayuki Yamamoto, Takayuki Tsukuba

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)–mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitro via attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-γ coactivator 1β and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.

Original languageEnglish
Pages (from-to)4011-4022
Number of pages12
JournalFASEB Journal
Volume31
Issue number9
DOIs
Publication statusPublished - Sep 1 2017
Externally publishedYes

Fingerprint

NFATC Transcription Factors
Osteogenesis
Protein Deficiency
Proteins
Mitochondrial Genes
Osteoclasts
Gene expression
Bone
Transcription Factors
Chemical activation
NF-E2-Related Factor 2
Gene Expression
Talus
Calcaneus
Peroxisome Proliferator-Activated Receptors
Oxidative stress
Macrophages
Kelch-Like ECH-Associated Protein 1
Oxidative Stress
Down-Regulation

Keywords

  • Blimp1
  • IRF-8
  • MafB
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization : A mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis. / Sakai, Eiko; Morita, Masanobu; Ohuchi, Masahiro; Kido, Mizuho A.; Fukuma, Yutaka; Nishishita, Kazuhisa; Okamoto, Kuniaki; Itoh, Ken; Yamamoto, Masayuki; Tsukuba, Takayuki.

In: FASEB Journal, Vol. 31, No. 9, 01.09.2017, p. 4011-4022.

Research output: Contribution to journalArticle

Sakai, Eiko ; Morita, Masanobu ; Ohuchi, Masahiro ; Kido, Mizuho A. ; Fukuma, Yutaka ; Nishishita, Kazuhisa ; Okamoto, Kuniaki ; Itoh, Ken ; Yamamoto, Masayuki ; Tsukuba, Takayuki. / Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization : A mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis. In: FASEB Journal. 2017 ; Vol. 31, No. 9. pp. 4011-4022.
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AU - Nishishita, Kazuhisa

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AB - Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)–mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitro via attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-γ coactivator 1β and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.

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