Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression

Yu Yamaguchi, Eiko Sakai, Hiroshi Sakamoto, Reiko Fumimoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Our recent studies have shown that heme-oxygenase-1 (HO-1), a stress-induced cytoprotective enzyme, plays an important role in OCL differentiation, although the pharmacological significance of this effect remains unknown. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ), a pharmacological HO-1 inducer, on in vitro differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D into OCLs. tBHQ inhibited the formation and the bone-resorbing activity of OCLs. Moreover, tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of OCL differentiation, and of OCL markers transcriptionally regulated by NFATc1, such as Src and cathepsin K. In addition, tBHQ impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase, Akt, and inhibitor of nuclear factor kappa B alpha (IκBα). Finally, we show that tBHQ inhibited the release of high mobility group box1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalJournal of Applied Toxicology
Volume34
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Fingerprint

NFATC Transcription Factors
Heme Oxygenase-1
Osteoclasts
Up-Regulation
Down-Regulation
Bone
Cathepsin K
Pharmacology
RANK Ligand
Phosphorylation
Macrophage Colony-Stimulating Factor
2-tert-butylhydroquinone
NF-kappa B
Macrophages
Differentiation Antigens
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Phosphotransferases
Cells
Bone and Bones

Keywords

  • Heme oxygenase-1
  • High mobility group box1
  • Nuclear factor of activated T cells cytoplasmic-1
  • Osteoclasts
  • tert-butylhydroquinone

ASJC Scopus subject areas

  • Toxicology

Cite this

Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression. / Yamaguchi, Yu; Sakai, Eiko; Sakamoto, Hiroshi; Fumimoto, Reiko; Fukuma, Yutaka; Nishishita, Kazuhisa; Okamoto, Kuniaki; Tsukuba, Takayuki.

In: Journal of Applied Toxicology, Vol. 34, No. 1, 01.2014, p. 49-56.

Research output: Contribution to journalArticle

Yamaguchi, Yu ; Sakai, Eiko ; Sakamoto, Hiroshi ; Fumimoto, Reiko ; Fukuma, Yutaka ; Nishishita, Kazuhisa ; Okamoto, Kuniaki ; Tsukuba, Takayuki. / Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression. In: Journal of Applied Toxicology. 2014 ; Vol. 34, No. 1. pp. 49-56.
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AU - Sakamoto, Hiroshi

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AB - Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Our recent studies have shown that heme-oxygenase-1 (HO-1), a stress-induced cytoprotective enzyme, plays an important role in OCL differentiation, although the pharmacological significance of this effect remains unknown. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ), a pharmacological HO-1 inducer, on in vitro differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D into OCLs. tBHQ inhibited the formation and the bone-resorbing activity of OCLs. Moreover, tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of OCL differentiation, and of OCL markers transcriptionally regulated by NFATc1, such as Src and cathepsin K. In addition, tBHQ impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase, Akt, and inhibitor of nuclear factor kappa B alpha (IκBα). Finally, we show that tBHQ inhibited the release of high mobility group box1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways.

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