title: Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression.
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 box 1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways.
authors.affiliation: Division of Oral Pathopharmacology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki, 852-8588, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Fumimoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fukuma
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nishishita
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
mesh_terms: D000818:Animals; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D006873:Hydroquinones; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D014157:Transcription Factors; C018855:2-tert-butylhydroquinone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D056657:Cathepsin K; C534132:Ctsk protein, mouse
keywords: heme oxygenase-1; high mobility group box 1; nuclear factor of activated T cells cytoplasmic-1; osteoclasts; tert-butylhydroquinone