title: The coffee diterpene kahweol prevents osteoclastogenesis via impairment of NFATc1 expression and blocking of Erk phosphorylation.
abstract: Osteoclasts (OCLs) are multinucleated bone resorbing cells whose differentiation is regulated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). It is known that inflammatory cytokines and oxidative stress stimulate differentiation of OCLs. Here we evaluated the effects of kahweol, a coffee-specific diterpene, which has been reported to possess anti-oxidant and anti-inflammatory properties, on the differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D cells into OCLs. Kahweol dose-dependently inhibited the formation of tartrate-resistant acid phosphatase staining-positive OCLs from both BMMs and RAW-D cells. In addition, kahweol prevented the bone resorbing activity of OCLs. Kahweol completely abolished RANKL-stimulated phosphorylation of extracellular signal-regulated kinase and impaired phosphorylation of Akt. Moreover, the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator for OCL differentiation; and OCL markers transcriptionally regulated by NFATc1 such as Src and cathepsin K were down-regulated by kahweol treatment. As one of the molecular mechanisms for the inhibitory effects of kahweol, we also showed that kahweol up-regulated heme oxygenase-1 and inhibited high mobility group box 1 release. Thus, kahweol in coffee is a useful constituent for inhibition of OCL differentiation.
authors.affiliation: Division of Oral Pathopharmacology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Fumimoto
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakai
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
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; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D003069:Coffee; D004224:Diterpenes / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D003069:Coffee; D004224:Diterpenes; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D047428:Protein Kinase Inhibitors; C053401:kahweol; D048049:Extracellular Signal-Regulated MAP Kinases