title: Caffeic acid phenethyl ester, an active component of honeybee propolis attenuates osteoclastogenesis and bone resorption via the suppression of RANKL-induced NF-kappaB and NFAT activity.
abstract: Receptor activator NF-kappaB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation and survival. Caffeic acid phenethyl ester (CAPE), a natural NF-kappaB inhibitor from honeybee propolis has been shown to have anti-tumor and anti-inflammatory properties. In this study, we investigated the effect of CAPE on the regulation of RANKL-induced osteoclastogenesis, bone resorption and signaling pathways. Low concentrations of CAPE (<1 microM) dose dependently inhibited RANKL-induced osteoclastogenesis in RAW264.7 cell and bone marrow macrophage (BMM) cultures, as well as decreasing the capacity of human osteoclasts to resorb bone. CAPE inhibited both constitutive and RANKL-induced NF-kappaB and NFAT activation, concomitant with delayed IkappaBalpha degradation and inhibition of p65 nuclear translocation. At higher concentrations, CAPE induced apoptosis and caspase 3 activities of RAW264.7 and disrupts the microtubule network in osteoclast like (OCL) cells. Taken together, our findings demonstrate that inhibition of NF-kappaB and NFAT activation by CAPE results in the attenuation of osteoclastogenesis and bone resorption, implying that CAPE is a potential treatment for osteolytic bone diseases.
authors.affiliation: Molecular Orthopaedic Laboratory, Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Estabelle S M
authors.initials: ES
authors.lastname: Ang
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.forename: Lee Y
authors.initials: LY
authors.lastname: Chai
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Tak S
authors.initials: TS
authors.lastname: Cheng
authors.forename: James H
authors.initials: JH
authors.lastname: Steer
authors.forename: David A
authors.initials: DA
authors.lastname: Joyce
authors.forename: Ming H
authors.initials: MH
authors.lastname: Zheng
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology*; D002109:Caffeic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives; D011429:Propolis / Q000737:chemistry; D053245:RANK Ligand / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase; D051996:Transcription Factor RelA / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002109:Caffeic Acids; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D053245:RANK Ligand; C498144:Rela protein, mouse; C505689:Tnfsf11 protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D011429:Propolis; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C505409:Casp3 protein, mouse; D053148:Caspase 3; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol