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

J Cell Physiol. 2009 Dec;221(3):642-9. doi: 10.1002/jcp.21898.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / metabolism
  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Apoptosis / drug effects
  • Bone Resorption / pathology*
  • Caffeic Acids / administration & dosage
  • Caffeic Acids / pharmacology*
  • Caspase 3 / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • I-kappa B Proteins / metabolism
  • Isoenzymes / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Mice
  • Mice, Inbred C57BL
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Phenylethyl Alcohol / analogs & derivatives
  • Propolis / chemistry
  • RANK Ligand / pharmacology*
  • Tartrate-Resistant Acid Phosphatase
  • Transcription Factor RelA / metabolism
  • Tumor Cells, Cultured


  • Caffeic Acids
  • I-kappa B Proteins
  • Isoenzymes
  • NF-kappa B
  • NFATC Transcription Factors
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • RANK Ligand
  • Rela protein, mouse
  • Tnfsf11 protein, mouse
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Propolis
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase
  • Casp3 protein, mouse
  • Caspase 3
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol