Abstract 16

Caffeic acid phenethylester, a natural component of honeybee propolis induces osteoclast apoptosis and attenuates osteoclastogenesis via the suppression of RANKL-induced NF-êB and NFAT activity

Estabelle Sym Mei Ang¹, Lee Ying Chai¹, Nathan Pavlos¹, Kirk H. M. Yip¹, James H. Steer², David A. Joyce², Ming H. Zheng¹, Jiake Xu¹

¹Molecular Orthopaedic Laboratory, School of Surgery and Pathology, ²Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA 6009, Australia

NF-êB is a key regulator of osteoclast differentiation, activation and survival. Caffeic acid phenethyl ester (CAPE), a natural NF-êB inhibitor from honeybee propolis has been shown to have anti-tumor and anti-inflammatory properties. However, the effect of CAPE on osteoclast formation and RANKL signaling is unknown. In this study, we investigated its effect on the regulation of RANKL-induced osteoclastogenesis and osteoclast survival. Both RAW264.7 cells and primary bone marrow cells were used to examine the effect of CAPE on RANKL-induced osteoclastogenesis. In order to determine the action of CAPE on signaling pathways, we used reporter gene assays for NF-êB and NFAT activity, and Western blotting for phospho-IKBá. To assess rates of apoptosis we measured changes in annexin staining, caspase-3 activity, chromatin and microtubule structure. Our results showed that low concentrations of CAPE (<0.5 uM) dose dependently inhibited RANKL-induced osteoclastogenesis in RAW 264.7 cells and in bone marrow cell cultures. At higher concentrations, CAPE induced apoptosis of RAW 264.7 cells and RAW 264.7 cell-derived osteoclast like cells (OLCs). Consistently, we found that CAPE increases caspase-3 activity and disrupts the microtubule network in OLCs. Furthermore, CAPE inhibited both basal and RANKL-induced NF-êB and NFAT activation in a dose dependent manner. This study implies that attenuation of osteoclastogenesis and induction of osteoclast apoptosis through the inhibition of NF-êB and NFAT activation by this natural compound might be useful for the treatment of osteolysis attended with enhanced osteoclast formation and activation.

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