Phenethyl isothiocyanate suppresses receptor activator of
NF-kappaB ligand (RANKL)-induced osteoclastogenesis by blocking activation of
ERK1/2 and p38 MAPK in RAW264.7 macrophages
Affiliations: Division of Food Science and Biotechnology, Graduate
School of Agriculture, Kyoto University, Kyoto, Japan
Note: [] Address for correspondence: Dr. Akira Murakami, Division of Food
Science and Biotechnology, Graduate School of Agriculture, Kyoto University,
Kyoto 606-8502, Japan. Tel.: +81 75 753 6282; Fax: +81 75 753 6284; E-mail:
cancer@kais.kyoto-u.ac.jp
Abstract: Osteoclastogenesis is induced by differentiation of hemopoietic
cells of monocyte-macrophage lineage into bone-resorbing osteoclasts. The
process is initiated by receptor activator of NF-kappaB ligand (RANKL) and
resultant activation of mitogen-activated protein kinases (MAPK), including
extracellular signal-regulated kinase (ERK)1/2, as well as the NFκB
pathway. Phenethyl isothiocyanate (PEITC), a phytochemical present in various
cruciferous plants, has been shown to disrupt those signaling pathways in
several cell types. In this study, we examined the efficacy of PEITC for
suppressing RANKL-induced osteoclastogenesis in RAW264.7 murine macrophages and
addressed the underlying molecular mechanisms. PEITC (2–10 μM)
suppressed osteoclastogenesis in a concentration dependent manner, as detected
by tartarate-resistant acid phosphatase (TRAP) activity and microscopic
observations. RANKL-up-regulated extracellular signal-regulated kinase (ERK)1/2
and p38 mitogen-activated protein kinase (MAPK) activities were attenuated by
PEITC, whereas c-Jun N-terminal kinase (JNK1/2) activation was increased. PEITC
also abrogated the RANKL-induced degradation of IκB-α, a
suppressive partner of nuclear factor kappaB (NFκB), thereby inhibiting
transcription activity, as detected by a reporter assay. In addition, PEITC
reduced the level of NFκB-dependent mRNA expression of
nuclear factor of activated T cell (NFAT)c1, a master regulator of
osteoclastogenesis. Our results indicate that PEITC is a promising agent for
treatment of osteoclastogenesis with a reasonable action mechanism.
