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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
Author(s) -
Murakami Akira,
Song Meiyu,
Ohigashi Hajime
Publication year - 2007
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520300101
Subject(s) - rankl , mapk/erk pathway , phenethyl isothiocyanate , p38 mitogen activated protein kinases , kinase , chemistry , microbiology and biotechnology , activator (genetics) , signal transduction , protein kinase a , cancer research , receptor , biology , biochemistry , apoptosis
Osteoclastogenesis is induced by differentiation of hemopoietic cells of monocyte‐macrophage lineage into boneresorbing 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 mitogenactivated 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.