Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression.
Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease. The effect of rotenone in RANKL-induced osteoclast differentiation was examined in this study. Rotenone inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) in a dose-dependent manner without any evidence of cytotoxicity. The mRNA expression of c-Fos, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs was inhibited by rotenone treatment. Rotenone strongly inhibited p38 and ERK phosphorylation and I-kappaB degradation in RANKL-stimulated BMMs, and did not inhibit JNK phosphorylation. Further, RANKL-induced c-Fos and NFATc1 protein expression was suppressed by rotenone. Rotenone additionally inhibited the bone resorptive activity of differentiated osteoclasts. A lipopolysaccharide (LPS)-induced bone erosion study was also performed to assess the effects of rotenone in vivo. Mice treated with rotenone demonstrated marked attenuation of bone erosion based on Micro CT and histologic analysis of femurs. These results collectively suggested that rotenone demonstrated inhibitory effects on osteoclast differentiation in vitro and suppressed inflammatory bone loss in vivo. Rotenone may therefore serve as a useful drug in the prevention of bone loss.
Kwak
Han Bok
HB
Department of Anatomy, Wonkwang University, Iksan, Jeonbuk 570-749, Korea.
Lee
Byeong Ki
BK
Oh
Jaemin
J
Yeon
Jeong-Tae
JT
Choi
Sik-Won
SW
Cho
Hae Joong
HJ
Lee
Myeung Su
MS
Kim
Jeong-Joong
JJ
Bae
Ji-Myung
JM
Kim
Seong Hwan
SH
Kim
Hun Soo
HS
D000818:Animals; D000831:Animals, Newborn; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D012402:Rotenone / Q000494:pharmacology*
D019485:Bone Morphogenetic Proteins; D006131:Growth Inhibitors; D007306:Insecticides; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D012402:Rotenone