Inhibition of osteoclast differentiation and bone resorption by sauchinone.
Osteoclasts are bone-specific multinucleated cells generated by differentiation of monocyte/macrophage lineage precursors. Regulation of osteoclast differentiation is considered an effective therapeutic approach to the treatment of bone-lytic diseases. In this study, we investigated effects of sauchinone, a lignan from Saururus chinensis, on osteoclastogenesis induced by the differentiation factor RANKL (receptor activator of nuclear factor kappa B ligand). Sauchinone strongly inhibited the osteoclastogenesis from primary bone marrow-derived macrophages (BMMs). This effect was accompanied by a significant decrease in the level of carbonic anhydrase II, calcitonin receptor, MMP9, and TRAP, which are normally upregulated during osteoclast differentiation. For the induction of osteoclastogenesis-associated genes, RANKL activates multiple transcription factors through mechanisms involving mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS). Sauchinone greatly attenuated the activation of ERK and, less prominently, that of p38 MAPKs by RANKL. The RANKL-stimulated induction of c-Fos and NFATc1 transcription factors was also abrogated by sauchinone. In addition, the activation of AP-1, NFAT, and NF-kappaB transcription factors was alleviated in sauchinone-treated cells. Sauchinone also diminished the RANKL-stimulated increase of ROS production in BMMs. Consistent with the in vitro anti-osteoclastogenic effect, sauchinone inhibited bone destruction and osteoclast formation caused by lipopolysaccharide in an animal model. Taken together, our data demonstrate that sauchinone inhibits RANKL-induced osteoclastogenesis by reducing ROS generation, which attenuates MAPK and NF-kappaB activation, ultimately leading to the suppression of c-Fos and NFATc1 induction. Also the in vivo effect of sauchinone on bone erosion strengthens the potential usefulness of this compound for diseases involving bone resorption.
Department of Cell and Developmental Biology, BK21 Program, and DRI, Seoul National University, Seoul 110-749, Republic of Korea.
Kyoung-Youn
KY
Han
Daum
D
Yang
Eun-Ju
EJ
Chang
Youngkyun
Y
Lee
Hao
H
Huang
Sang Hyun
SH
Sung
Zang Hee
ZH
Lee
Young Choong
YC
Kim
Hong-Hee
HH
Kim
D000818:Animals; D000831:Animals, Newborn; D001578:Benzopyrans / Q000494:pharmacology*; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors
D001578:Benzopyrans; D004149:Dioxoles; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C410958:sauchinone; D020928:Mitogen-Activated Protein Kinases