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.
Han
Kyoung-Youn
KY
Department of Cell and Developmental Biology, BK21 Program, and DRI, Seoul National University, Seoul 110-749, Republic of Korea.
Yang
Daum
D
Chang
Eun-Ju
EJ
Lee
Youngkyun
Y
Huang
Hao
H
Sung
Sang Hyun
SH
Lee
Zang Hee
ZH
Kim
Young Choong
YC
Kim
Hong-Hee
HH
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