Inhibition of osteoclast differentiation and bone resorption by sauchinone

• Published in: Biochemical pharmacology 2007-09, Vol.74 (6), p.911-923
• Main Authors: Han, Kyoung-Youn, Yang, Daum, Chang, Eun-Ju, Lee, Youngkyun, Huang, Hao, Sung, Sang Hyun, Lee, Zang Hee, Kim, Young Choong, Kim, Hong-Hee
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Benzopyrans - pharmacology; Biological and medical sciences; Bone Resorption - drug therapy; Cell Differentiation - drug effects; Dioxoles - pharmacology; Down-Regulation - drug effects; ERK; Inhibition of differentiation and bone resorption; LPS-induced bone destruction; Macrophages - cytology; Medical sciences; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Osteoclast; Osteoclasts - cytology; Osteoclasts - drug effects; Osteogenesis - drug effects; Pharmacology. Drug treatments; RANK Ligand - pharmacology; Reactive Oxygen Species - metabolism; ROS production; Sauchinone; Saururus; Transcription Factors
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2007.06.044

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-κB 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-κB 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.