Inhibition of osteoclast differentiation and bone resorption by sauchinone

Biochem Pharmacol. 2007 Sep 15;74(6):911-23. doi: 10.1016/j.bcp.2007.06.044. Epub 2007 Jul 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzopyrans / pharmacology*
  • Bone Resorption / drug therapy*
  • Cell Differentiation / drug effects*
  • Dioxoles / pharmacology*
  • Down-Regulation / drug effects
  • Macrophages / cytology
  • Mice
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinases
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteogenesis / drug effects
  • RANK Ligand / pharmacology
  • Reactive Oxygen Species / metabolism
  • Transcription Factors

Substances

  • Benzopyrans
  • Dioxoles
  • RANK Ligand
  • Reactive Oxygen Species
  • Transcription Factors
  • sauchinone
  • Mitogen-Activated Protein Kinases