The phosphatidylinositol 3-kinase-mediated production of interferon-β is critical for the lipopolysaccharide inhibition of osteoclastogenesis

Youngkyun Lee, Hao Huang, Hyung Joon Kim, Chul Kyu Park, Hong Hee Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Aims: This study was performed to define molecular mechanisms underlying lipopolysaccharide (LPS)-induced inhibition of osteoclastogenesis. Main methods: The LPS-dependent signaling pathways leading to the inhibition of osteoclastogenesis were examined using chemical inhibitors and neutralizing antibodies. Key findings: Lipopolysaccharide (LPS) has been shown to induce massive bone loss in vivo by stimulating osteoclast differentiation and activity. However, the direct effect of LPS on osteoclastogenesis in vitro is complex. Based on the context of the differentiation state of precursors, LPS has been shown to either augment or inhibit osteoclast differentiation. When added to receptor activator of NF-κB ligand (RANKL)-primed precursors, LPS enhances osteoclast differentiation via the production of TNF-α. On the other hand, LPS inhibits osteoclastogenesis from early precursors like bone marrow macrophages by hitherto unknown mechanism. In the present study, we investigated the mechanism by which LPS inhibits osteoclastogenesis. We have identified that the phosphatidylinositol 3-kinase (PI 3-kinase) dependent production of IFN-β and resultant inhibition of c-Fos expression upon LPS stimulation of bone marrow macrophages are responsible for the LPS-induced inhibition of osteoclastogenesis. Inhibition of PI 3-kinase, neutralization of IFN-β, and overexpression of c-Fos respectively prevented the LPS-induced inhibition of osteoclast differentiation. Significance: Our results provide a molecular understanding of the differentiation stage-specific dual effect of LPS on osteoclastogenesis.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalLife Sciences
Volume83
Issue number9-10
DOIs
StatePublished - Aug 29 2008

Keywords

  • Inhibition
  • Interferon-β
  • Lipopolysaccharide
  • Osteoclast
  • Phosphatidylinositol 3-kinase
  • c-Fos

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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