Life sciences

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

PMID 18675826


This study was performed to define molecular mechanisms underlying lipopolysaccharide (LPS)-induced inhibition of osteoclastogenesis. The LPS-dependent signaling pathways leading to the inhibition of osteoclastogenesis were examined using chemical inhibitors and neutralizing antibodies. 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-kappaB ligand (RANKL)-primed precursors, LPS enhances osteoclast differentiation via the production of TNF-alpha. 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-beta 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-beta, and overexpression of c-Fos respectively prevented the LPS-induced inhibition of osteoclast differentiation. Our results provide a molecular understanding of the differentiation stage-specific dual effect of LPS on osteoclastogenesis.

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(2-Hydroxypropyl)-γ-cyclodextrin, solid