Stimulation by Toll-like receptor 5 modulates osteoclast differentiation through STAT1/IFN-β (94.20)

Abstract

Abstract Stimulation of Toll-like receptors (TLRs) has been shown to differently modulate osteoclast differentiation, depending on experimental condition. However, the molecular mechanism by which stimulation by TLRs modulates osteoclast differentiation still remains to be elucidated. In the present study, we examined the effect of flagellin, a specific microbial ligand of TLR5, on receptor activator of NF-κB ligand (RANKL)-stimulated osteoclastogenesis. Flagellin suppressed RANKL induction of c-Fos protein expression in bone marrow-derived macrophages, without affecting c-Fos mRNA expression. Ectopic overexpression of c-Fos and an active form of NFATc1 reversed flagellin-induced anti-osteoclastogenic effect. The inhibitory effect of flagellin was mediated by IFN-β production. Flagellin stimulated IFN-β expression and release in BMMs and IFN-β-neutralizing antibody prevented flagellin-induced c-Fos down-regulation and anti-osteoclastogenic effect. IFN-β gene induction by flagellin, LPS, or RANKL was dependent on STAT1 activation. Treatment with flagellin or RANKL stimulated STAT1 activation, and STAT1-deficiency or a JAK2 inhibitor AG490 dramatically prevented IFN-β induction in response to flagellin or RANKL. Taken together, these results demonstrate that IFN-β acts as a critical modulator for osteoclastogenesis in response to TLR5 activation.