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Stimulation by TLR5 Modulates Osteoclast Differentiation through STAT1/IFN-β¹

Hyunil Ha^*, Jong-Ho Lee^*, Ha-Neui Kim^*, Han Bok Kwak^*, Hyun-Man Kim^*, Shee Eun Lee, Joon Haeng Rhee, Hong-Hee Kim^* and Zang Hee Lee^2,*

^* Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul; and Research Institute of Vibrio Infection and Genome Research Center for Enteropathogenic Bacteria, Chonnam National University Medical School, Gwangju, Republic of Korea

Osteoclasts are bone-resorbing cells that are differentiated from hemopoietic precursors of the monocyte-macrophage lineage. Stimulation of TLRs has been shown to positively or negatively modulate osteoclast differentiation, depending on the experimental condition. However, the molecular mechanism by which this modulation takes place remains unclear. In the present study, we examined the effects of flagellin, a specific microbial ligand of TLR5, on the receptor activator of NF-B 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 a constitutively active form of NFATc1 reversed the flagellin-induced anti-osteoclastogenic effect. The inhibitory effect of flagellin was mediated by IFN-β production. Flagellin stimulated IFN-β expression and release in bone marrow-derived macrophages, and IFN-β-neutralizing Ab prevented the flagellin-induced c-Fos down-regulation and the 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 the JAK2 inhibitor AG490 dramatically prevented IFN-β induction in response to flagellin or RANKL. In addition, STAT1 deficiency abolished the anti-osteoclastogenic effect induced by flagellin or LPS. In contrast, flagellin stimulated osteoclast differentiation in cocultures of osteoblasts and bone marrow cells without inducing IFN-β. Thus, IFN-β acts as a critical modulator of osteoclastogenesis in response to TLR5 activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060480).

² Address correspondence and reprint requests to Dr. Zang Hee Lee, Department of Cell and Developmental Biology, College of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongro-Gu, Seoul 110-749, Republic of Korea. E-mail address: zang1959{at}snu.ac.kr

³ Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; RANK, receptor activator of NF-B; NFATc1, cytoplasmic, calcineurin-dependent NFAT 1; TRIF, TIR-related adaptor protein inducing interferon-β; BMM, bone marrow-derived macrophage; TRAP, tartrate-resistant acid phosphatase; iNOS, inducible NO synthase; IRF, IFN regulatory factor; I-TAC, IFN-inducible T cell chemoattractant; GAS, IFN--activated site.