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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900072v1 183/11/7223    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Ji, J.-D. Articles by Ivashkiv, L. B. PubMed PubMed Citation Articles by Ji, J.-D. Articles by Ivashkiv, L. B.

Inhibition of RANK Expression and Osteoclastogenesis by TLRs and IFN- in Human Osteoclast Precursors¹

Jong-Dae Ji,^* Kyung-Hyun Park-Min,^* Zenxin Shen, Roberto J. Fajardo, Steven R. Goldring,^* Kevin P. McHugh, and Lionel B. Ivashkiv^2*

*Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021; Division of Rheumatology, College of Medicine, Korea University, Seoul, Korea; Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215; and Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021

TLRs have been implicated in promoting osteoclast-mediated bone resorption associated with inflammatory conditions. TLRs also activate homeostatic mechanisms that suppress osteoclastogenesis and can limit the extent of pathologic bone erosion associated with infection and inflammation. We investigated mechanisms by which TLRs suppress osteoclastogenesis. In human cell culture models, TLR ligands suppressed osteoclastogenesis by inhibiting expression of receptor activator of NF-B (RANK), thereby making precursor cells refractory to the effects of RANKL. Similar but less robust inhibition of RANK expression was observed in murine cells. LPS suppressed generation of osteoclast precursors in mice in vivo, and adsorption of LPS onto bone surfaces resulted in diminished bone resorption. Mechanisms that inhibited RANK expression were down-regulation of RANK transcription, and inhibition of M-CSF signaling that is required for RANK expression. TLRs inhibited M-CSF signaling by rapidly down-regulating cell surface expression of the M-CSF receptor c-Fms by a matrix metalloprotease- and MAPK-dependent mechanism. Additionally, TLRs cooperated with IFN- to inhibit expression of RANK and of the CSF1R gene that encodes c-Fms, and to synergistically inhibit osteoclastogenesis. Our findings identify a new mechanism of homeostatic regulation of osteoclastogenesis that targets RANK expression and limits bone resorption during infection and inflammation.

Correspondence: ² Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: IvashkivL{at}hss.edu

¹ This work was supported by grants from the National Institutes of Health (to L.B.I.), the Arthritis Foundation (to K.-H.P.-M.), and by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A084224 to J.-D.J.).