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

Authors
Ji, Jong-DaePark-Min, Kyung-HyunShen, ZenxinFajardo, Roberto J.Goldring, Steven R.McHugh, Kevin P.Ivashkiv, Lionel B.
Issue Date
1-Dec-2009
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.183, no.11, pp.7223 - 7233
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF IMMUNOLOGY
Volume
183
Number
11
Start Page
7223
End Page
7233
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/118762
DOI
10.4049/jimmunol.0900072
ISSN
0022-1767
Abstract
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-kappa 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-gamma to inhibit expression of RANK and of the CSFIR 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. The Journal of Immunology, 2009, 183: 7223-7233.
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