Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-γ in human osteoclast precursors

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

    Research output: Contribution to journalArticlepeer-review

    114 Citations (Scopus)

    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-κB (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-γ 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.

    Original languageEnglish
    Pages (from-to)7223-7233
    Number of pages11
    JournalJournal of Immunology
    Volume183
    Issue number11
    DOIs
    Publication statusPublished - 2009 Dec 1

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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