title: Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors.
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-kappaB (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 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.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Jong-Dae
authors.initials: JD
authors.lastname: Ji
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.forename: Zenxin
authors.initials: Z
authors.lastname: Shen
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Fajardo
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.forename: Kevin P
authors.initials: KP
authors.lastname: McHugh
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis*; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011971:Receptors, Immunologic; C505686:TNFRSF11A protein, human; C498715:TREM2 protein, human; D051193:Toll-Like Receptors; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma