title: TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J.
abstract: Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the J(κ) site (RBP-J) strongly suppresses TNF-induced osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-κB (RANK) signaling. In the absence of RBP-J, TNF effectively induced osteoclastogenesis and bone resorption in RANK-deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos activation and suppressing induction of B lymphocyte-induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10065, USA.
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhao
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Grimes
authors.forename: Susan
authors.initials: S
authors.lastname: Li
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000378:metabolism*; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D017353:Gene Deletion; D005822:Genetic Vectors / Q000235:genetics; D015151:Immunoblotting; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
chemical_list: D050071:Bone Density Conservation Agents; D017931:DNA Primers; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D050835:Interferon Regulatory Factors; D050778:NFATC Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099185:Interferon Regulatory Factor-8; C513258:Prdm1 protein, mouse; C497571:Rbpj protein, mouse