title: RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis.
abstract: Increased osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α-induced osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow-derived macrophages/osteoclast precursors during inflammatory osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced osteoclastogenesis program induced by TNF-α in RBP-J-deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte-induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α-mediated osteoclastogenesis. Thus, RBP-J-regulated miR-182 promotes TNF-α-induced osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α-induced osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits osteoclastogenesis and suggest that targeting of the newly described RBP-J-miR-182-Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone resorption.
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021;
authors.forename: Christine H
authors.identifier: 0000-0003-2176-9516
authors.initials: CH
authors.lastname: Miller
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021;
authors.forename: Sinead M
authors.identifier: 0000-0003-3460-3590
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021;
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Elguindy
authors.affiliation: Genomics Resources Core Facility, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Tuo
authors.identifier: 0000-0001-5396-918X
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Genomics Resources Core Facility, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Jenny Z
authors.initials: JZ
authors.lastname: Xiang
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China;
authors.forename: Xiaoyu
authors.identifier: 0000-0002-4289-6998
authors.initials: X
authors.lastname: Hu
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065; and.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; Department of Medicine, Weill Cornell Medical College, New York, NY 10065 zhaob@hss.edu.
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001862:Bone Resorption; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C486455:Maml1 protein, mouse; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; C513258:Prdm1 protein, mouse; C497571:Rbpj protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000074462:Positive Regulatory Domain I-Binding Factor 1