title: Intravenous Immunoglobulin (IVIG) Attenuates TNF-Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression.
abstract: Investigations on the therapeutic effects of intravenous immunoglobulin (IVIG) have focused on the suppression of autoantibody and immune complex-mediated inflammatory pathogenesis. Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone-resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast-mediated pathologic bone resorption. IVIG or cross-linking of Fcγ receptors with plate-bound IgG suppressed receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteoclastogenesis and expression of osteoclast-related genes such as integrin β3 and cathepsin K in a dose-dependent manner. Mechanistically, IVIG or plate-bound IgG suppressed osteoclastogenesis by downregulating RANKL-induced expression of NFATC1, the master regulator of osteoclastogenesis. IVIG suppressed NFATC1 expression by attenuating RANKL-induced NF-κB signaling, explained in part by induction of the inflammatory signaling inhibitor A20. IVIG administration attenuated in vivo osteoclastogenesis and suppressed bone resorption in the tumor necrosis factor (TNF)-induced calvarial osteolysis model. Our findings show that, in addition to suppressing inflammation, IVIG directly inhibits osteoclastogenesis through a mechanism involving suppression of RANK signaling. Direct suppression of osteoclast differentiation may provide beneficial effects on preserving bone mass when IVIG is used to treat rheumatic disorders.
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.
authors.forename: Min Joon
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.
authors.forename: Elisha
authors.initials: E
authors.lastname: Lim
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Mun
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Bae
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murata
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021 USA.|Department of Medicine, Weill Cornell Medical College, New York, NY 10021 US.|Drs. Park-Min and Ivashkiv contributed equally to this work.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
authors.affiliation: Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research, Hospital for Special Surgery, New York, NY 10021 USA.|Department of Medicine, Weill Cornell Medical College, New York, NY 10021 US.|Drs. Park-Min and Ivashkiv contributed equally to this work.
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D012216:Rheumatic Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016756:Immunoglobulins, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse