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Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone\u2010resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast\u2010mediated pathologic bone resorption. IVIG or cross\u2010linking of Fc\u03b3 receptors with plate\u2010bound IgG suppressed receptor activator of nuclear factor\u2010\u03ba B ligand (RANKL)\u2010induced osteoclastogenesis and expression of osteoclast\u2010related genes such as integrin \u03b23 and cathepsin K in a dose\u2010dependent manner. Mechanistically, IVIG or plate\u2010bound IgG suppressed osteoclastogenesis by downregulating RANKL\u2010induced expression of <jats:italic>NFATC1<\/jats:italic>, the master regulator of osteoclastogenesis. IVIG suppressed <jats:italic>NFATC1<\/jats:italic> expression by attenuating RANKL\u2010induced NF\u2010\u03baB 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)\u2010induced 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. J. Cell. Physiol. 231: 449\u2013458, 2016. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.25091","type":"journal-article","created":{"date-parts":[[2015,7,17]],"date-time":"2015-07-17T14:06:59Z","timestamp":1437142019000},"page":"449-458","source":"Crossref","is-referenced-by-count":18,"title":["Intravenous Immunoglobulin (IVIG) Attenuates TNF\u2010Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression"],"prefix":"10.1002","volume":"231","author":[{"given":"Min Joon","family":"Lee","sequence":"first","affiliation":[{"name":"Arthritis and Tissue Degeneration Program, David Z. Rosensweig Center for Genomic Research Hospital for Special Surgery New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisha","family":"Lim","sequence":"additional","affiliation":[{"name":"Arthritis and Tissue Degeneration Program, David Z. 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