title: Elevated Response to Type I IFN Enhances RANKL-Mediated Osteoclastogenesis in Usp18-Knockout Mice.
abstract: A balance between bone formation and bone resorption is critical for the maintenance of bone mass. In many pathological conditions, including chronic inflammation, uncontrolled activation of osteoclast differentiation often causes excessive bone resorption that results in osteoporosis. In this study, we identified the osteopenia phenotype of mice lacking Usp18 (also called Ubp43), which is a deISGylating enzyme and is known as a negative regulator of type I IFN signaling. The expression of Usp18 was induced in preosteoclasts upon receptor activator of NF-κB ligand (RANKL) treatment. In an in vitro osteoclast-differentiation assay, bone marrow macrophages from Usp18-deficient mice exhibited an enhanced differentiation to multinucleated cells, elevated activation of NFATc1, and an increased expression of osteoclast marker genes upon RANKL treatment. Furthermore, in vitro quantification of bone resorption revealed a great increase in osteoclastic activities in Usp18-deficient cells. Interestingly, proinflammatory cytokine genes, such as IP-10 (CXCL10), were highly expressed in Usp18-deficient bone marrow macrophages upon RANKL treatment compared with wild-type cells. In addition, serum cytokine levels, especially IP-10, were significantly high in Usp18-knockout mice. In sum, we suggest that, although type I IFN is known to restrict osteoclast differentiation, the exaggerated activation of the type I IFN response in Usp18-knockout mice causes an osteopenia phenotype in mice.
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, South Korea; Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea;
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Yim
authors.affiliation: Department of Cell and Developmental Biology, Brain Korea 21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, South Korea;
authors.forename: Cheolkyu
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Cell and Developmental Biology, Brain Korea 21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, South Korea;
authors.forename: Yong Deok
authors.initials: YD
authors.lastname: Lee
authors.affiliation: Department of Pathology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Arimoto
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742, South Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea;
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Pathology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.affiliation: Department of Cell and Developmental Biology, Brain Korea 21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, South Korea;
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, South Korea; kikim@sookmyung.ac.kr.
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000276:immunology; D010024:Osteoporosis / Q000276:immunology*; D053245:RANK Ligand / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D007370:Interferon Type I; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase