title: 5-Azacytidine-induced protein 2 (AZI2) regulates bone mass by fine-tuning osteoclast survival.
abstract: 5-Azacytidine-induced protein 2 (AZI2) is a TNF receptor (TNFR)-associated factor family member-associated NF-κB activator-binding kinase 1-binding protein that regulates the production of IFNs. A previous in vitro study showed that AZI2 is involved in dendritic cell differentiation. However, the roles of AZI2 in immunity and its pleiotropic functions are unknown in vivo. Here we report that AZI2 knock-out mice exhibit normal dendritic cell differentiation in vivo. However, we found that adult AZI2 knock-out mice have severe osteoporosis due to increased osteoclast longevity. We revealed that the higher longevity of AZI2-deficient osteoclasts is due to an augmented activation of proto-oncogene tyrosine-protein kinase Src (c-Src), which is a critical player in osteoclast survival. We found that AZI2 inhibits c-Src activity by regulating the activation of heat shock protein 90 (Hsp90), a chaperone involved in c-Src dephosphorylation. Furthermore, we demonstrated that AZI2 indirectly inhibits c-Src by interacting with the Hsp90 co-chaperone Cdc37. Strikingly, administration of a c-Src inhibitor markedly prevented bone loss in AZI2 knock-out mice. Together, these findings indicate that AZI2 regulates bone mass by fine-tuning osteoclast survival.
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, maruyama@biken.osaka-u.ac.jp.
authors.forename: Kenta
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, the Life Science Research Center, Corporate R&D Development Division, Nitto Denko Corporation, 1-1-2 Shimohozumi, Ibaraki, Osaka 567-8680, and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukasaka
authors.affiliation: the Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccine, Institute for Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.affiliation: the Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, 53 Shogokuin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, the Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871.
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.affiliation: From the Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, the Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, sakira@biken.osaka-u.ac.jp.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000235:genetics / Q000502:physiology*; D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins; D015151:Immunoblotting; D018345:Mice, Knockout; D018832:Molecular Chaperones; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C582344:AZI2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases
keywords: AZI2; Cell Death; Macrophage; Osteoblast; Osteoclast; Osteoporosis