title: CCAAT/enhancer binding protein β (C/EBPβ) regulates the transcription of growth arrest and DNA damage-inducible protein 45 β (GADD45β) in articular chondrocytes.
abstract: Osteoarthritis (OA) is a whole joint disease characterized by cartilage degradation, which causes pain and disability in older adults. Our previous work showed that growth arrest and DNA damage-inducible protein 45 β (GADD45β) is upregulated in chondrocyte clusters in OA cartilage, especially in the early stage of this disease. CCAAT/enhancer binding protein β (C/EBPβ) is expressed in the hypertrophic growth plate chondrocytes and functions in synergy with GADD45β. Here, the presence and localization of these proteins was assessed by immunohistochemistry using articular cartilage from OA patients, revealing colocalization of C/EBPβ and GADD45β in OA chondrocytes. GADD45β promoter analysis was performed to determine whether C/EBPβ directly regulates GADD45β transcription. Furthermore, we analyzed the effect of C/EBPβ on Gadd45β gene regulation in articular chondrocytes in vivo and in vitro. Immunohistochemical analysis of C/ebpβ-haploinsufficient mice (C/ebpβ(+/-)) cartilage showed that C/ebpβ haploinsufficiency led to reduced Gadd45β gene expression in these cells. In vitro, we evaluated the effects of conditional C/EBPβ overexpression driven by the cartilage oligomeric matrix protein (Comp) promoter in mComp-tTA;pTRE-Tight-BI-DsRed-mC/ebpβ transgenic mice. C/EBPβ overexpression significantly stimulated Gadd45β gene expression in articular chondrocytes. Taken together, our data demonstrate that C/EBPβ plays a central role in controlling Gadd45β gene expression in these cells.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. Electronic address: hshimada@m2.kufm.kagoshima-u.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Laboratory for Cartilage Biology, Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Otero
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Onga Nakama Medical Association, Onga Hospital, Fukuoka, Japan.
authors.forename: Kaneyuki
authors.initials: K
authors.lastname: Tsuchimochi
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hiroshima University, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Sakakima
authors.affiliation: Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sakasegawa
authors.affiliation: The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Setoguchi
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine And Faculty of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Laboratory for Cartilage Biology, Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.affiliation: Department of Human Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Setsuro
authors.initials: S
authors.lastname: Komiya
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Ijiri
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic; D000097642:GADD45 Proteins
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: Immunohistochemistry; Osteoarthritis; Ransgenic mice