Previous Article | Next Article 
Molecular and Cellular Biology, August 2006, p. 6105-6116, Vol. 26, No. 16
0270-7306/06/$08.00+0 doi:10.1128/MCB.02429-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Regulates Osteoblast Differentiation
Ken Shirakawa,1,2,
Shingo Maeda,1,
Tomomi Gotoh,3
Makoto Hayashi,1,4
Kenichi Shinomiya,2
Shogo Ehata,1
Riko Nishimura,5
Masataka Mori,3
Kikuo Onozaki,6
Hidetoshi Hayashi,6
Satoshi Uematsu,7
Shizuo Akira,7
Etsuro Ogata,8
Kohei Miyazono,1,9 and
Takeshi Imamura1*
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo,1 Section of Orthopedic and Spinal Surgery, Department of Frontier Surgical Therapeutics, Division of Advanced Therapeutical Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo,2 Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto,3 Department of Biological Sciences, Graduate School of Bioscienceand Biotechnology, Tokyo Institute of Technology, Yokohama,4 Department of Biochemistry, Graduate School of Dentistry, Osaka University, Osaka,5 Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya,6 Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Department of Host Defense, and The 21st Century COE, Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka,7 Cancer Institute Hospital, Tokyo,8 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan9
Received 21 December 2005/ Returned for modification 20 February 2006/ Accepted 26 May 2006
Differentiation
of committed osteoblasts is controlled by complex activities involving
signal transduction and gene expression, and Runx2 and Osterix function
as master regulators for this process. Recently, CCAAT/enhancer-binding
proteins (C/EBPs) have been reported to regulate osteogenesis in
addition to adipogenesis. However, the roles of C/EBP transcription
factors in the control of osteoblast differentiation have yet to be
fully elucidated. Here we show that C/EBP homologous protein (CHOP;
also known as C/EBP
) is expressed in bone as well as in
mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP
reduces alkaline phosphatase activity in primary osteoblasts and
suppresses the formation of calcified bone nodules. CHOP-deficient
osteoblasts differentiate more strongly than their wild-type
counterparts, suggesting that endogenous CHOP plays an important role
in the inhibition of osteoblast differentiation. Furthermore,
endogenous CHOP induces differentiation of calvarial osteoblasts upon
bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers
with C/EBPß and inhibits the DNA-binding activity as well as
Runx2-binding activity of C/EBPß, leading to inhibition of
osteocalcin gene transcription. These findings indicate that CHOP acts
as a dominant-negative inhibitor of C/EBPß and prevents
osteoblast differentiation but promotes BMP signaling in a
cell-type-dependent manner. Thus, endogenous CHOP may have dual roles
in regulating osteoblast differentiation and bone
formation.
* Corresponding author. Mailing address: Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan. Phone: 81-3-3570-0459. Fax: 81-3-3570-0459. E-mail: timamura-ind{at}umin.ac.jp.
These
authors contributed equally.
Molecular and Cellular Biology, August 2006, p. 6105-6116, Vol. 26, No. 16
0270-7306/06/$08.00+0 doi:10.1128/MCB.02429-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
This article has been cited by other articles:
-
Zanotti, S., Stadmeyer, L., Smerdel-Ramoya, A., Durant, D., Canalis, E.
(2009). Misexpression of CCAAT/enhancer binding protein beta causes osteopenia. J Endocrinol
201: 263-274
[Abstract] [Full Text] -
Tominaga, H., Maeda, S., Hayashi, M., Takeda, S., Akira, S., Komiya, S., Nakamura, T., Akiyama, H., Imamura, T.
(2008). CCAAT/Enhancer-binding Protein {beta} Promotes Osteoblast Differentiation by Enhancing Runx2 Activity with ATF4. Mol. Biol. Cell
19: 5373-5386
[Abstract] [Full Text] -
Cucinotta, M., Visalli, M., Aguennouz, M., Valenti, A., Loddo, S., Altucci, L., Teti, D.
(2008). Regulation of Interleukin-8 Gene at a Distinct Site of Its Promoter by CCAAT Enhancer-binding Protein Homologous Protein in Prostaglandin E2-treated Human T Cells. J. Biol. Chem.
283: 29760-29769
[Abstract] [Full Text] -
Yamakawa, T., Whitson, R. H., Li, S.-L., Itakura, K.
(2008). Modulator Recognition Factor-2 Is Required for Adipogenesis in Mouse Embryo Fibroblasts and 3T3-L1 Cells. Mol. Endocrinol.
22: 441-453
[Abstract] [Full Text] -
Hayashi, M., Maeda, S., Aburatani, H., Kitamura, K., Miyoshi, H., Miyazono, K., Imamura, T.
(2008). Pitx2 Prevents Osteoblastic Transdifferentiation of Myoblasts by Bone Morphogenetic Proteins. J. Biol. Chem.
283: 565-571
[Abstract] [Full Text] -
Wiper-Bergeron, N., St-Louis, C., Lee, J. M.
(2007). CCAAT/Enhancer Binding Protein {beta} Abrogates Retinoic Acid-Induced Osteoblast Differentiation via Repression of Runx2 Transcription. Mol. Endocrinol.
21: 2124-2135
[Abstract] [Full Text] -
Lawrence, M. C., McGlynn, K., Naziruddin, B., Levy, M. F., Cobb, M. H.
(2007). Inaugural Article: Differential regulation of CHOP-10/GADD153 gene expression by MAPK signaling in pancreatic beta-cells. Proc. Natl. Acad. Sci. USA
104: 11518-11525
[Abstract] [Full Text] -
Mameli, G., Deshmane, S. L., Ghafouri, M., Cui, J., Simbiri, K., Khalili, K., Mukerjee, R., Dolei, A., Amini, S., Sawaya, B. E.
(2007). C/EBPbeta regulates human immunodeficiency virus 1 gene expression through its association with cdk9. J. Gen. Virol.
88: 631-640
[Abstract] [Full Text]
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»