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Molecular and Cellular Biology Volume 26, 2006 - Issue 16
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Article

CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Regulates Osteoblast Differentiation

Ken Shirakawa1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo;2 Section of Orthopedic and Spinal Surgery, Department of Frontier Surgical Therapeutics, Division of Advanced Therapeutical Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo
,
Shingo Maeda1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo
,
Tomomi Gotoh3 Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto
,
Makoto Hayashi1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo;4 Department of Biological Sciences, Graduate School of Bioscienceand Biotechnology, Tokyo Institute of Technology, Yokohama
,
Kenichi Shinomiya2 Section of Orthopedic and Spinal Surgery, Department of Frontier Surgical Therapeutics, Division of Advanced Therapeutical Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo
,
Shogo Ehata1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo
,
Riko Nishimura5 Department of Biochemistry, Graduate School of Dentistry, Osaka University, Osaka
,
Masataka Mori3 Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto
,
Kikuo Onozaki6 Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya
,
Hidetoshi Hayashi6 Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya
,
Satoshi Uematsu7 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
,
Shizuo Akira7 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
,
Etsuro Ogata8 Cancer Institute Hospital, Tokyo
,
Kohei Miyazono1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo;9 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
&
Takeshi Imamura1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, TokyoCorrespondence[email protected]
 show all
Pages 6105-6116 | Received 21 Dec 2005, Accepted 26 May 2006, Published online: 27 Mar 2023
 
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Abstract

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/EBPζ) 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/EBPβ and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBPβ, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBPβ 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.

We thank A. Hanyu, N. Kaneniwa, E. Kobayashi, and Y. Yuuki (The Cancer Institute) for technical assistance.

This research was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. T.I. was supported by the Tokyo Biochemical Research Foundation and the Takeda Science Foundation. S.M. was supported by the Takeda Science Foundation and the Uehara Memorial Foundation.

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