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Vol. 19, Issue 12, 5373-5386, December 2008

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CCAAT/Enhancer-binding Protein β Promotes Osteoblast Differentiation by Enhancing Runx2 Activity with ATF4

Hiroyuki Tominaga^*,, Shingo Maeda^*,, Makoto Hayashi^*, Shu Takeda, Shizuo Akira, Setsuro Komiya, Takashi Nakamura^||, Haruhiko Akiyama^||, and Takeshi Imamura^*

*Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Department of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Department of Neuromusculoskeletal Disorder, Orthopedic Surgery, Graduate School of Medicine and Dentistry, Kagoshima University, Kagoshima 890-8520, Japan; and ^||Department of Orthopedic Surgery, Kyoto University, Kyoto 606-8507, Japan

Submitted March 28, 2008; Revised September 16, 2008; Accepted September 26, 2008
Monitoring Editor: Marianne Bronner-Fraser

Although CCAAT/enhancer-binding protein β (C/EBPβ) is involved in osteocalcin gene expression in osteoblast in vitro, the physiological importance of and molecular mechanisms governing C/EBPβ in bone formation remain to be elucidated. In particular, it remains unclear whether C/EBPβ acts as a homodimer or a heterodimer with other proteins during osteoblast differentiation. Here, deletion of the C/EBPβ gene from mice resulted in delayed bone formation with concurrent suppression of chondrocyte maturation and osteoblast differentiation. The expression of type X collagen as well as chondrocyte hypertrophy were suppressed in mutant bone, providing new insight into the possible roles of C/EBPβ in chondrocyte maturation. In osteoblasts, luciferase reporter, gel shift, DNAP, and ChIP assays demonstrated that C/EBPβ heterodimerized with activating transcription factor 4 (ATF4), another basic leucine zipper transcription factor crucial for osteoblast maturation. This complex interacted and transactivated osteocalcin-specific element 1 (OSE1) of the osteocalcin promoter. C/EBPβ also enhanced the synergistic effect of ATF4 and Runx2 on osteocalcin promoter transactivation by enhancing their interaction. Thus, our results provide evidence that C/EBPβ is a crucial cofactor in the promotion of osteoblast maturation by Runx2 and ATF4.

Address correspondence to: Shingo Maeda (shingo.maeda{at}jfcr.or.jp).

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