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J. Biol. Chem., Vol. 278, Issue 26, 23270-23277, June 27, 2003

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Activation of Peroxisome Proliferator-activated Receptor- Inhibits the Runx2-mediated Transcription of Osteocalcin in Osteoblasts^*

Min Jae Jeon  , Jeong Ah Kim , Sung Hee Kwon ¶, Sang Wan Kim , Kyong Soo Park  ||, Sung-Woo Park ¶, Seong Yeon Kim  || and Chan Soo Shin  || **

From the Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea, the Hormone Research Center, Seoul National University Hospital Clinical Research Institute, Seoul 110-744, Korea, the ^||Institute of Endocrinology, Nutrition, and Metabolism, Seoul National University Medical Research Center, Seoul 110-744, Korea, and the ^¶Department of Internal Medicine, College of Medicine, Hallym University, Gyeonggi 431-070, Korea

Mesenchymal cells are able to differentiate into several distinct cell types, including osteoblasts and adipocytes. The commitment to a particular lineage may be regulated by specific transcription factors. Peroxisome proliferator-activated receptor- (PPAR), acting in conjunction with CCAAT/enhancer-binding protein-, has been suggested as a key regulator of adipogenic differentiation. Previous studies have shown that the activation of PPAR in osteoblasts suppresses osteoblast differentiation and the expression of osteocalcin, an osteoblast-specific protein. However, the mechanism of this inhibition remains unclear. We investigated the effect of PPAR activation on the expression of osteocalcin and analyzed the molecular mechanism. Mouse osteoblastic MC3T3-E1 cells expressed PPAR, which was transcriptionally active, whereas rat osteosarcoma ROS 17/2.8 cells did not. Treatment of MC3T3-E1 osteoblasts and ROS 17/2.8 cells stably transfected with PPAR2 with the PPAR activator 15-deoxy-^12,14-prostaglandin J₂ inhibited the mRNA expression of osteocalcin and Runx2, the latter of which is a key transcription factor in osteoblast differentiation. This decreased expression of osteocalcin and Runx2 was partly explained by the decreased level of Runx2 resulting from the suppressed transcription from the Runx2 promoter. However, in addition to this indirect effect, the activation of PPAR by 15-deoxy-^12,14-prostaglandin J₂ directly suppressed the Runx2-mediated induction of the activities of the osteocalcin promoter and the artificial promoter p6OSE2, which contains six tandem copies of osteoblast-specific element-2, the Runx2-binding promoter sequence. This inhibition was mediated by a physical interaction between PPAR and Runx2 and the subsequent repression of the transcriptional activity at the osteoblast-specific element-2 sequence. Thus, this study demonstrates that the activation of PPAR inhibits osteocalcin expression both by suppressing the expression of Runx2 and by interfering with the transactivation ability of Runx2.

Received for publication, November 14, 2002 , and in revised form, April 15, 2003.

^* This work was supported by Grant 01-PJ1-PG1-01CH08-0001 from the Ministry of Health and Welfare of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Internal Medicine, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Gu, Seoul 110-744, Korea. Tel.: 82-2-760-3734; Fax: 82-2-762-9662; E-mail: csshin{at}plaza.snu.ac.kr.

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