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J. Biol. Chem., Vol. 282, Issue 41, 29958-29966, October 12, 2007

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Mechanistic Roles of Leptin in Osteogenic Stimulation in Thoracic Ligament Flavum Cells^*

Dongwei Fan, Zhongqiang Chen¹, Yupeng Chen, and Yongfeng Shang²

From the Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China and Department of Orthopedics, Peking University Third Hospital, Beijing 100083, China

Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF.

Received for publication, December 22, 2006 , and in revised form, August 14, 2007.

^* This work was supported by National Natural Science Foundation of China Grants 30571868 (to Z. C.) and 30621002, 30393110, and 30470912 (to Y. S.), Ministry of Education of China Grant 20050001147 (to Z. C.), and Ministry of Science and Technology of China grants (973 Program 2005CB522404 and 863 Program 2006AA02Z466 (to Y. S.). 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.

¹ To whom correspondence may be addressed: Dept. of Orthopedics, Peking University Third Hospital, Beijing 100083, China. Tel.: 86-10-62017691; Fax: 86-10-62016928; E-mail: chenzq{at}bjmu.edu.cn. ² To whom correspondence may be addressed: Dept. of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xue Yuan Rd., Beijing 100083, China. Tel.: 86-10-82805118; Fax: 86-10-82801355; E-mail: yshang{at}hsc.pku.edu.cn.

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