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J. Biol. Chem., Vol. 279, Issue 48, 49795-49803, November 26, 2004

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Transcriptional Induction of FosB/FosB Gene by Mechanical Stress in Osteoblasts^*

Daisuke Inoue, Shinsuke Kido, and Toshio Matsumoto

From the Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan

Mechanical stress to bone plays a critical role in maintaining bone mass and strength. However, the molecular mechanism of mechanical stress-induced bone formation is not fully understood. In the present study, we demonstrate that FosB and its spliced variant FosB, which is known to increase bone mass by stimulating bone formation in vivo, is rapidly induced by mechanical loading in mouse hind limb bone in vivo and by fluid shear stress (FSS) in mouse calvarial osteoblasts in vitro both at the mRNA and protein levels. FSS induction of FosB/FosB gene expression was dependent on gadlinium-sensitive Ca²⁺ influx and subsequent activation of ERK1/2. Analysis of the mouse FosB/FosB gene upstream regulatory region with luciferase reporter gene assays revealed that the FosB/FosB induction by FSS occurred at the transcriptional level and was conferred by a short fragment from –603 to –327. DNA precipitation assays and DNA decoy experiments indicated that ERK-dependent activation of CREB binding to a CRE/AP-1 like element (designated "CRE2") at the position of –413 largely contributed to the transcriptional effects of FSS. These results suggest that FosB participates in mechanical stress-induced intracellular signaling cascades that activate the osteogenic program in osteoblasts.

Received for publication, April 13, 2004 , and in revised form, September 13, 2004.

^* This work was supported by grants as part of the "Ground Research Announcement for Space Utilization" promoted by the Japan Science Forum (to T. M. and D. I.) and Grants-in-aid for Scientific Research on Priority Areas 12137207 (to T. M.) and Scientific Research (B) 14370329 (to T. M.) from the Ministry of Education, Science, Sports and Culture of Japan, and a Research fellowship of the Japan Society for the Promotion of Science for Young Scientists (to S. K.). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF093624.

To whom correspondence should be addressed: Dept. of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Tel.: 81-88-633-9266; Fax: 81-88-633-7121; E-mail: inoued{at}clin.med.tokushima-u.ac.jp.

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