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J. Biol. Chem., Vol. 282, Issue 17, 12907-12915, April 27, 2007

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Lack of Schnurri-2 Expression Associates with Reduced Bone Remodeling and Osteopenia^*

Yoshitomo Saita, Tsuyoshi Takagi, Keiichiro Kitahara, Michihiko Usui, Kohei Miyazono^¶, Yoichi Ezura^||, Kazuhisa Nakashima^**1, Hisashi Kurosawa, Shunsuke Ishii², and Masaki Noda^||**3

From the Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Ibaraki 305-0074, ^¶Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Department of Orthopedics, Juntendo University, School of Medicine, Tokyo 113-8421, and ^**21st Century Center of Excellence (COE) Program for the Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, ^||Advanced Bone and Joint Science Integrated Action Initiative in JSPS Core to Core Program, and Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo 101-0062, Japan

Regulation of bone remodeling determines the levels of bone mass and its imbalance causes major skeletal diseases such as osteoporosis. A zinc finger protein, Schnurri-2 (SHN-2), was recently demonstrated to regulate bone morphogenetic protein-dependent adipogenesis and lymphogenesis. However, the role of SHN-2 in bone is not known. Here, we investigated the effects of Shn-2 deficiency on bone metabolism and cell function in Shn-2-null mice. Lack of SHN-2 expression reduced bone remodeling by suppressing both osteoblastic bone formation and osteoclastic bone resorption activities in vivo. Shn-2 deficiency suppressed osterix and osteocalcin expression as well as in vitro mineralization. Conversely, Shn-2 overexpression enhanced osteocalcin promoter activity and bone morphogenetic protein-dependent osteoblastic differentiation. Shn-2 deficiency suppressed Nfatc1 and c-fos expression leading to reduction of tartrate-resistant acid phosphatase-positive cell development in vivo as well as in the cultures of bone marrow cells. These studies demonstrate that SHN-2 regulates the activities of critical transcription factors required for normal bone remodeling.

Received for publication, December 6, 2006 , and in revised form, January 12, 2007.

^* This work was supported by grants-in-aid from the Japanese Ministry of Education (21st Century Center of Excellence Program, Frontier Research for Molecular Destruction and Reconstitution of Tooth and Bone, 17012008, 18109011, 18659438, 18123456), grants from the Japan Space Forum, National Space Development Agency of Japan (NASDA), and Japan Society for Promotion of Science (JSPS Core to Core Program on Advanced Bone and Joint Science, Research for the Future Program, Genome Science). 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 Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai, 2-chome, Chiyoda-ku, Tokyo 101, Japan. Tel.: 81-3-5280-8067; Fax: 81-3-5280-8067; E-mail: kxn.mph{at}mri.tmd.ac.jp.

² To whom correspondence may be addressed: Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan. Tel.: 81-29-836-9031; Fax: 81-29-836-9030; E-mail: sishii{at}rtc.riken.go.jp.

³ To whom correspondence may be addressed. Tel.: 81-3-5280-8066; Fax: 81-3-5280-8066; E-mail: noda.mph{at}mri.tmd.ac.jp.

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