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J. Biol. Chem., Vol. 281, Issue 44, 33814-33824, November 3, 2006

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A Crucial Role for Matrix Metalloproteinase 2 in Osteocytic Canalicular Formation and Bone Metabolism^*

Keiichi Inoue^¶1, Yuko Mikuni-Takagaki^||, Kaoru Oikawa, Takeshi Itoh^**, Masaki Inada, Takanori Noguchi, Jin-Sung Park^¶, Takashi Onodera^¶, Stephen M. Krane, Masaki Noda², and Shigeyoshi Itohara³

From the Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, the Department of Molecular Pharmacology, Medical Research Institute, and the Center of Excellence Program for Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062, Japan, the ^¶Department of Molecular Immunology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo, Tokyo 113-8657, Japan, the ^||Division of Biochemistry and Molecular Biology, Department of Functional Biology, Kanagawa Dental College, Yokosuka, Kanagawa 238-8580, Japan, the ^**Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan, and the Center for Immunology and Inflammatory Diseases, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02129

Extracellular matrix production and degradation by bone cells are critical steps in bone metabolism. Mutations of the gene encoding MMP-2, an extracellular matrix-degrading enzyme, are associated with a human genetic disorder characterized by subcutaneous nodules, arthropathy, and focal osteolysis. It is not known how the loss of MMP-2 function results in the pathology. Here, we show that Mmp2^-/- mice exhibited opposing bone phenotypes caused by an impaired osteocytic canalicular network. Mmp2^-/- mice showed decreased bone mineral density in the limb and trunk bones but increased bone volume in the calvariae. In the long bones, there was moderate disruption of the osteocytic networks and reduced bone density throughout life, whereas osteoblast and osteoclast function was normal. In contrast, aged but not young Mmp2^-/- mice had calvarial sclerosis with osteocyte death. Severe disruption of the osteocytic networks preceded osteocyte loss in Mmp2^-/- calvariae. Successful transplantation of wild-type periosteum restored the osteocytic canalicular networks in the Mmp2^-/- calvariae, suggesting local roles of MMP-2 in determining bone phenotypes. Our results indicate that MMP-2 plays a crucial role in forming and maintaining the osteocytic canalicular network, and we propose that osteocytic network formation is a determinant of bone remodeling and mineralization.

Received for publication, August 1, 2006 , and in revised form, September 7, 2006.

^* This work was supported in part by a grant from the Ministry for Welfare and Health of Japan (to S. I.), by a Sasagawa Scientific Research Grant from the Japan Science Society (to K. I.), by a grant from the Japan Space Forum, National Space Development Agency of Japan (NASDA) (to N. M.), and by a research grant from the National Institutes of Health (to S. M. 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.

¹ Present address: Center for Neurobiology and Behavior, Dept. of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th St., New York, NY 10038.

² To whom correspondence may be addressed: Dept. of Molecular Pharmacology, Medical Research Institute, Tokyo Medical & Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan. Tel.: 81-3-5280-8067; Fax: 81-3-5280-8067; E-mail: noda.mph{at}mri.tmd.ac.jp.

³ To whom correspondence may be addressed: Laboratory for Behavioral Genetics, RIKEN BSI, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel.: 81-48-467-9724; Fax: 81-48-467-9725; E-mail: sitohara{at}brain.riken.jp.

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