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J. Biol. Chem., Vol. 283, Issue 30, 21002-21010, July 25, 2008

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In Vivo Targeted Deletion of Calpain Small Subunit, Capn4, in Cells of the Osteoblast Lineage Impairs Cell Proliferation, Differentiation, and Bone Formation^*

Masako Shimada¹, Peter A. Greer, Andrew P. McMahon^¶, Mary L. Bouxsein^||, and Ernestina Schipani

From the Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02114, the Queen's University Cancer Research Institute, Kingston, Ontario, Canada K7L 3N6, the ^¶Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, and the ^||Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215

Calpains are intracellular cysteine proteases, which include widely expressed µ- and m-calpains (1). Both µ-calpains and m-calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit. The calpain small subunit encoded by the gene Capn4 directly binds to the intracellular C-terminal tail (C-tail) of the receptor for parathyroid hormone and parathyroid hormone-related peptide and modulates its cellular functions in osteoblasts in vitro (2). To investigate a potential role of the calpain small subunit in osteoblasts in vivo, we generated osteoblast-specific Capn4 knock-out mice using the Cre-LoxP system (3). Mutant mice had smaller bodies with shorter limbs, reduced trabecular bone with thinner cortices, and decreased osteoblast number. In vitro analysis confirmed that deletion of Capn4 in osteoblasts severely affected multiple osteoblast functions including proliferation, differentiation, and matrix mineralization. Collectively, our findings provide the first in vivo demonstration that the calpain small subunit is essential for proper osteoblast activity and bone remodeling.

Received for publication, December 19, 2007 , and in revised form, May 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 DK072102 (to M. S.). This work was also supported by Canadian Institutes of Health Research Grant MOP-81189 (to P. A. G.). 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 should be addressed. Tel.: 617-726-3966; Fax: 617-726-1703; E-mail: shimada{at}helix.mgh.harvard.edu.

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