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J. Biol. Chem., Vol. 282, Issue 48, 35318-35327, November 30, 2007

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Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption^*

Hyeonju Yeo, Lauren H. Beck, Sunnie R. Thompson, Mary C. Farach-Carson^¶, Jay M. McDonald, Thomas L. Clemens, and Majd Zayzafoon¹

From the Departments of Pathology and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182 and the Department of ^¶Biological Sciences, University of Delaware, Newark, Delaware 19716

We recently reported that the pharmacological inhibition of calcineurin (Cn) by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether Cn exerts direct actions in osteoblasts, we generated mice lacking Cnb1 (Cn regulatory subunit) in osteoblasts (Cnb1^OB) using Cre-mediated recombination methods. Transgenic mice expressing Cre recombinase, driven by the human osteocalcin promoter, were crossed with homozygous mice that express loxP-flanked Cnb1 (Cnb1^f/f). Microcomputed tomography analysis of tibiae at 3 months showed that Cnb1^OB mice had dramatic increases in bone mass compared with controls. Histomorphometric analyses showed significant increases in mineral apposition rate (67%), bone volume (32%), trabecular thickness (29%), and osteoblast numbers (68%) as well as a 40% decrease in osteoclast numbers as compared with the values from control mice. To delete Cnb1 in vitro, primary calvarial osteoblasts, harvested from Cnb1^f/f mice, were infected with adenovirus expressing the Cre recombinase. Cre-expressing osteoblasts had a complete inhibition of Cnb1 protein levels but differentiated and mineralized more rapidly than control, green fluorescent protein-expressing cells. Deletion of Cnb1 increased expression of osteoprotegerin and decreased expression of RANKL. Co-culturing Cnb1-deficient osteoblasts with wild type osteoclasts demonstrated that osteoblasts lacking Cnb1 failed to support osteoclast differentiation in vitro. Taken together, our findings demonstrate that the inhibition of Cnb1 in osteoblasts increases bone mass by directly increasing osteoblast differentiation and indirectly decreasing osteoclastogenesis.

Received for publication, March 21, 2007 , and in revised form, September 13, 2007.

^* This work was supported by National Institutes of Health Grants AR050235 and CA109119 (to J. M. M.), P01-CA098912 (to M. Z.), and R01-AR053898 (to M. Z.). 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: University of Alabama at Birmingham, 813 Shelby Biomedical Research Bldg., 1825 University Blvd., Birmingham, AL 35294-2182. Tel.: 205-934-5574; Fax: 205-996-6119; E-mail: mzayzafo{at}uab.edu.

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