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J. Biol. Chem., Vol. 280, Issue 8, 7049-7059, February 25, 2005

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Calmodulin and Calmodulin-dependent Kinase II Regulate Osteoblast Differentiation by Controlling c-fos Expression^*

Majd Zayzafoon, Keertik Fulzele, and Jay M. McDonald¶

From the Department of Pathology, University of Alabama at Birmingham and the Veterans Administration Medical Center, Birmingham, Alabama 35233

Ca²⁺/calmodulin-dependent protein kinase II (-CaMKII) was once thought to be exclusively expressed in neuronal tissue, but it is becoming increasingly evident that CaMKII is also expressed in various extraneural cells. CaMKII plays a critical role in regulating various signaling pathways leading to modulation of several aspects of cellular functions, including proliferation, differentiation, cytoskeletal structure, and gene expression. The purpose of this study was to examine the expression of CaMKII in osteoblast-like cells (MC4) and to elucidate its role in osteoblast differentiation. We demonstrated that CaMKII, specifically the isoform, is expressed in osteoblasts both in vitro and in vivo. Inhibition of CaMKII by the calmodulin antagonist trifluoperazine or the CaMKII antagonist KN93 reduces alkaline phosphatase activity and mineralization, as well as causes 85 and 56% decreases in alkaline phosphatase and osteocalcin gene expression, respectively. CaM and CaMKII antagonists, using the newborn mouse calvaria in vivo model, cause a 50% decrease in osteoblast number (N.Ob-BS) and a 32% decrease in mineralization (BV/TV). Pharmacologic and genetic inhibition of -CaMKII by using trifluoperazine, KN93, and -CaMKII small interfering RNA decreases the phosphorylation of ERK and of cAMP-response element-binding protein, leading to a significant decrease in the transactivation of serum response element and cAMP-response element. Inhibition of -CaMKII decreases the expression of c-fos, AP-1 transactivation, and AP-1 DNA binding activity. Our findings demonstrated that -CaMKII is expressed in osteoblasts and is involved in c-fos expression via regulation of serum response element and cAMP-response element. Inhibition of -CaMKII results in a decrease in c-fos expression and AP-1 activation, leading to inhibition of osteoblast differentiation.

Received for publication, November 9, 2004 , and in revised form, December 1, 2004.

^* This work was supported by National Institutes of Health Grant 1R01-AR050235 and National Aeronautics and Space Administration Grant NNJ04HB27G (NAG-9-1562). 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.

^¶ To whom correspondence should be addressed: The University of Alabama at Birmingham, 220 West Pavilion, 619 S. 19th St., Birmingham, AL 35233-7331. Tel.: 205-934-4303; Fax: 205-934-5499; E-mail: mcdonald{at}path.uab.edu.

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