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Originally published In Press as doi:10.1074/jbc.M001758200 on April 14, 2000

J. Biol. Chem., Vol. 275, Issue 26, 19992-20001, June 30, 2000
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Glucocorticoids Inhibit Developmental Stage-specific Osteoblast Cell Cycle
DISSOCIATION OF CYCLIN A-CYCLIN-DEPENDENT KINASE 2 FROM E2F4-p130 COMPLEXES*

Elisheva SmithDagger §, Rebecca A. RedmanDagger §, Christopher R. LoggDagger , Gerhard A. Coetzee||**, Nori KasaharaDagger , and Baruch FrenkelDagger §Dagger Dagger §§

From the Departments of Dagger Dagger  Orthopaedic Surgery, Dagger  Biochemistry and Molecular Biology,  Pathology, || Urology, § Institute for Genetic Medicine and ** Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033

Unique cell cycle control is instituted in confluent osteoblast cultures, driving growth to high density. The postconfluent dividing cells share features with cells that normally exit the cell cycle; p27kip1 is increased, p21waf1/cip1 is decreased, free E2F DNA binding activity is reduced, and E2F4 is primarily nuclear. E2F4-p130 becomes the predominant E2F-pocket complex formed on E2F sites, but, unlike the complex that typifies resting cells, cyclin A and CDK2 are also present. Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G1/S transition. The glucocorticoid-mediated cell cycle attenuation is also accompanied by, but not attributable to, increased p27kip1 and decreased p21waf1/cip1 levels. The attenuation of osteoblast growth to high density by dexamethasone is associated with severe impairment of mineralized extracellular matrix formation, unless treatment commences in cultures that have already grown to high density. Both the antimitotic and the antiphenotypic effects are reversible, and both are antagonized by RU486. Thus, glucocorticoids induce premature attenuation of the osteoblast cell cycle, possibly contributing to the osteoporosis induced by these drugs in vivo.

* This work was supported by the Donald E. and Delia B. Baxter Foundation, by the Wright Foundation, and by National Institutes of Health Grant T32 CA 09659.The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Inst. for Genetic Medicine, University of Southern California Keck School of Medicine, 2250 Alcazar St., CSC/IGM240, Los Angeles, CA 90033. Tel.: 323-442-1322; Fax: 323-442-2764; E-mail: frenkel@hsc.usc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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