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Originally published In Press as doi:10.1074/jbc.M109708200 on February 27, 2002

J. Biol. Chem., Vol. 277, Issue 20, 18191-18197, May 17, 2002
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Glucocorticoids Inhibit Cell Cycle Progression in Differentiating Osteoblasts via Glycogen Synthase Kinase-3beta *

Elisheva SmithDagger , Gerhard A. Coetzee§, and Baruch FrenkelDagger ||

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

Differentiating osteoblasts in culture undergo a commitment stage, during which cobblestone-like cells grow to high density past confluency. In contrast to earlier proliferative stages, the cell cycle during this commitment stage is inhibited by glucocorticoids (GC). Chronic GC treatment also impedes mineral deposition if steroid administration commences early enough during commitment. This study defines a role for glycogen synthase kinase-3beta (GSK3beta ) and its target, c-Myc, in the GC-sensitive osteoblast persistent cell cycle. c-Myc levels decreased as cells reached confluence, but then increased during growth to high density. GC administration at this stage resulted in down-regulation of c-Myc. This was accompanied by GC-mediated attenuation of GSK3beta Ser9 inhibitory phosphorylation and increased GSK3beta kinase activity. Down-regulation of c-Myc was attributable to enhanced Thr58 phosphorylation, leading to accelerated degradation. In contrast, GC did not inhibit the c-Myc synthesis rate or the level of beta -catenin, a transcriptional coactivator of c-myc. The attenuated cell cycle and the reduced c-Myc level were returned to control levels by specific inhibition of GSK3beta using lithium chloride. These results suggest that tonal GSK3beta repression at the cobblestone stage of osteoblast differentiation permits osteoblast growth to high density. GC interfere with this growth-permissive axis by GSK3beta activation, resulting in c-Myc down-regulation and impediment of the G1/S cell cycle transition.

* This work were supported by Grants RO1-AR47052 and T32-CA09659 from the National Institutes of Health and by grants from the Arthritis Foundation and the Zumberge Foundation.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 © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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