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Papers In Press, published online ahead of print February 27, 2002
Department of Ortopaedic Surgery , Biochemistry & Molecular Biology, University of Southern California, Los Angeles, CA 90033
Corresponding Author: frenkel{at}hsc.usc.edu
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. The present study defines a role for the glycogen synthase kinase 3ß (GSK3ß) and its target, c-MYC, in the GC-sensitive, osteoblast persistent cell cycle. c-MYC levels decrease as cells reach confluence, but then increase during growth to high density. GC administration at this stage results in down-regulation of c-MYC. This is accompanied by GC-mediated attenuation of GSK3ß Ser9 inhibitory phosphorylation and increased GSK3ß kinase activity. The down-regulation of c-MYC is attributable to enhanced Thr58 phosphorylation, leading to accelerated degradation. In contrast, GC did not inhibit c-MYC synthesis rate or the level of ß-catenin, a transcriptional co-activator of c-myc. The attenuated cell cycle, as well as the reduced c-MYC level, was rescued back to control levels by specific inhibition of GSK3ß using lithium chloride. These results suggest that tonal GSK3ß repression at the cobblestone stage of osteoblast differentiation permits osteoblast growth to high density. GC interfere with this growth-permissive axis by GSK3ß activation, resulting in c-MYC down-regulation and impediment of the G1/S cell cycle transition.
J. Biol. Chem, 10.1074/jbc.M109708200
Submitted on October 9, 2001
Revised on February 27, 2002
Accepted on February 27, 2002
Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase
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