Glucocorticoids, widely used as immune suppressors, cause osteoporosis by 
inhibiting bone formation. In MC3T3-E1 osteoblast-like cultures, dexamethasone 
(DEX) activates glycogen synthase kinase-3beta (GSK3beta) and inhibits a 
differentiation-related cell cycle that occurs at a commitment stage immediately 
after confluence. Here we show that DEX inhibition of the 
differentiation-related cell cycle is associated with a decrease in beta-catenin 
levels and inhibition of LEF/TCF-mediated transcription. These inhibitory 
activities are no longer observed in the presence of lithium, a GSK3beta 
inhibitor. DEX decreased the serum-responsive phosphorylation of protein kinase 
B/Akt-Ser(473) within minutes, and this inhibition was also observed after 12 h. 
When the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was inhibited by 
wortmannin, DEX no longer inhibited beta-catenin levels. Furthermore, 
DEX-mediated inhibition of LEF/TCF transcriptional activity was attenuated in 
the presence of dominant negative forms of either PI3K or protein kinase B/Akt. 
These results suggest cross-talk between the PI3K/Akt and Wnt signaling 
pathways. Consistent with a role for Wnt signaling in the osteoblast 
differentiation-related cell cycle, wortmannin partially negated the DEX 
inhibition of this cell cycle. DEX also induced histone deacetylase (HDAC) 1, 
which is known to inhibit LEF/TCF transcriptional activity. Overexpression of 
HDAC1 negated the inhibitory effect of DEX on LEF/TCF transcriptional activity. 
In the presence of trichostatin A, a deacetylase inhibitor, DEX-mediated 
inhibition of the differentiation-related cell cycle was partially negated. When 
administered together, wortmannin and trichostatin A completely negated the 
inhibitory effect of DEX on the differentiation-related cell cycle. These 
results suggest that inhibition of a PI3K/Akt/GSK3beta/beta-catenin/LEF axis and 
stimulation of HDAC1 cooperate to mediate the inhibitory effect of DEX on Wnt 
signaling and the osteoblast differentiation-related cell cycle.