Dexamethasone inhibits bone resorption by indirectly inducing apoptosis ofthe bone-resorbing osteoclasts via the action of osteoblastic cells

Although glucocorticoids (GCs) are physiologically essential for bone metab olism, it is generally accepted that high doses of GCs cause bone loss thro ugh a combination of decreased bone formation and increased bone resorption . However, the action of GCs on mature osteoclasts remains contradictory. I n this study, we have examined the effect of GCs on osteoclastic bone-resor bing activity and osteoclast apoptosis, by using two different cell types, rabbit unfractionated bone cells and highly enriched mature osteoclasts (> 95% of purity). Dexamethasone (Dex, 10(-10)-10(-7) M) inhibited resorption pit formation on a dentine slice by the unfractionated bone cells in a dose - and time-dependent manner. However, Dex had no effect on the bone-resorbi ng activity of the isolated mature osteoclasts. When the isolated osteoclas ts were co-cultured with rabbit osteoblastic cells, the osteoclastic bone r esorption decreased in response to Dex, dependent on the number of osteobla stic cells. Like the effect on the bone resorption, Dex induced osteoclast apoptosis in cultures of the unfractionated bone cells, whereas it did not promote the apoptosis of the isolated osteoclasts. An inhibitor of caspases , Z-Asp-CH2-DCB attenuated both the inhibitory effect on osteoclastic bone resorption and the stimulatory effect on the osteoclast apoptosis. In addit ion, the osteoblastic cells were required for the osteoclast apoptosis indu ced by Dex. These findings indicate that the main target cells of GCs are n on-osteoclastic cells such as osteoblasts and that GCs indirectly inhibit b one resorption by inducing apoptosis of the mature osteoclasts through the action of non-osteoclastic cells. This study expands our knowledge about th e multifunctional roles of GCs in bone metabolism.