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

Abstract

Although glucocorticoids (GCs) are physiologically essential for bone metabolism, it is generally accepted that high doses of GCs cause bone loss through a combination of decreased bone formation and increased bone resorption. However, the action of GCs on mature osteoclasts remains contradictory. In this study, we have examined the effect of GCs on osteoclastic bone-resorbing 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-resorbing activity of the isolated mature osteoclasts. When the isolated osteoclasts were co-cultured with rabbit osteoblastic cells, the osteoclastic bone resorption decreased in response to Dex, dependent on the number of osteoblastic 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 addition, the osteoblastic cells were required for the osteoclast apoptosis induced by Dex. These findings indicate that the main target cells of GCs are non-osteoclastic cells such as osteoblasts and that GCs indirectly inhibit bone resorption by inducing apoptosis of the mature osteoclasts through the action of non-osteoclastic cells. This study expands our knowledge about the multifunctional roles of GCs in bone metabolism.