Glucocorticoids suppress bone formation via the osteoclast

Abstract

The pathogenesis of glucocorticoid-induced (GC-induced) bone loss is unclear. For example, osteoblast apoptosis is enhanced by GCs in vivo, but they stimulate bone formation in vitro. This conundrum suggests that an intermediary cell transmits a component of the bone-suppressive effects of GCs to osteoblasts in the intact animal. Bone remodeling is characterized by tethering of the activities of osteoclasts and osteoblasts. Hence, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To define the direct impact of GCs on bone-resorptive cells, we compared the effects of dexamethasone (DEX) on WT osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells (GR oc-/-mice). While the steroid prolonged longevity of osteoclasts, their bone-degrading capacity was suppressed. The inhibitory effect of DEX on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. DEX specifically arrested M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances GR oc-/-mice were spared the impact of DEX on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GR oc-/-mice are protected from the steroid's inhibition of bone formation.

Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

“…Our study is in accordance with this absence of effect on resorption area generated by human OCs, (13,15) but not with others, where less purified mouse or rat OCs were used and where GCs rather decreased total resorption areas. (10,12,14) We speculate that this decrease could be due to use of OCs from other animal species or to the presence of other cell types.…”

“…(2,8) There is, however, confusing information in the literature about the mechanism of action of GCs on OC bone resorption, as assessed in vitro. Increased OC survival is stressed in several studies, (9)(10)(11) but according to other studies, OC survival is decreased by GCs or not affected. (12)(13)(14) Enhanced OC differentiation also has been proposed, (13,15,16) but others found that OC differentiation was decreased by GCs or not affected.…”

“…(12)(13)(14) Enhanced OC differentiation also has been proposed, (13,15,16) but others found that OC differentiation was decreased by GCs or not affected. (10,17,18) One would expect that besides survival and differentiation, the resorptive activity of existing OCs is also stimulated by GCs because of the very early increase in bone-resorption markers induced by GCs in patients. (5,6) However, we are not aware of any mechanistic OC culture study supporting this view.…”

“…Instead, primary OCs isolated from rat bones eroded the surfaces of bone slices less extensively in the presence of high-dose GC. (12,14) So also did OCs generated from mouse bone marrow cells cultured in the presence of macrophage colonystimulating factor (M-CSF) and receptor-activator of NF-kB ligand (RANKL), (10) whereas human OCs generated from peripheral blood mononuclear cells in the presence of the same cytokines and seeded on bone slices did not respond to high-dose GCs. (13,15) This absence of direct stimulation of the resorptive activity of OCs in vitro would fit an indirect mechanism of action of GCs on OCs.…”

“…On the other hand, studies based on transgenic mice, where GCs become inactivated specifically in OCs, elegantly show that GCs are able to affect OCs directly. (9,10) Thus in vitro experiments failed so far to explain the early bone fragilization and early increase in bone-resorption markers in GCtreated patients through a direct effect of GCs on OC bone resorption. In order to investigate this hypothesis further, we generated human OCs from purified blood CD14 þ cells, seeded them on bone slices in the presence and absence of high-dose prednisolone similar to the one used in patients, and evaluated bone resorption, not limiting ourselves to the extent of boneresorption areas as in earlier studies but also paying attention to the morphology of the resorption features.…”