Effect of corticosteroids on human osteoclast formation and activity

Abstract

Chronic corticosteroid treatment is known to induce bone loss and osteoporosis. Osteoclasts are specialised boneresorbing cells that are formed from mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have examined the effect of the synthetic glucocorticoid, dexamethasone, on human osteoclast formation and bone-resorbing activity. Human monocytes were cultured for up to 21 days on glass coverslips and dentine slices, with soluble receptor activator for nuclear factor B ligand (RANKL; 30 ng/ml) and human macrophage-colony stimulating factor (M-CSF; 25 ng/ml) in the presence and absence of dexamethasone (10 8 M). The addition of dexamethasone over a period of 7 and 14 days of culture of monocytes (during which cell proliferation and differentiation predominantly occurred) resulted in a marked increase in the formation of tartrate-resistant acid phosphatase-positive multinucleated cells and an increase in lacunar resorption. The addition of dexamethasone to monocyte cultures after 14 days (when resorptive activity of osteoclasts had commenced) reduced the extent of lacunar resorption compared with cultures to which no dexamethasone had been added. The addition of dexamethasone to osteoclasts isolated from giant cell tumours of bone significantly inhibited resorption pit formation. Our findings indicate that dexamethasone has a direct effect on osteoclast formation and activity, stimulating the proliferation and differentiation of human osteoclast precursors and inhibiting the bone-resorbing activity of mature osteoclasts.

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

“…Noteworthy, the generation of a high proportion of trenches in the presence of GCs is also supported by pictures from another study performed with human OCs generated from peripheral blood mononucleated cells, (13) but this report does not comment on the morphology of the excavations and mentions only the absence of effect of GCs on total resorption area. 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.…”

“…(46) Furthermore, the serum levels of CTX are increased in GC-treated patients, (5,6) as are also the levels of CTX in the present pit assay in the presence of GCs. However, as stressed in the introduction, GC-induced osteoporosis is multifactorial (2,8) and also may result from increased OC survival and differentiation (9)(10)(11)13,15,16) and may be due both to direct effects and mediation by other cell types. (2,7,8,17) Therefore, the contribution of the effect of GC on resorptive activity revealed in this study should be considered in this general context.…”

“…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. (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.…”

“…(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. A series of indirect mechanisms have been proposed, (2,8) including elevation in parathyroid hormone (PTH) levels resulting from GC-induced impaired calcium uptake in the gut and the kidney, GC-induced reduction of gonadal hormones, and mediation through OB lineage cells.…”

Gender- and age-related differences in osteoclast formation from circulating precursors

“…Dexamethasone is known to promote expression of membrane-bound M-CSF in murine osteoblasts but the mechanism whereby it stimulates osteoclast formation from circulating precursors is unknown (Rubin et al 1998). Our own and previous studies suggest that this is due primarily to an effect on osteoclast proliferation and differentiation rather than osteoclast activity (Tobias & Chambers 1989, Hirayama et al 2000.…”