Glucocorticoid activity, inactivity and the osteoblast

Although excess circulating glucocorticoids have detrimental effects on bone health, the processes underlying these effects are not well understood. We review what is currently known about the effects of glucocorticoids on osteoblast proliferation and differentiation, with particular emphasis on osteoblast expression of glucocorticoid metabolic enzymes as a mechanism for regulating corticosteroid activity in bone. The adverse effects on bone of increased circulating concentrations of endogenous glucocorticoids have been recognised since Harvey Cushing’s original description of Cushing’s disease (Cushing 1912). The increasing use of synthetic glucocorticoids for inflammatory diseases has increased the pressure to understand, and ultimately modify, the processes underlying their deleterious effects on bone. The clinical impact of the problem is reflected both by a doubling of the overall fracture risk in patients taking prednisolone (7·5 mg for 6 months) and the development of low bone mineral density in 50% of patients taking higher doses of glucocorticoid (Eastell 1995). Several mechanisms have been proposed for these effects, including reduction in endogenous sex steroid production, decreased muscle mass, and altered gastrointestinal and renal calcium handling causing secondary hyperparathyroidism (Canalis 1996). However, it appears increasingly likely that the most important effect of glucocorticoids is to alter the proliferation and differentiation of cells of the osteoblast lineage. Bone formation in vivo is clearly a complex dynamic process, involving the actions of multiple morphogens, growth factors and hormones. Glucocorticoids could affect any part of the differentiation pathway from initial skeletal patterning and mesoderm induction, commitment of primitive multipotent mesodermal progenitor cells to the osteoblast lineage, or the proliferation and differentiation of preosteoblasts through to mature osteoblasts, to bone-lining cells and osteocytes (Fig. 1). All these stages are likely to occur in normal bone turnover and during fracture healing. For each of these stages, the effects of glucocorticoids, their mechanisms of action and, equally important, the reasons for their lack of action, upon other osteoblasts within the bone microenvironment require explanation. These are outlined in the following review, with particular emphasis on osteoblast expression of glucocorticoid metabolic enzymes as a mechanism for regulating steroid activity in bone.