Glucocorticoid‐Induced Osteoporosis: Both In Vivo and In Vitro Concentrations of Glucocorticoids Higher Than Physiological Levels Attenuate Osteoblast Differentiation

SINCE HENCH ET AL. (1) first reported the use of cortisone for treatment of patients with rheumatoid arthritis, glucocorticoids (GCs) have been widely used for anti-inflammatory and immunosuppressive therapy. However, GCs have major effects on several organ systems, including the cardiovascular, endocrine, gastrointestinal, ophthalmic, and musculoskeletal systems, and these often lead to major side effects. Among the most dramatic side effects of in vivo long-term GC excess is the development of GC-induced osteoporosis. Several lines of evidence indicate that the major mechanisms whereby GCs induce osteoporosis are decreased bone matrix deposition by osteoblasts, stimulation of osteoclastic bone resorption, and decreased intestinal calcium resorption with resulting mild secondary hyperparathyroidism (for reviews see Refs. 3, 5–8). However, the diverse and complex effects of GCs on bone metabolism are still incompletely understood, mainly due to differences in experimental outcomes in different systems and culture conditions, which could be a result of species differences, age of the experimental animals used, maturation stage of the cells studied, heterogeneity of osteoblast populations, differences between transformed cells and normal cells, or length and dose of GC treatment used. In this brief review, we will focus on the effects of GCs on bone formation. With regard to this aspect of GC effects, it has been reported in a variety of in vitro systems that GCs induce cells of the osteoblast lineage to differentiate into mature cells expressing the osteoblastic phenotype, e.g., parathyroid hormone–stimulated cAMP synthesis, osteopontin, bone sialoprotein, alkaline phosphatase (AP), and mineralized bone nodule formation. However, in several in vitro systems, GCs have also been shown to decrease type I collagen synthesis and mRNA levels, osteocalcin production and mRNA levels, and the expression of insulin-like growth factor I (IGF-I) and selected IGF-binding proteins (IGFBPs) which enhance IGF activity (e.g., IGFBP-3 and IGFBP-5). The reason for the observed differences is not clear, but it is known that the GC receptor can mediate not only transcriptional activation but also repression of transcriptional expression by interfering with the binding or activity of other transcription factors or by interacting directly with negative glucocorticoid response elements (nGREs). For example, the GC-induced inhibition of 1,25-dihydroxyvitamin D3– mediated osteocalcin transcription is likely to occur by binding of the GC receptor to a nGRE overlapping the TATA box in the proximal promoter region of osteocalcin gene. In addition, mRNA levels can also be controlled by GCs through selective changes in mRNA stability. Indeed, Delany et al. have shown that GC-mediated down-regulation of a1(I) collagen mRNA occurs by a decrease in the stability of a1(I) collagen mRNA in bone cell populations derived from fetal rat calvariae. Although a number of such mechanisms for negative-transcriptional or post-transcriptional gene regulation by GCs have been described, it is still unclear in many systems how positive and negative regulation interact to result in the observed effects (for review see Ref. 38). Furthermore, the observed differences may well be related to the fact that the effects of GCs are often dependent on the timing of GC treatment and the stage of differentiation of the osteoblast-like cells used. For example, when cultures obtained from chick embryo calvariae were continuously exposed to dexamethasone (Dex) from the onset of culture, Dex increased AP activity, but when Dex was added late in the culture period after bone had formed, AP activity decreased. In addition, Dietrich et al. have shown that in fetal rat calvariae, 30–100 nM