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The Departments of Research and Medicine Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105
Address all correspondence and requests for reprints to: Ernesto Canalis, M.D., Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299. E-mail: ecanalis{at}stfranciscare.org
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Introduction |
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Glucocorticoids decrease the replication of skeletal cells, and as such they deplete a cell population capable of synthesizing appropriate matrix proteins. In addition, they have direct effects on the skeletal matrix, down-regulating type I collagen gene expression by transcriptional and posttranscriptional mechanisms, and up-regulating collagenase 3 expression by posttranscriptional mechanisms (2). Collagenase 3, a matrix metalloproteinase expressed by osteoblasts and chondrocytes, is capable of degrading type I and type II collagens, which are major constituents of the bone and cartilage matrix. Consequently, glucocorticoids not only decrease the synthesis of important matrix proteins but also increase the levels of proteases capable of their degradation. This would result in a decrease in a skeletal matrix necessary for appropriate growth and mineralization.
Glucocorticoids not only decrease bone mass, but they also impair the longitudinal growth of children. Although much attention has been turned to the GH/insulin-like growth factor (IGF)-I axis, the cause of the impaired growth due to glucocorticoid excess has remained elusive. Glucocorticoids decrease IGF-I expression in liver cells, the main source of circulating IGF-I; however, the circulating levels of IGF-I are not decreased in patients receiving glucocorticoids in excess (5, 6). Similarly, there is no consistent decrease in GH levels; therefore, actions of glucocorticoids on the activity of GH or on the expression and activity of growth factors secreted by cartilage cells have been postulated. This concept is further supported by the fact that glucocorticoids have marked effects on the synthesis of IGF-I and IGF-binding proteins (IGFBP) in skeletal and nonskeletal cells (2). In osteoblast cultures, glucocorticoids decrease IGF-I messenger RNA and polypeptide levels by inhibiting IGF-I transcription, and decrease the expression of IGFBP-1, 3, 4, and 5 (7, 8). E-Box binding sites in the -70 to +22 region of the IGFBP-5 gene appear responsible for the inhibitory action of glucocorticoids on IGFBP-5 transcription. This effect is of particular interest because IGFBP-5 is a binding protein with the potential to enhance the effects of IGF-I on bone cell growth. Therefore, a decrease in IGFBP-5 could result in further impairment of IGF-I actions on the skeleton. Although glucocorticoids do not have a consistent inhibitory effect on IGF-II expression, they increase IGFBP-6 transcription, and as a result IGFBP-6 polypeptide levels in osteoblasts (2). Because IGFBP-6 binds IGF-II with higher efficacy than IGF-I and prevents IGF-II biological effects, its increase by glucocorticoids may be a way of reducing the levels of free IGF-II in the local bone microenvironment, and decreasing its effects on the skeleton.
In the current issue of the journal, Jux et al. (9) extend our knowledge of glucocorticoid actions on the skeleton and examine the actions of GH in chondrocytes and its interactions with locally produced IGF-I. The studies reported demonstrate that glucocorticoids decrease basal, GH-, and IGF-I-induced chondrocyte cell replication. The effects of GH on chondrocyte growth are mediated by IGF-I and are prevented by IGF-I neutralizing antibodies. This observation confirms the relevance of local factors on skeletal growth. The inhibitory actions of glucocorticoids on IGF-I secretion in chondrocytes are similar to those observed in osteoblasts, indicating that they cause a generalized decrease in skeletal IGF-I expression. This effect may be, at least in part, responsible for the inhibitory actions of glucocorticoids on skeletal growth and bone formation. This concept is strengthened by the fact that IGF-I is among the most abundant growth factors present in skeletal tissue, and its effects are opposite to those of glucocorticoids on bone formation (2, 7). IGF-I has modest mitogenic activity for skeletal cells, whereas glucocorticoids are inhibitory. IGF-I increases collagen synthesis and decreases collagenase 3 expression by skeletal cells, whereas glucocorticoids decrease collagen and increase collagenase synthesis in these cells. The opposing actions of glucocorticoids and IGF-I favor the concept that their effects on IGF-I expression play a central role in the inhibition of skeletal cell function.
The studies described by Jux et al. (9) also explain peripheral tissue insensitivity to GH because glucocorticoids prevented GH and IGF-I mitogenesis and induction of their respective receptors in chondrocytes. It is worth noting that the effects of glucocorticoids on GH and IGF-I receptors in skeletal and nonskeletal cells have been somewhat variable. Glucocorticoids increase GH receptor transcript and number in liver cells, cartilage growth plate, and osteoblasts (10, 11). Although the discrepancy may be due to differences in cells or culture conditions, as the authors point out, it is important to note that glucocorticoids did not decrease basal expression of GH receptors in chondrocytes, but prevented their induction by the hormone. Similar to the effects described by Jux et al. in chondrocytes, glucocorticoids decrease GH receptors in cultured fibroblasts, supporting the notion that this may be a mechanism for GH insensitivity in patients exposed to glucocorticoids (12). Additional effects of glucocorticoids on IGF-I receptors help explain the insensitivity to GH in tissues exposed to glucocorticoids. However, it is important to note that the steroids prevented the induction of IGF-I receptors by IGF-I, but as in the case of GH, they did not alter basal IGF-I receptor expression. Similarly, glucocorticoids do not modify IGF-I receptors in unstimulated osteoblasts, suggesting that their effects may depend on the local concentration of IGF-I. Glucocorticoids caused a decrease in IGF-II receptor transcription and levels in unstimulated osteoblasts (12). Because the IGF-II receptor acts primarily as an IGFBP, its decreased expression by glucocorticoids could explain additional effects of these steroids on skeletal growth.
A reduced number of GH and IGF-I receptors explains the opposing effect of glucocorticoids on the growth-promoting action of GH. However, children with impaired linear growth due to glucocorticoid excess may respond to GH therapy (13). This indicates that at pharmacological concentrations GH can override the glucocorticoid inhibitory effect. There may be cell selectivity in the actions of glucocorticoids even among skeletal cells, in view of their stimulatory effect on GH receptors in osteoblasts (11). This may suggest that insensitivity to GH may be more relevant to the actions of glucocorticoids on chondrocytes and may apply to changes in longitudinal growth and not in bone mass. It is also possible that changes in GH receptors in osteoblasts are not as relevant as they are in chondrocytes. GH has a modest stimulatory effect on IGF-I expression by the osteoblast, and it does not have consistent stimulatory effects on bone formation in vitro (14). In fact, PTH is a more potent stimulator of IGF-I expression in osteoblastic cells than GH, and IGF-I mediates anabolic effects of intermittent PTH on bone formation (14).
Regardless of the differences in some of the results obtained by Jux et al. with previously published work, it is clear that IGF-I plays a central role in the local regulation of cartilage and bone growth and that selected effects of glucocorticoids on the skeleton are mediated by a decrease in IGF-I expression. This adds relevance to the role of local factors as mediators of hormonal action, particularly in view of normal circulating levels of IGF-I in patients receiving glucocorticoids. The results described do not preclude direct actions of glucocorticoids on important genes expressed by skeletal cells, or on the expression of other growth factors and their receptors. For example, glucocorticoids activate transforming growth factor-ß (TGF-ß) in osteoblasts but oppose its effects on bone cells by shifting the binding of TGF-ß from signal-transducing to nonsignal-transducing receptors (15). Additional effects may occur at the level of synthesis or receptor binding of other growth factors secreted by skeletal cells; however, clinical studies suggest a fundamental role of the locally produced IGF-I in skeletal metabolism.
The finding of decreased GH and IGF-I receptors and IGF-I levels in chondrocytes exposed to glucocorticoids offers new perspectives on the mechanism of action of glucocorticoids on the skeleton and may prove useful in the development of new therapeutic alternatives for glucocorticoid-induced growth arrest and osteoporosis. Although children exposed to glucocorticoids have increased growth velocity following therapy with GH, other agents that induce IGF-I or that modify its receptor binding in chondrocytes might prove more effective.
Received May 6, 1998.
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1 on bone cells by
glucocorticoid. J Biol Chem 273:4892–4896This article has been cited by other articles:
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  S. C. Manolagas Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis Endocr. Rev., April 1, 2000; 21(2): 115 - 137. [Abstract] [Full Text]
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 G. K. Miller, M. G. Valerio, M. V. Pino, J. L. Larson, A. Viau, N. Hamelin, R. Labbe, and C. M. Banks Chronic Effects of the Novel Glucocorticosteroid RPR 106541 Administered to Beagle Dogs by Inhalation Toxicol Pathol, March 1, 2000; 28(2): 226 - 236. [Abstract] [PDF]
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