Effects of Glucocorticoids on Fetal Rat Bone Collagen Synthesis in Vitro*

Dietrich, John W.; Canalis, Ernesto; Maina, Donna M.; Raisz, Lawrence G.

doi:10.1210/endo-104-3-715

Cited by 166 publications

(56 citation statements)

References 35 publications

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“…Glucocorticoid can stimulate, inhibit, or have a biphasic effect on collagen mRNA expression, depending on the osteoblast systems and culture conditions (Dietrich et al 1979, Kasugai et al 1991, Shalhoub et al 1992, Yao et al 1994. In rat BMSC, dexamethasone decreased the level of type I collagen mRNA during the first 6 or 7 days of treatment, followed by a rebound to near control on day 9 and, finally, an increase of four-to fivefold 14-28 days after treatment (Kasugai et al 1991, Leboy et al 1991, Yao et al 1994.…”

Section: Discussionmentioning

confidence: 99%

“…They appear to depend upon whether physiological or pharmacological concentrations of the hormone are used, on the time and duration of exposure to the drug, and on the particular system investigated (Bellows et al 1987). Experiments using organ cultures of fetal or neonatal bone have shown that exposure to glucocorticoids increases collagen synthesis and alkaline phosphatase activityparameters of osteoblast differentiation -after 24 h of culture, but decreases these parameters after 96 h (Dietrich et al 1979, Canalis 1983, Kream et al 1997. In addition, both stimulation and inhibition of cell proliferation by glucocorticoids have been reported in these organ cultures (Tenenbaum & Heersche 1985, McCulloch & Tenenbaum 1986, Kream et al 1997.…”

Section: Introductionmentioning

confidence: 99%

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Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss

Sl²,

Gs³

1999

Journal of Endocrinology

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It is well documented that glucocorticoid excess causes bone loss, but the mechanisms of these effects remain poorly defined. To understand further the mechanisms of glucocorticoid-induced osteoporosis, we investigated the effects of glucocorticoids on bone formation and bone resorption by examining the proliferation, functional activities, and cytokine secretion of cultured human bone marrow stromal cells (hBMSC). Treatment with dexamethasone for 24 h at the concentration of 10 8 M significantly suppressed [ 3 H]thymidine incorporation and further inhibition was observed with longer treatment (8 days) or higher concentration (10 7 M). Alkaline phosphatase activity of hBMSC was markedly stimulated with addition of dexamethasone (10 8 M), to 191 22% (after 4 days) and 317 46% (after 7 days) of control. Dexamethasone (10 8 M) treatment for 48 h decreased the incorporation of [ 3 H]proline into collagenasedigestible protein (CDP; 43·7 7·9% of control) and non-collagen protein (65·2 8·4% of control), with a greater effect on CDP. Northern blot analysis indicated that 1(I)-collagen mRNA level was decreased by dexamethasone to 27·6 9·0% of the control value after 1 day of exposure, and to 55·2 6·2% after 7 days. Dexamethasone markedly suppressed basal production of interleukin (IL)-6 and IL-11 and that stimulated by parathyroid hormone (PTH), IL-1 , or tumour necrosis factor-in a dose-dependent manner. These results suggest that the glucocorticoid-induced bone loss is derived at least in part via inhibition of bone formation, which includes the suppression of osteoblast proliferation and collagen synthesis. As both basal and PTH-stimulated production of IL-6 and IL-11 are decreased by dexamethasone, the increased bone resorption observed in glucocorticoidinduced osteopenia does not appear to be mediated by IL-6 or IL-11.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss

Sl²,

Gs³

1999

Journal of Endocrinology

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“…These results could also be explained if cortisol inhibited the proliferation of a separate, IGF I-unresponlsive population of cells, siniee these studies were performed in cutltures containinig it mixedl cell population. Althouigh in vivo stuidies have inidicaited that skeletal growtlh is inhibited by glticocorticoids (32), in vitro experimiienits have stuggested that glticocorticoids have two dlifferenit effects on bone formiiation, oine stimiiulatory-probably related to an effect on the (lifferenitiated osteol)last-and another inhibitory -related to the suppressioni of precursor cell proliferation (13). In ad-(litioni to the effect of cortisol enhanicinig the stimulailtory effect of IGF I on bone collageni synthesis, this steroid appears to have other important funietions in the regtulationi of skeletal growth, since it is necessary for the synthesis or release of IGF and its carrier protein by the liver (28).…”

Section: Discussionmentioning

confidence: 99%

Effect of insulinlike growth factor I on DNA and protein synthesis in cultured rat calvaria.

Canalis¹

1980

J. Clin. Invest.

382

151

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whereas 30 nM ICF I caused a two-to threefold increment and had a maximal effect. A smaller effect on the labeling of noncollagen protein (NCP) was also observed. The effect of CDP and NCP appeared and was maximal after 12 h and was suistained for 96 h. IGF I increased the total collagen content of bones. The IGF I stimulatory effect on the incorporation of [3H] HistologyTo study the effect of' IGF I on bone morplhology ancd cell mitosis, calvaria were cultured and n -desacetvl-n -methyl colchiiciuie (Colcemicl,4 ,uM 710Erntesto Canialis RESULTSDNA synthesis. The incorporation of [3H]thymidine into acid-insoluble residues, the DNA content, and the number of mitoses per histological section after colcemid in calvaria incubated in the absence of hormones were similar after 0 (or 3) to 24 h of culture (Table I). ILThere was a 50% decrease in the incorporation of [3H]-thymidine after 12 h of culture, which was concomitant with a decrease of similar magnitude on the uptake of the label into the acid-extractable pool (data not shown).After 24 h of culture in the presence of IFG I, there was an increase in the incorporation of [3H]thymidine into the acid-insoluble fraction of cultured calvaria of 24-164%. In contrast, IGF I did not increase significantly the uptake of the label into the acid-extractable pool (-5-15%). The dose-response curve demonstrated two effects, one observed at concentrations of 0.01-3 nM, which was small and not clearly dose related, and another, marked and dose related, observed at 10-100 nM (Fig. 1). Concentrations <0.01 nM were not effective, and the greatest effect occurred at 100 nM, which was the highest dose tested. The time-course of the IGF I effect on [3H]thymidine incorporation was studied by adding 10 nM IGF I at various times before the end of the culture period in an experiment where all bones (IGF I-treated and control) were cultured for 24 h. Treatment with IGF I for 1.5-3 h did not alter the incorporation of [3H]thymidine. Thereafter, the effect steadily increased, and it was maximal after 12 h (Fig. 2). The stimulatory effect of IGF I was sustained for 96 h. The incorporation of [3H]thymidine in calvaria cultured in control medium was 9.2+±0.9 dpm/,g (mean +SE; n = 6) and it was increased to 17.2+2.0 dpm/,ug (Table II). The incorporation of [3H]proline into NCP anid the bone collageni contenit were unchanged from 0 to 24 h of culttire. While IGF in-creased the labeling of CDP coompared with cointrol bones cultured for 24 h, this effect was snialler than the valuies observed in control bones cultured for 3-h periodis.After 24 h of ctulture, IGF I caused a dose-related stimulation of the incorporation of [3H]proline into

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“…However, inhibition of bone formation appears to be due to a direct effect of steroids on osteoblast function. Evidence supporting a direct effect of corticosteroids on bone synthesis includes decreased collagen synthesis (12)(13)(14), decreased alkaline phosphatase activity (14), decreased production of bone Gla-protein (BGP, or osteocalcin) (IS), and decreased incorporation of 3H-thymidine into DNA and of 3H-uridine into RNA (12,13) by bone cells in vitro, after treatment with glucocorticoids.…”

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confidence: 99%

Relationship of glucocorticoid dosage to serum bone gla‐protein concentration in patients with rheumatologic disorders

Kotowicz

Hall

Hunder

et al. 1990

Arthritis & Rheumatism

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Serum bone Gla-protein (BGP) measurements in 50 rheumatic disease patients receiving long-term prednisone therapy revealed an inverse relationship (r = -0.71, P < 0.001) between serum BGP levels and prednisone dosage. Multiple regression analysis demonstrated significant relationships (R' = 0.72, P < 0.001) between serum BGP'" and prednisone dosage, dosage', serum creatinine, age, and an age-creatinine interaction. This model predicts the suppression of serum BGP with low dosages of steroids and 50% suppression with dosages of 20-25 mg/day.Osteoporosis is a serious complication of glucocorticoid therapy. During treatment, bone loss occurs principally in regions of the skeleton that have a high content of cancellous bone, such as the ribs and vertebrae, and this may result in fractures at these sites (1). In a prospective study of glucocorticoidtreated asthmatic patients, the incidence of vertebral or rib fractures was 45% (2). Based on measurements made at the distal radius by single-photon absorptiometry, the prevalence of osteopenia among steroidtreated patients attending rheumatology clinics was 38% (3).Microradiography of rib (4) and histomorphometric analysis of iliac crest bone ( 5 ) from patients with excess levels of glucocorticoids have demonstrated both increased bone resorption and decreased bone formation. Increased bone resorption has been attributed to secondary hyperparathyroidism resulting from glucocorticoid inhibition of gastrointestinal calcium absorption (6-8) and increased urinary calcium loss (9). Other investigators (10,l I) have been unable to find an increase in serum immunoreactive parathyroid hormone (iPTH) and postulate that there may be increased bone sensitivity to iPTH. However, inhibition of bone formation appears to be due to a direct effect of steroids on osteoblast function. Evidence supporting a direct effect of corticosteroids on bone synthesis includes decreased collagen synthesis (12-14), decreased alkaline phosphatase activity (14), decreased production of bone Gla-protein (BGP, or osteocalcin) (IS), and decreased incorporation of 3H-thymidine into DNA and of 3H-uridine into RNA (12,13) by bone cells in vitro, after treatment with glucocorticoids.Bone formation can be assessed indirectly by measurement of serum BGP levels. BGP, the most abundant of the noncollagenous bone proteins, is synthesized by osteoblasts (16,17). Circulating BGP levels have been shown to reflect bone formation, but not resorption, as determined by histomorphometric techniques, in patients with postmenopausal osteoporosis (18), primary hyperparathyroidism, or hyper-

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Effects of Glucocorticoids on Fetal Rat Bone Collagen Synthesis in Vitro*

Cited by 166 publications

References 35 publications

Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss

Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss

Effect of insulinlike growth factor I on DNA and protein synthesis in cultured rat calvaria.

Relationship of glucocorticoid dosage to serum bone gla‐protein concentration in patients with rheumatologic disorders

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