Role of Apoptosis in Glucocorticoid-Induced Osteoporosis and Osteonecrosis

Zalavras, Charalampos G.; Shah, Swapnil; Birnbaum, Mark J.; Frenkel, Baruch

doi:10.1615/critreveukaryotgeneexpr.v13.i24.140

Cited by 88 publications

(66 citation statements)

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“…Other studies have also reported that Dex treatment suppresses OB apoptosis in vitro [Zalavras et al, 2003]. A potential explanation for these discrepancies is that glucocorticoids promote OB apoptosis in vitro when cell culture conditions do not fully support differentiation (e.g., sub-confluent cultures), while they suppress in vitro PCD when OB differentiation is enhanced (e.g., confluent cultures) [Zalavras et al, 2003]. In the case of the HOB cell lines, in vitro differentiation of these cells is promoted when the cultures are incubated at non-permissive temperatures, and the temperature-sensitive T-antigen is inactivated [Bodine and Komm, 2002].…”

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Bodine¹,

Billiard²,

Moran³

et al. 2005

J of Cellular Biochemistry

156

113

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Mechanisms controlling human bone formation remain to be fully elucidated. We have used differential display-polymerase chain reaction analysis to characterize osteogenic pathways in conditionally immortalized human osteoblasts (HOBs) representing distinct stages of differentiation. We identified 82 differentially expressed messages and found that the Wnt antagonist secreted frizzled-related protein (sFRP)-1 was the most highly regulated of these. Transient transfection of HOBs with sFRP-1 suppressed canonical Wnt signaling by 70% confirming its antagonistic function in these cells. Basal sFRP-1 mRNA levels increased 24-fold during HOB differentiation from pre-osteoblasts to pre-osteocytes, and then declined in mature osteocytes. This expression pattern correlated with levels of cellular viability such that the preosteocytes, which had the highest levels of sFRP-1 mRNA, also had the highest rate of cell death. Basal sFRP-1 mRNA levels also increased 29-fold when primary human mesenchymal stem cells were differentiated to osteoblasts supporting the developmental regulation of the gene. Expression of sFRP-1 mRNA was induced 38-fold following prostaglandin E 2 (PGE 2 ) treatment of pre-osteoblasts and mature osteoblasts that had low basal message levels. In contrast, sFRP-1 expression was down-regulated by as much as 80% following transforming growth factor (TGF)-b1 treatment of preosteocytes that had high basal mRNA levels. Consistent with this, treatment of pre-osteoblasts and mature osteoblasts with PGE 2 increased apoptosis threefold, while treatment of pre-osteocytes with TGF-b1 decreased cell death by 50%. Likewise, over-expression of sFRP-1 in HOBs accelerated the rate of cell death threefold. These results establish sFRP-1 as an important negative regulator of human osteoblast and osteocyte survival.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Bodine¹,

Billiard²,

Moran³

et al. 2005

J of Cellular Biochemistry

156

113

View full text Add to dashboard Cite

show abstract

“…Interestingly, the glucocorticoidmediated inhibition of terminal differentiation in this osteoblast culture model is not accompanied by either inhibition of Runx2 (4,31) or stimulation of apoptosis (12,30). Using standard (short-term) transient transfection assays, we were initially unable to recapitulate the strong glucocorticoid-mediated repression seen with the endogenous OC gene in these cells (4,11).…”

mentioning

confidence: 88%

“…2 and 3). Impaired osteoblast function is multifaceted and includes inhibition of the action of growth factors, such as insulin-like growth factor 1 (IGF-1) and IGF binding proteins, hepatocyte growth factor (2,3), and bone morphogenetic protein 2 (4); inhibition of osteoblastic cell proliferation (5), in particular a cell cycle that persists during commitment to the osteoblast phenotype (6,7); a decrease in the messenger RNA (mRNA) and protein levels of bone phenotypic markers, including Runx2 (8) and type I collagen (4,(9)(10)(11); and acceleration of apoptosis (5,12).…”

mentioning

confidence: 99%

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer

Leclerc¹,

Noh²,

Khokhar³

et al. 2005

Arthritis & Rheumatism

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Objective. Glucocorticoids are widely used for the management of rheumatoid arthritis. Osteoporosis is a major side effect of glucocorticoid therapy and is attributable to inhibition of bone formation. We developed an osteoblast culture system in which glucocorticoids strongly inhibit development of the osteoblast phenotype, including expression of the bone-specific osteocalcin (OC) gene. Using this gene as a model, the goal of this study was to discover glucocorticoid-sensitive transcriptional mechanisms in osteoblasts.Methods. Dexamethasone (DEX; 1 M) was administered to murine MC3T3-E1 osteoblastic cultures under conditions that inhibit mineralized extracellular matrix formation and OC messenger RNA levels by >10-fold. Because standard (short-term) transient transfection assays with OC promoter-reporter constructs did not recapitulate the strong DEX-mediated repression, mapping of OC negative glucocorticoid response elements (GREs) was performed initially by stable transfection and then with long-term transient transfection assays. Transcription factor binding to the OC negative GRE was studied by electrophoretic mobility shift assays.Results. Several-fold repression of OC-luciferase constructs was recapitulated in stable and long-term transient transfection assays, in which the transfected cells were allowed to progress to a sufficiently advanced developmental stage. Analysis of a 5 promoter deletion series mapped an OC negative GRE to a 15-bp G/C-rich motif (؊161/؊147) located just upstream of the binding site for the osteoblast master transcription factor Runx2. Oligonucleotides encompassing this element and MC3T3-E1 cell extracts formed a protein-DNA complex that contained an Egr/Krox family member(s). Complex formation was competed by either an oligonucleotide containing 2 consensus Egr motifs or by anti-Egr2/Krox20 antibodies. Three copies of this Kroxbinding element conferred 20-fold transcriptional activation on the 147-bp basal OC promoter in osteoblasts, and the enhancer activity was inhibited by DEX. Enhancer activity was not observed in 10T1/2 fibroblasts unless these cells were cotransfected with Runx2.Conclusion. An Egr2/Krox20-binding site located immediately upstream of the Runx2 site of the mouse OC promoter was identified as an enhancer in osteoblasts, whose activity is repressed by glucocorticoids. Sequence similarity suggests that such a mechanism is likely operative in both murine and human cells. Because glucocorticoids inhibit Egr2/Krox20 expression in osteoblasts, and because trabecular bone formation is arrested in Egr2/Krox20-knockout mice, the inhibition of Egr2/Krox20 activity likely contributes to glucocorticoid-induced osteoporosis.Since the 1950 Nobel laureates E. Kendall, T. Reichstein, and P. Hench introduced glucocorticoids for the treatment of rheumatoid arthritis, these drugs have been widely used for the treatment of autoimmune and inflammatory diseases. The enthusiasm with which glucocorticoids were initially accepted was quickly dampened upon realization of their deleter...

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“…Autophagy may be responsible for these observed localised osteocyte perilacunar changes, occurring as a self-protection mechanism during GC treatment (Xia et al 2010). High-dose GC therapy in several animal and human models has also been shown to induce osteocyte apoptosis (Zalavras et al 2003).…”

Section: Effects Of Gc On Osteoclasts and Osteocytesmentioning

confidence: 99%

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

Wood

Souček

Wong

et al. 2018

Journal of Endocrinology

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Glucocorticoids (GCs) are effective for the treatment of many chronic conditions, but their use is associated with frequent and wide-ranging adverse effects including osteoporosis and growth retardation. The mechanisms that underlie the undesirable effects of GCs on skeletal development are unclear, and there is no proven effective treatment to combat them. An in vivo model that investigates the development and progression of GC-induced changes in bone is, therefore, important and a wellcharacterized pre-clinical model is vital for the evaluation of new interventions. Currently, there is no established animal model to investigate GC effects on skeletal development and there are pros and cons to consider with the different protocols used to induce osteoporosis and growth retardation. This review will summarize the literature and highlight the models and techniques employed in experimental studies to date.

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Role of Apoptosis in Glucocorticoid-Induced Osteoporosis and Osteonecrosis

Cited by 88 publications

References 0 publications

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

The Wnt antagonist secreted frizzled‐related protein‐1 controls osteoblast and osteocyte apoptosis

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

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