Biphasic Glucocorticoid-Dependent Regulation of Wnt Expression and Its Inhibitors in Mature Osteoblastic Cells

Mak, Wendy; Shao, Xinyu; Dunstan, Colin R.; Seibel, Markus J.; Zhou, Hong

doi:10.1007/s00223-009-9303-1

Cited by 81 publications

(73 citation statements)

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“…Corticosterone at 10 -7 mol·L -1 also increased expression of the Wnt inhibitors, sFRP-1 and DKK-1 by 2-to 3-fold. These dose dependent biphasic actions may explain the observations that glucocorticoids both enhance and impair osteoblast differentiation from mesenchymal progenitor cells, and indicate that this is at least in part through the regulation of Wnt expression in osteogenic cultures (39). This suggests that the contrasting anabolic and catabolic effects of glucocorticoids on bone are, at least in part, mediated through the regulation of Wnt expression and its inhibitors in mature osteoblasts.…”

Section: Role Of Glucocorticoids and Wnt Signaling In Mesenchymal Celmentioning

confidence: 94%

“…As such, a number of transgenic mouse lines have been generated using bone cell-specific transgenic expression of 11βHSD2 to disrupt intracellular glucocorticoid signaling. The range of osteoblast specific promoters (Figure 2) used to drive either 11βHSD2 gene expression or to delete the GR gene by Cre expression in the bone lineage ranges from those that target early multi-potential cells (Dermo1-Cre; GR fl/fl ) (31-32) to early committed osteoblastic progenitors (Runx2-Cre; GR fl/fl ) (33), pre-osteoblasts (Col3.6-11βHSD2) (34), mature osteoblasts (Col2.3-11βHSD2) (35)(36)(37)(38)(39)(40), and later stage mature osteoblast to osteocytes (OG2-11βHSD2) (11). Findings utilizing these models will be discussed throughout this review.…”

Section: Figurementioning

confidence: 99%

“…Among these cells, mature osteoblasts appear to be the dominant source of Wnt proteins, as they express a wide range of Wnt molecules at significantly higher level than early mesenchymal precursor cells (37)(38)(39)47), especially Wnt7b, Wnt10b and Wnt9a, all of which are important regulators of osteoblastogenesis (47)(48)(49)(50)(51)(52). Furthermore, the glucocorticoid-induced upregulation of Wnt signaling is observed only in differentiated osteoblasts with no observable effect of glucocorticoids on precursor cells (39).…”

Section: Role Of Glucocorticoids and Wnt Signaling In Mesenchymal Celmentioning

confidence: 99%

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Endogenous Glucocorticoids and Bone

2013

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While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells. Keywords: glucocorticoids; mechanisms of action; bone; osteoblasts; skeletal development; Wnt signaling Bone Research (2013) 2: 107-119. doi: 10.4248/BR201302001 IntroductionThe adverse effects of high dose therapeutic glucocorticoids on bone are well described and include osteoporosis and osteonecrosis. These effects are primarily mediated through toxic effects on osteoblasts (the bone forming cells) and osteocytes (long-lived cells related to osteoblasts which are resident within bone tissue). By contrast, it is also clear that glucocorticoids have an important and often essential role in the differentiation of osteoblasts cultured in vitro. These data suggest that endogenous glucocorticoids could have a positive, rather than a negative, effect on bone development and metabolism. Resent in vivo studies have advanced our knowledge of the effects of endogenous glucocorticoids on bone and bone cells. The data obtained from experiments utilizing genetically modified mouse models demonstrate that glucocorticoids direct cell lineage commitment of early mesenchymal progenitors through effects on osteoblasts. These actions, at least in part, are regulated through the Wnt/β-catenin signaling pathway in mature osteoblasts. This glucocorticoid regulated signaling pathway within mature osteoblasts is essential for normal intramembranous (i.e. calvarial) bone development. During bone modeling and remodeling, glucocorticoids also appear to play an important positive role in maintaining bone structure. However, with ageing, these beneficial effects of endogenous glucocorticoidsare less evident and may in fact be detrimental e.g. causing bone loss and reduced levels of proteins associated with bone formation such as osteocalcin. These detrimental actions appear to result from a combination of a subtle increase in circulating glucocorticoid levels with age and an increased local production of glucocorticoids within osteoblasts with age. This review will discuss the effects of endogenous glucoc...

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Section: Role Of Glucocorticoids and Wnt Signaling In Mesenchymal Celmentioning

confidence: 94%

Section: Figurementioning

confidence: 99%

Section: Role Of Glucocorticoids and Wnt Signaling In Mesenchymal Celmentioning

confidence: 99%

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Endogenous Glucocorticoids and Bone

2013

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“…The involved mechanisms include the regulation of the canonical Wnt-␤-catenin signaling pathway and its inhibitors (27). The canonical Wnt signaling pathway is important for the growth and differentiation of OBs (23) and for the inhibition of adipocyte differentiation (42).…”

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confidence: 99%

High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment

Brunetti

Faienza

Piacente

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Children with 21-hydroxylase deficiency (21-OHD) need chronic glucocorticoid (cGC) therapy to replace congenital deficit of cortisol synthesis, and this therapy is the most frequent and severe form of drug-induced osteoporosis. In this study, we enrolled 18 patients (9 females) and 18 sex-and agematched controls. We found in 21-OHD patients high serum and leukocyte levels of dickkopf-1 (DKK1), a secreted antagonist of the Wnt/␤-catenin signaling pathway known to be a key regulator of bone mass. In particular, we demonstrated by flow cytometry, confocal microscopy, and real-time PCR that monocytes, T lymphocytes, and neutrophils from patients expressed high levels of DKK1, which may be related to the cGC therapy. In fact, we showed that dexamethasone treatment markedly induced the expression of DKK1 in a dose-and time-dependent manner in leukocytes. The serum from patients containing elevated levels of DKK1 can directly inhibit in vitro osteoblast differentiation and receptor activator of NF-B ligand (RANKL) expression. We also found a correlation between both DKK1 and RANKL or COOH-terminal telopeptides of type I collagen (CTX) serum levels in 21-OHD patients on cGC treatment. Our data indicated that DKK1, produced by leukocytes, may contribute to the alteration of bone remodeling in 21-OHD patients on cGC treatment.dickkopf-1; 21-hydroxylase deficiency patients; glucocorticoid-induced osteoporosis; leukocytes; glucocorticoids CHILDREN WITH 21-HYDROXYLASE DEFICIENCY (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH) due to deletions or mutations of the P450 21-hydroxylase gene (CYP21), need chronic glucocorticoid (cGC) therapy as soon as the diagnosis has been made to replace congenital deficit in cortisol synthesis and to reduce androgen secretion by adrenal cortex (18). One of the most serious problems of cGC therapy is glucocorticoid-induced osteoporosis (GIO), although the patients are treated with glucocorticoids (GCs) at replacement doses. However, the risk of GC overreplacement or neuroendocrine modifications during treatment (i.e., abnormal growth hormone secretion and pulsatility) should be taken in consideration as potential factors determining bone loss even in subjects treated with apparent "physiological doses" of GCs (29, 54). GIO results in an early, transient increase in bone resorption accompanied by a decrease in bone formation, which is maintained for the duration of GC therapy (3). Therefore, 21-OHD patients are at risk of a great incidence of low bone mass, although studies on bone mineral density (BMD) have reported discordant results. In fact, an increased (46), decreased (2,8,12,15,16,20,36,44), or normal BMD (5, 13, 14, 30, 47), as well as contrasting results about the evaluation of serum biochemical markers of bone turnover, has been reported in these patients (12,13,36,44). In our previous work (10), we demonstrated a high osteoclastogenic potential of peripheral blood mononuclear cells in children with 21-OHD on cGC treatment, which seems to be supported by the pr...

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“…The significant SNPs at this locus fall within an intergenic region between WNT4 and ZBTB40. 12 Although preliminary data suggest that WNT4 is expressed in mouse osteoblasts, 13 little is known about this gene with regard to basic skeletal biology and nothing is known about ZBTB40 in bone. It is here that the mouse, or another appropriate model system, is needed.…”

Section: Reviewmentioning

confidence: 99%

The need for mouse models in osteoporosis genetics research

Ackert‐Bicknell¹,

Hibbs²

2012

BoneKEy Reports

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Osteoporosis, the progressive loss of bone mass resulting in fragility fractures, affects ~ 75 million people in the United States, Europe and Japan. Bone mineral density (BMD) correlates with fracture risk and is widely used in clinical settings to predict fracture. Numerous studies have demonstrated that peak bone mass is highly heritable and consequently a number of genome-wide association studies (GWASs) have been conducted to identify the genes that regulate BMD. Traditional intercross mapping in the mouse has met with limited successes in the field of skeletal biology. With the advent of human GWAS, questions have arisen about the continued need for mouse models in genetics research. However, significant advances have been made in the field of mouse genetics, including new genetics resource populations and loci mapping techniques, which enable gene-level mapping resolution. In this review, we discuss the need for mouse models to help understand the skeletal biology underlying novel human GWAS findings, how loci discovered in the mouse can be used to complement GWAS analysis and highlight the recent advances made in the field of skeletal biology from the use of these new and developing resources. We conclude this paper with a discussion of the need for systems-level approaches in the skeletal biology field, with an emphasis on the need for pathway and network analyses.

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Biphasic Glucocorticoid-Dependent Regulation of Wnt Expression and Its Inhibitors in Mature Osteoblastic Cells

Cited by 81 publications

References 32 publications

Endogenous Glucocorticoids and Bone

Endogenous Glucocorticoids and Bone

High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment

The need for mouse models in osteoporosis genetics research

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