Article

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 06/2011; 286(36):31425-36. DOI: 10.1074/jbc.M111.247734
Source: PubMed

ABSTRACT Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated
effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids
(GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of 45Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast
differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by
ATRA, release of 45Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased
by ATRA. All retinoid acid receptors (RARα/β/γ) were expressed in calvarial bones. Agonists with affinity to all receptor
subtypes or specifically to RARα enhanced the release of 45Ca and mRNA expression of Rankl, whereas agonists with affinity to RARβ/γ or RARγ had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RARα antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory
effects of ATRA on 45Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased
Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GRdim mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RARα receptors,
a response that can be inhibited by monomeric GR.

Download full-text

Full-text

Available from: Emma Persson, Mar 27, 2015
0 Followers
 · 
141 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin A is known to influence post-natal bone content, with excess intake being associated with reduced bone mineral density and increased fracture risk. Despite this, the roles retinoids play in regulating osteoclastogenesis, particularly in vivo, remain unresolved. This study therefore aimed to determine the effect of loss of retinoic acid receptors (RAR)α or RARγ on bone mass (analyzed by histomorphometry and dual-energy X-ray absorptiometry) and osteoclastogenesis in mice in vivo. RARγ null mice had significantly less trabecular bone at 8 weeks of age compared to wildtype littermates. In contrast, no change in trabecular bone mass was detected in RARα null mice at this age. Further histomorphometric analysis revealed a significantly greater osteoclast surface in bones from 8-week-old RARγ null male mice. This in vivo effect was cell lineage autonomous, and was associated with increased osteoclastogenesis in vitro from hematopoietic cells obtained from 8-week-old RARγ null male mice. The use of highly selective agonists in RANKL-induced osteoclast differentiation of wild type mouse whole bone marrow cells and RAW264.7 cells in vitro showed a stronger inhibitory effect of RARγ than RARα agonists, suggesting that RARγ is a more potent inhibitor of osteoclastogenesis. Furthermore, NFAT activation was also more strongly inhibited by RARγ than RARα agonists. While RARα and RARγ antagonists did not significantly affect osteoclast numbers in vitro, larger osteoclasts were observed in cultures stimulated with the antagonists, suggesting increased osteoclast fusion. Further investigation into the effect of retinoids in vivo revealed that oral administration of 5mg/kg/day ATRA for 10 days protected against bone loss induced by granulocyte colony-stimulating factor (G-CSF) by inhibiting the pro-osteoclastogenic action of G-CSF. Collectively, our data indicates a physiological role for RARγ as a negative regulator of osteoclastogenesis in vivo and in vitro, and reveals distinct influences of RARα and RARγ in bone structure regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Journal of steroid biochemistry and molecular biology 03/2015; 150. DOI:10.1016/j.jsbmb.2015.03.005 · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: For a number of years, there has been a widespread view that the adverse side-effects of prolongued glucocorticoid (GC) treatment are a result of glucocorticoid receptor (GR)-mediated gene activation, whilst the beneficial anti-inflammatory effects result from GR-mediated 'transrepression'. Since the introduction of the dimerisation-deficient GR mutant, GR(dim), which apparently was unable to activate genes yet retained the ability to repress pro-inflammatory genes, the search for novel GR modulators has centred on the separation of gene activation from repression by prevention of GR dimerisation. However, recent work has questioned the conclusions drawn from these early GR(dim) studies, with evidence that GR(dim) mutants not only activate gene transcription, but that, in direct contradiction to the initial GR(dim) work, are also capable of forming dimers. This review of the current literature highlights the versatility of the GR in forming homodimer interactions, as well as the ability to bind to alternate nuclear receptors, and investigates the potential implications such varying GR dimer conformations may have for the design of GR ligands with a safer side effect profile.
    Steroids 11/2012; 78(1). DOI:10.1016/j.steroids.2012.09.013 · 2.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GR(dim/dim) mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents.
    Endocrinology 02/2013; 154(3). DOI:10.1210/en.2012-2045 · 4.64 Impact Factor