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- Conaway, H Herschel, et al.
(författare)
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Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor.
- 2011
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Ingår i: The Journal of biological chemistry. - 1083-351X .- 0021-9258. ; 286:36, s. 31425-36
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Tidskriftsartikel (refereegranskat)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 (45)Ca 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 (45)Ca 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 (45)Ca 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 (45)Ca 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 (GR(dim) 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.
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| 2. |
- Van Bogaert, Tom, et al.
(författare)
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Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice A STRONG SIGNAL TOWARD LETHAL SHOCK
- 2011
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 286:30, s. 26555-26567
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Tidskriftsartikel (refereegranskat)abstract
- As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNF alpha, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNF alpha-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNF alpha lethality was completely abolished when it was administered after TNF alpha stimulation, indicating compromised GR function upon TNF alpha challenge. TNF alpha-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNF alpha down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNF alpha also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNF alpha-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNF alpha inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNF alpha is intimately involved.
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