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: 4.57). 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.

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