title: Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor.
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.
authors.affiliation: Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: H Herschel
authors.initials: HH
authors.lastname: Conaway
authors.forename: Amir
authors.initials: A
authors.lastname: Pirhayati
authors.forename: Emma
authors.initials: E
authors.lastname: Persson
authors.forename: Ulrika
authors.initials: U
authors.lastname: Pettersson
authors.forename: Olle
authors.initials: O
authors.lastname: Svensson
authors.forename: Catharina
authors.initials: C
authors.lastname: Lindholm
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000139:chemically induced*; D051379:Mice; D053244:Osteoprotegerin; D010521:Periosteum / Q000473:pathology*; D053245:RANK Ligand / Q000819:agonists* / Q000037:antagonists & inhibitors; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; C000607072:Rara protein, mouse; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014212:Tretinoin