Title: RAR gamma is a negative regulator of osteoclastogenesis
Authors: Green, AC
Poulton, IJ
Vrahnas, C
Hausler, KD
Walkley, CR
Wu, JY
Martin, TJ
Gillespie, MT
Chandraratna, RAS
Quinn, JMW
Sims, NA
Purton, LE
Issue Year: 2015
Series J. Steroid Biochem. Mol. Biol.:
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)alpha or RAR gamma on bone mass (analyzed by histomorphometry and dual-energy X-ray absorptiometry) and osteoclastogenesis in mice in vivo. RAR gamma 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 RAR alpha null mice at this age. Further histomorphometric analysis revealed a significantly greater osteoclast surface in bones from 8-week-old RAR gamma 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 RAR gamma 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 RAR gamma than RAR alpha agonists, suggesting that RAR gamma is a more potent inhibitor of osteoclastogenesis. Furthermore, NFAT activation was also more strongly inhibited by RAR gamma than RAR alpha agonists. While RAR alpha and RAR gamma 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 5 mg/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 RAR gamma as a negative regulator of osteoclastogenesis in vivo and in vitro, and reveals distinct influences of RAR alpha and RAR gamma in bone structure regulation. (C) 2015 Elsevier Ltd. All rights reserved.
URI: https://publications.svi.edu.au/publications/2289
Other Identifiers 10.1016/j.jsbmb.2015.03.005
Publication type Article
Grant ID GNT1019703;GNT0502612; GNT0502625