RARg is a negative regulator of osteoclastogenesis.
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)Î± or RARÎ³ on bone mass (analyzed by histomorphometry and dual-energy X-ray absorptiometry) and osteoclastogenesis in mice in vivo. RARÎ³ 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 RARÎ± null mice at this age. Further histomorphometric analysis revealed a significantly greater osteoclast surface in bones from 8-week-old RARÎ³ 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 RARÎ³ 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 RARÎ³ than RARÎ± agonists, suggesting that RARÎ³ is a more potent inhibitor of osteoclastogenesis. Furthermore, NFAT activation was also more strongly inhibited by RARÎ³ than RARÎ± agonists. While RARÎ± and RARÎ³ 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 RARÎ³ as a negative regulator of osteoclastogenesis in vivo and in vitro, and reveals distinct influences of RARÎ± and RARÎ³ in bone structure regulation.
|Authors||Green, A.C.; Poulton, I.J.; Vrahnas, C.; Hausler, K.D.; Walkley, C.R.; Wu, J.Y.; Martin, T.J.; Gillespie, M.T.; Chandraratna, R.A.S.; Quinn, J.M.W.; Sims, N.A.; Purton, L.E.|
|Publisher Name||JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25800721|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12644|