RARγ is a negative regulator of osteoclastogenesis. Issue 150 (June 2015)

• Record Type: Journal Article
• Authors: Green, Alanna C.; Poulton, Ingrid J.; Vrahnas, Christina; Häusler, Karl D.; Walkley, Carl R.; Wu, Joy Y.; Martin, T. John; Gillespie, Matthew T.; Chandraratna, Roshantha A.S.; Quinn, Julian M.W.; Sims, Natalie. A.; Purton, Louise E.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 150(2015)
• Page Start: 46
• Page End: 53
• Publication Date: 2015-06
• Subjects: RAR retinoic acid receptor -- RXR retinoid X receptor -- ATRA all-trans retinoic acid -- BMM bone marrow macrophages -- G-CSF granulocyte colony stimulating factor -- RANKL receptor activator of nuclear factor kappa-B -- NFAT nuclear factor of activated T cells -- WBM whole bone marrow -- BMD bone mineral density -- DXA dual X-ray absorptiometry -- TNFα tumour necrosis factorα; Retinoic acid receptor -- Vitamin A -- Osteoclast -- Bone -- Osteoclastogenesis; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.03.005
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: We analysed the bone phenotype of RARγ knockout mice. RARγ null mice have less bone than wildtype mice. Activation of RARγ using a selective agonist inhibits osteoclastogenesis in vitro. ATRA administration protects against G-CSF-induced bone loss in mice. 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)α or RARγ on bone mass (analyzed by histomorphometry and dual-energy X-ray absorptiometry) and osteoclastogenesis in mice in vivo . RARγ 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 RARα null mice at this age. Further histomorphometric analysis revealed a significantly greater osteoclast surface in bones from 8-week-old RARγ 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 RARγ 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 RARγ than RARα agonists, suggesting that RARγ is a more potent inhibitor of osteoclastogenesis. Furthermore, NFAT activation was also more strongly inhibited by RARγ than RARα agonists. While RARα and RARγ 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 RARγ as a negative regulator of osteoclastogenesis in vivo and in vitro, and reveals distinct influences of RARα and RARγ in bone structure regulation.