Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells
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- 作者：A.C. Green<sup>asup><sup> ; sup><sup>bsup> ; P. Kocovski<sup>asup> ; T. Jovic<sup>asup> ; M.K. Walia<sup>asup> ; R.A.S. Chandraratna<sup>csup> ; T.J. Martin<sup>asup><sup> ; sup><sup>bsup> ; E.K. Baker<sup>asup><sup> ; sup><sup>bsup> ; L.E. Purton<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>lpurton@svi.edu.ausup>
- 关键词：Retinoic acid receptor ; Osteoblast ; Osteoblast differentiation ; Sfrp4 ; Wnt signalling ; Bone
- 刊名：Experimental Cell Research
- 出版年：2017
- 出版时间：1 January 2017
- 年：2017
- 卷：350
- 期：1
- 页码：284-297
- 全文大小：2348 K
- 卷排序：350
文摘
Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice.