title: Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells.
abstract: 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.
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3065, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Green
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Kocovski
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Jovic
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia.
authors.forename: M K
authors.initials: MK
authors.lastname: Walia
authors.affiliation: IO Therapeutics, Inc., Santa Ana, CA 92705, USA.
authors.forename: R A S
authors.initials: RAS
authors.lastname: Chandraratna
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3065, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Martin
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3065, Australia.
authors.forename: E K
authors.initials: EK
authors.lastname: Baker
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria 3065, Australia; Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3065, Australia. Electronic address: lpurton@svi.edu.au.
authors.forename: L E
authors.initials: LE
authors.lastname: Purton
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins
keywords: Bone; Osteoblast; Osteoblast differentiation; Retinoic acid receptor; Sfrp4; Wnt signalling