title: Glucocorticoids Hijack Runx2 to Stimulate Wif1 for Suppression of Osteoblast Growth and Differentiation.
abstract: Inhibition of Runx2 is one of many mechanisms that suppress bone formation in glucocorticoid (GC)-induced osteoporosis (GIO). We profiled mRNA expression in ST2/Rx2(dox) cells after treatment with doxycycline (dox; to induce Runx2) and/or the synthetic GC dexamethasone (dex). As expected, dex typically antagonized Runx2-driven transcription. Select genes, however, were synergistic stimulated and this was confirmed by RT-qPCR. Among the genes synergistically stimulated by GCs and Runx2 was Wnt inhibitory Factor 1 (Wif1), and Wif1 protein was readily detectable in medium conditioned by cultures co-treated with dox and dex, but neither alone. Cooperation between Runx2 and GCs in stimulating Wif1 was also observed in primary preosteoblast cultures. GCs strongly inhibited dox-driven alkaline phosphatase (ALP) activity in control ST2/Rx2(dox) cells, but not in cells in which Wif1 was silenced. Unlike its anti-mitogenic activity in committed osteoblasts, induction of Runx2 transiently increased the percentage of cells in S-phase and accelerated proliferation in the ST2 mesenchymal pluripotent cell culture model. Furthermore, like the inhibition of Runx2-driven ALP activity, dex antagonized the transient mitogenic effect of Runx2 in ST2/Rx2(dox) cultures, and this inhibition eased upon Wif1 silencing. Plausibly, homeostatic feedback loops that rely on Runx2 activation to compensate for bone loss in GIO are thwarted, exacerbating disease progression through stimulation of Wif1. J. Cell. Physiol. 232: 145-153, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departments of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Eri
authors.initials: E
authors.lastname: Morimoto
authors.affiliation: Bioinformatics Service Program, Norris Medical Library, University of Southern California, Los Angeles, California.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Aysha B
authors.initials: AB
authors.lastname: Khalid
authors.affiliation: Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Krum
authors.affiliation: Department of Medicine, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Nyam-Osor
authors.initials: NO
authors.lastname: Chimge
authors.affiliation: Departments of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. frenkel@usc.edu.|Department of Orthopedic Surgery, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. frenkel@usc.edu.
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050659:Core Binding Factor Alpha 1 Subunit; D016326:Extracellular Matrix Proteins; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; C493716:Runx2 protein, mouse; D014157:Transcription Factors; C118544:Wif1 protein, mouse; D003907:Dexamethasone