title: Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin.
abstract: Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/-mice. The high bone mass exhibited by Sost-/-mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/-mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/-mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Sato
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Meloney
authors.initials: M
authors.lastname: Cregor
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Delgado-Calle
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Condon
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA. tbellido@iupui.edu.|Department of Internal Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA. tbellido@iupui.edu.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA. tbellido@iupui.edu.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D006023:Glycoproteins / Q000172:deficiency*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010024:Osteoporosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530105:Ccnd1 protein, mouse; D005938:Glucocorticoids; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; C486030:Sost protein, mouse; C506031:Tnfrsf11b protein, mouse; D019938:Cyclin D1
keywords: CORTICOSTEROIDS; GENETIC ANIMAL MODELS; MOLECULAR PATHWAYS - REMODELING; OSTEOPOROSIS; WNT/β-CATENIN/LRPS