title: Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice.
abstract: Endoplasmic reticulum (ER) stress is associated with increased reactive oxygen species (ROS), results from accumulation of misfolded/unfolded proteins, and can trigger apoptosis. ER stress is alleviated by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits protein translation allowing the ER to recover, thus promoting cell viability. We investigated whether osteoblastic cell apoptosis induced by glucocorticoids (GCs) is due to induction of ROS/ER stress and whether inhibition of eIF2α dephosphorylation promotes survival opposing the deleterious effects of GC in vitro and in vivo. Apoptosis of osteocytic MLO-Y4 and osteoblastic OB-6 cells induced by dexamethasone was abolished by ROS inhibitors. Like GC, the ER stress inducing agents brefeldin A and tunicamycin induced osteoblastic cell apoptosis. Salubrinal or guanabenz, specific inhibitors of eIF2α dephosphorylation, blocked apoptosis induced by either GC or ER stress inducers. Moreover, GC markedly decreased mineralization in OB-6 cells or primary osteoblasts; and salubrinal or guanabenz increased mineralization and prevented the inhibitory effect of GC. Furthermore, salubrinal (1 mg/kg/day) abolished osteoblast and osteocyte apoptosis in cancellous and cortical bone and partially prevented the loss of BMD at all sites and the decreased vertebral cancellous bone formation induced by treatment with prednisolone for 28 days (1.4 mg/kg/day). We conclude that part of the pro-apoptotic actions of GC on osteoblastic cells is mediated through ER stress, and that inhibition of eIF2α dephosphorylation protects from GC-induced apoptosis of osteoblasts and osteocytes in vitro and in vivo and from the deleterious effects of GC on the skeleton.
authors.affiliation: Department of Anatomy & 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 & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tu
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: McAndrews
authors.affiliation: Department of Anatomy & 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 & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA. Electronic address: tbellido@iupui.edu.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation
chemical_list: D005938:Glucocorticoids
keywords: Endoplasmic reticulum stress; Glucocorticoid-induced osteoporosis; Osteoblasts; Osteocytes