Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice |
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| Affiliation: | 1. Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA;2. Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA;3. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA;1. Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA;2. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA;3. Department of Biomedical Engineering, University of Rochester Medical Center, Rochester, NY 14642, USA;4. Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA;1. Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA;2. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;3. Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;1. Department of Pediatrics, The Children''s Hospital of Philadelphia, Philadelphia, PA, USA;2. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, USA;3. Department of Physical Therapy, D''Youville College, Buffalo, NY, USA;4. The Lewin Group, Falls Church, VA, USA;1. Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Informatics IT, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065, USA;3. Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Imaging-West Point, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA;5. Biometrics Research, Merck Research Laboratories, RY34-300, 126 Lincoln Avenue, Rahway, NJ 07065, USA;6. Compound Management and Engineering, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065, USA |
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| 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. |
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