title: Salubrinal improves mechanical properties of the femur in osteogenesis imperfecta mice.
abstract: Salubrinal is an agent that reduces the stress to the endoplasmic reticulum by inhibiting de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). We and others have previously shown that the elevated phosphorylation of eIF2α stimulates bone formation and attenuates bone resorption. In this study, we applied salubrinal to a mouse model of osteogenesis imperfecta (Oim), and examined whether it would improve Oim's mechanical property. We conducted in vitro experiments using RAW264.7 pre-osteoclasts and bone marrow derived cells (BMDCs), and performed in vivo administration of salubrinal to Oim (+/-) mice. The animal study included two control groups (wildtype and Oim placebo). The result revealed that salubrinal decreased expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and suppressed osteoclast maturation, and it stimulated mineralization of mesenchymal stem cells from BMDCs. Furthermore, daily injection of salubrinal at 2 mg/kg for 2 months made stiffness (N/mm) and elastic module (GPa) of the femur undistinguishable to those of the wildtype control. Collectively, this study supported salubrinal's beneficial role to Oim's femora. Unlike bisphosphonates, salubrinal stimulates bone formation. For juvenile OI patients who may favor strengthening bone without inactivating bone remodeling, salubrinal may present a novel therapeutic option.
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA; Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Takigawa
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Frondorf
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA; Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China.
authors.forename: Shengzhi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA; Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China.
authors.forename: Baiyan
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wallace
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA; Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan. Electronic address: hamak@dpc.agu.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000502:physiology; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology* / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000037:antagonists & inhibitors
chemical_list: D002934:Cinnamates; D004268:DNA-Binding Proteins; C103652:Elf2 protein, mouse; D014157:Transcription Factors; C496827:salubrinal; D013890:Thiourea
keywords: Bone marrow derived cells; Mechanical test; Osteoclasts; Osteogenesis imperfecta; Salubrinal