Salubrinal improves mechanical properties of the femur in osteogenesis imperfecta mice

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• 作者：Shinya Takigawa^a ; ^b ; Brian Frondorf^a ; Shengzhi Liu^a ; ^c ; Yang Liu^a ; ^c ; Baiyan Li^c ; Akihiro Sudo^b ; Joseph M. Wallace^a ; Hiroki Yokota^a ; Kazunori Hamamura^a ; ^d ; ^{hamak@dpc.agu.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Salubrinal ; Osteogenesis imperfecta ; Osteoclasts ; Bone marrow derived cells ; Mechanical test
• 刊名：Journal of Pharmacological Sciences
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：132
• 期：2
• 页码：154-161
• 全文大小：1192 K

文摘

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.