Browsing by Subject "Salubrinal"

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    Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis
    (The British Editorial Society of Bone & Joint Surgery, 2015-05) Hamamura, K.; Nishimura, A.; Iino, T.; Takigawa, S.; Sudo, A.; Yokota, H.; Department of Engineering Technology, School of Engineering and Technology
    OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92.
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    Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells
    (Springer Nature, 2013-07-01) Yokota, Hiroki; Hamamura, Kazunori; Chen, Andy; Dodge, Todd R.; Tanjung, Nancy; Abedinpoor, Aysan; Zhang, Ping; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal. We addressed a question: are salubrinal's actions more potent to the cells isolated from the osteoporotic mice than those isolated from the control mice? Methods: Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and β-glycerophosphate. Results: The results revealed that salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate-resistant acid phosphatase. Conclusions: The results support the notion that salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples.
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    Enhancement of osteoblastogenesis and suppression of osteoclastogenesis by inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha
    (Smart Science and Technology, LLC, 2015) Hamamura, Kazunori; Chen, Andy; Yokota, Hiroki; Department of Anatomy and Cell Biology, IU School of Medicine
    The phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) is activated in response to various stresses such as viral infection, nutrient deprivation, and stress to the endoplasmic reticulum. Severe stress to the endoplasmic reticulum, for instance, induces an apoptotic pathway, while mild stress, on the contrary, leads to a pro-survival pathway. Little has been known about the elaborate role of eIF2α phosphorylation in the development of bone-forming osteoblasts and bone-resorbing osteoclasts. Using salubrinal and guanabenz as inhibitors of the de-phosphorylation of eIF2α, we have recently reported that the phosphorylation of eIF2α significantly alters fates of both osteoblasts and osteoclasts. Based on our recent findings, we review in this research highlight the potential mechanisms of the enhancement of osteoblastogenesis and the suppression of osteoclastogenesis through the elevated level of phosphorylated eIF2α.