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Salubrinal promotes healing of surgical wounds in rat femurs

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Phosphorylation of eukaryotic initiation factor 2α (eIF2α), transiently activated by various cellular stresses, is known to alleviate stress-induced cellular damage. Here, we addressed a question: does elevation of eIF2α phosphorylation by salubrinal (a pharmacological inhibitor of eIF2α dephosphorylation) enhance healing of bone wounds? We hypothesized that salubrinal would accelerate a closure of surgically generated bone holes by modifying expression of stress-sensitive genes. To examine this hypothesis, we employed a rat wound model. Surgical wounds were generated on anterior and posterior femoral cortexes, and salubrinal was locally administered on the anterior side. The results showed that, compared to a contralateral control, the size of surgical wounds was reduced by 10.8 % (day 10) and 18.0 % (day 20) on the anterior side (both p < 0.001), and 4.1 % (day 10; p < 0.05) and 11.1 % (day 20; p < 0.001) on the posterior side. In addition, salubrinal locally elevated cortical thickness and increased BMD and BMC. Pharmacokinetic analysis revealed that subcutaneous injection of salubrinal transiently increased its concentration in plasma followed by a rapid decrease within 24 h, and its half-life in plasma was 1.2 h. Salubrinal altered the phosphorylation level of eIF2α as well as the mRNA levels of ATF3, ATF4, and CHOP, and suppressed cell death induced by stress to the endoplasmic reticulum. In summary, the results herein demonstrate that subcutaneous administration of salubrinal accelerates healing of surgically generated bone holes through the modulation of eIF2α phosphorylation.

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Acknowledgments

This work was in part supported by DOD Congressionally Directed Medical Research Program PR100092 (HY), NIH R03AR55322 (PZ), and NIH R01AR52144 (HY).

Conflict of interest

The authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Indiana University–Purdue University Indianapolis, SL220, 723 West Michigan Street, Indianapolis, IN, 46202, USA

    Ping Zhang, Kazunori Hamamura, Chang Jiang, Liming Zhao & Hiroki Yokota

  2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Hiroki Yokota

  3. School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, People’s Republic of China

    Ping Zhang

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  1. Ping Zhang
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  2. Kazunori Hamamura
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  3. Chang Jiang
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  4. Liming Zhao
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  5. Hiroki Yokota
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Correspondence to Hiroki Yokota.

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Zhang, P., Hamamura, K., Jiang, C. et al. Salubrinal promotes healing of surgical wounds in rat femurs. J Bone Miner Metab 30, 568–579 (2012). https://doi.org/10.1007/s00774-012-0359-z

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  • DOI: https://doi.org/10.1007/s00774-012-0359-z

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