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Nrf2 Deficiency Impairs Fracture Healing in Mice

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Abstract

Oxidative stress plays an important role in wound healing but data relating oxidative stress to fracture healing are scarce. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the major transcription factor that controls the cellular defence essential to combat oxidative stress by regulating the expression of antioxidative enzymes. This study examined the impact of Nrf2 on fracture healing using a standard closed femoral shaft fracture model in wild-type (WT) and Nrf2-knockout (Nrf2-KO)-mice. Healing was evaluated by histology, real-time RT-PCR, µCT and biomechanical measurements. We showed that Nrf2 expression is activated during fracture healing. Bone healing and remodelling were retarded in the Nrf2-KO compared to the WT-mice. Nrf2-KO-mice developed significantly less callus tissue compared to WT-mice. In addition, biomechanical testing demonstrated lower strength against shear stress in the Nrf2-KO-group compared to WT. The expression of vascular endothelial growth factor (VEGF) and osteocalcin is reduced during fracture healing in Nrf2-KO-mice. Taken together, our results demonstrate that Nrf2 deficiency in mice results in impaired fracture healing suggesting that Nrf2 plays an essential role in bone regeneration. Pharmacological activation of Nrf2 may have therapeutic potential for the enhancement of fracture healing.

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Acknowledgments

We thank S. Echterhagen, C. Jaeschke, M. Nicolau, A. Rüben and L. Shen for their excellent technical assistance. This work has been supported in part by the Christian-Albrecht-University of Kiel and by a Grant from the AO Germany to S.L. This research project was also in part supported by the Excellence Initiative of the German federal and state governments, the START-Program and by the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (T9-3; T9-5; T11-3). This work was in part supported by the DFG (PU 214/5-2, 4-2, 3-2).

Human and Animal Rights and Informed Consent

All experiments were in keeping with the local ethics committees guidelines and permission was obtained.

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Authors and Affiliations

  1. Department of Trauma Surgery, University Medical Center of Schleswig–Holstein, Campus Kiel, Kiel, Germany

    Sebastian Lippross, Nadine Streubesand, Ferda Ayub & Deike Varoga

  2. Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Rainer Beckmann, Mersedeh Tohidnezhad, Thomas Pufe & Christoph Jan Wruck

  3. Section Biomedical Imaging, Department of Diagnostic Radiology, University Hospital Schleswig–Holstein, Campus Kiel, Kiel, Germany

    Graeme Campbell

  4. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    Yuet Wai Kan

  5. Department of Dental Materials and Biomaterials Research, RWTH Aachen University Hospital, Aachen, Germany

    Fischer Horst

  6. Department of Cranio-Maxillofacial Surgery, RWTH Aachen University Hospital, Aachen, Germany

    Tolga Taha Sönmez

  7. Department of of Orthopaedic Trauma Surgery, RWTH Aachen University Hospital, Aachen, Germany

    Philipp Lichte

  8. Department of Orthopaedic Surgery, RWTH Aachen University Hospital, Aachen, Germany

    Holger Jahr

Authors
  1. Sebastian Lippross
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  2. Rainer Beckmann
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  3. Nadine Streubesand
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  6. Graeme Campbell
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  7. Yuet Wai Kan
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  8. Fischer Horst
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  9. Tolga Taha Sönmez
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  10. Deike Varoga
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  11. Philipp Lichte
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  12. Holger Jahr
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  13. Thomas Pufe
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  14. Christoph Jan Wruck
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Corresponding author

Correspondence to Sebastian Lippross.

Additional information

Sebastian Lippross, Rainer Beckmann, Thomas Pufe, and Christoph Jan Wruck, have contributed equally to this work.

All authors state that they have no conflicts of interest.

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Lippross, S., Beckmann, R., Streubesand, N. et al. Nrf2 Deficiency Impairs Fracture Healing in Mice. Calcif Tissue Int 95, 349–361 (2014). https://doi.org/10.1007/s00223-014-9900-5

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  • DOI: https://doi.org/10.1007/s00223-014-9900-5

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