Calcified Tissue International

, Volume 105, Issue 4, pp 341–352 | Cite as

Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress

  • Yusuke KuboEmail author
  • Christoph Jan Wruck
  • Athanassios Fragoulis
  • Wolf Drescher
  • Hans Christoph Pape
  • Philipp Lichte
  • Horst Fischer
  • Mersedeh Tohidnezhad
  • Frank Hildebrand
  • Thomas Pufe
  • Holger Jahr


Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.


Fracture healing Reactive oxygen species Oxidative stress Nuclear factor erythroid 2-related factor 2 


Author Contributions

YK and HJ designed the study and prepared the first draft of the paper. They are guarantors. CW and TP did the literature search and recommended the papers to be evaluated. All authors contributed in reading and writing sections of the review and all authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Conflict of interest

Yusuke Kubo, Christoph Jan Wruck, Athanassios Fragoulis, Wolf Drescher, Hans Christoph Pape, Philipp Lichte, Horst Fischer, Mersedeh Tohidnezhad, Frank Hildebrand, Thomas Pufe, and Holger Jahr declare that they have no competing interest.


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Authors and Affiliations

  • Yusuke Kubo
    • 1
    Email author
  • Christoph Jan Wruck
    • 1
  • Athanassios Fragoulis
    • 1
  • Wolf Drescher
    • 2
    • 3
  • Hans Christoph Pape
    • 4
  • Philipp Lichte
    • 5
  • Horst Fischer
    • 6
  • Mersedeh Tohidnezhad
    • 1
  • Frank Hildebrand
    • 5
  • Thomas Pufe
    • 1
  • Holger Jahr
    • 1
    • 7
  1. 1.Department of Anatomy and Cell BiologyRWTH Aachen UniversityAachenGermany
  2. 2.Department of OrthopaedicsRWTH Aachen UniversityAachenGermany
  3. 3.Department of Orthopaedic Surgery of the Lower Limb and ArthroplastyHospital RummelsbergSchwarzenbruckGermany
  4. 4.Department of Trauma SurgeryUniversity Hospital ZurichZurichSwitzerland
  5. 5.Department of Orthopaedic Trauma SurgeryRWTH Aachen UniversityAachenGermany
  6. 6.Department of Dental Materials and Biomaterials ResearchRWTH Aachen University HospitalAachenGermany
  7. 7.Department of Orthopaedic SurgeryMaastricht University Medical Center+6229 HX MaastrichtThe Netherlands

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