title: Nrf2 deficiency impairs fracture healing in mice.
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.
authors.affiliation: Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany, Sebastian.lippross@uksh-kiel.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lippross
authors.forename: Rainer
authors.initials: R
authors.lastname: Beckmann
authors.forename: Nadine
authors.initials: N
authors.lastname: Streubesand
authors.forename: Ferda
authors.initials: F
authors.lastname: Ayub
authors.forename: Mersedeh
authors.initials: M
authors.lastname: Tohidnezhad
authors.forename: Graeme
authors.initials: G
authors.lastname: Campbell
authors.forename: Yuet Wai
authors.initials: YW
authors.lastname: Kan
authors.forename: Fischer
authors.initials: F
authors.lastname: Horst
authors.forename: Tolga Taha
authors.initials: TT
authors.lastname: Sönmez
authors.forename: Deike
authors.initials: D
authors.lastname: Varoga
authors.forename: Philipp
authors.initials: P
authors.lastname: Lichte
authors.forename: Holger
authors.initials: H
authors.lastname: Jahr
authors.forename: Thomas
authors.initials: T
authors.lastname: Pufe
authors.forename: Christoph Jan
authors.initials: CJ
authors.lastname: Wruck
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001861:Bone Regeneration; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology; D005269:Femur / Q000473:pathology; D017102:Fracture Healing; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics*; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D018384:Oxidative Stress; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D015675:Osteocalcin