title: Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation.
abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. The aim of this study was to investigate the role of Nrf2 in load-driven bone metabolism using Nrf2 knockout (KO) mice. Compared to age-matched littermate wild-type controls, Nrf2 KO mice have significantly lowered femoral bone mineral density (-7%, p<0.05), bone formation rate (-40%, p<0.05), as well as ultimate force (-11%, p<0.01). The ulna loading experiment showed that Nrf2 KO mice were less responsive than littermate controls, as indicated by reduction in relative mineralizing surface (rMS/BS, -69%, p<0.01) and relative bone formation rate (rBFR/BS, -84%, p<0.01). Furthermore, deletion of Nrf2 suppressed the load-driven gene expression of antioxidant enzymes and Wnt5a in cultured primary osteoblasts. Taken together, the results suggest that the loss-of-function mutation of Nrf2 in bone impairs bone metabolism and diminishes load-driven bone formation.
authors.affiliation: Department of Rehabilitation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, PR China; Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. Electronic address: sunyxjp@hotmail.com.
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Sun
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang Province 163316, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Corry
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, PR China; Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Himes
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Cristina Layla
authors.initials: CL
authors.lastname: Mihuti
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. Electronic address: jilili@iupui.edu.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001696:Biomechanical Phenomena; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005269:Femur / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005456:Fluorescent Dyes / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D016474:Weight-Bearing; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D000975:Antioxidants; D005456:Fluorescent Dyes; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Biomechanics; Bone formation; Mechanotransduction; Nrf2; Osteoblast; Wnt5a