Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation |
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| Affiliation: | 1. Department of Rehabilitation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, PR China;2. Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;3. Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang Province 163316, PR China;1. Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic;2. Clinic for Sports Medicine, Lucerne Cantonal Hospital, Lucerne, Switzerland;3. Exercise Physiology Lab, Institute of Human Movement Sciences, ETH Zurich, Zurich, Switzerland;4. Department of Statistics, Faculty of Mathematics and Physics, Charles University in Prague, Prague, Czech Republic;1. Internal Medicine, Hospital of Piombino, Livorno, Italy;2. FADOI Foundation, Research Department, Milan, Italy;3. Department of Locomotor System, Division of Rheumatology, ASL3-Azienda Sanitaria Genovese, Genoa, Italy;4. Section of Osteoporosis and Musculoskeletal Diseases, Department of Radiological, Oncological and Anatomical–Pathological Sciences, University “La Sapienza”, Rome, Italy;5. Rheumatology, “G. Pini” Institute, Milan, Italy;6. Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy;7. Internal Medicine, Hospital of Ceva, Cuneo, Italy;8. Internal Medicine, Hospital Pugliese-Ciaccio, Catanzaro, Italy;9. Internal Medicine, Azienda Ospedaliero-Universitaria “S. Anna”, Ferrara, Italy;10. QBGroup SpA, Padova, Italy;11. Department of Internal Medicine I, Arcispedale S. Maria Nuova, Reggio Emilia, Italy;12. Medical Department, “Civile” Hospital, Legnano, Italy;13. Department of Internal Medicine, Hospital “Maggiore della Carità”, Novara, Italy;1. Department of Medicine, University of California, San Francisco, CA, USA;2. Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA;3. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA;4. Department of Surgery, University of California, San Francisco, CA, USA;5. Medical Service, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA;6. Surgical Service, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA |
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| 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. |
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