Deletion of Nrf2 Reduces Skeletal Mechanical Properties and Decreases Load-Driven Bone Formation


Yong-Xi, Lei Li, Kylie A. Corry, Pei Zhang, Yang Yang, Evan Himes, Cristina Layla Mihuti, Cecilia Nelson, Guoli Dai, Jiliang Li


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 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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