Effects of Nrf2 Deficiency on Bone Microarchitecture in an Experimental Model of Osteoporosis

OBJECTIVE Redox imbalance contributes to bone fragility. We have evaluated the in vivo role of nuclear factor erythroid derived 2-related factor-2 (Nrf2), an important regulator of cellular responses to oxidative stress, in bone metabolism using a model of postmenopausal osteoporosis. METHODS Ovariectomy was performed in both wild-type and mice deficient in Nrf2 (Nrf2(-/-)). Bone microarchitecture was analyzed by μCT. Serum markers of bone metabolism were also measured. Reactive oxygen species production was determined using dihydrorhodamine 123. RESULTS Sham-operated or ovariectomized Nrf2(-/-) mice exhibit a loss in trabecular bone mineral density in femur, accompanied by a reduction in cortical area in vertebrae. Nrf2 deficiency tended to increase osteoblastic markers and significantly enhanced osteoclastic markers in sham-operated animals indicating an increased bone turnover with a main effect on bone resorption. We have also shown an increased production of oxidative stress in bone marrow-derived cells from sham-operated or ovariectomized Nrf2(-/-) mice and a higher responsiveness of bone marrow-derived cells to osteoclastogenic stimuli in vitro. CONCLUSION We have demonstrated in vivo a key role of Nrf2 in the maintenance of bone microarchitecture.