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

Abstract

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.

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

“…Previous studies with Nrf2 knockout (KO) mice have shown sexual dimorphism in the skeletal phenotype of Nrf2 KO mice 1,9,23,24 . Female Nrf2 KO mice always show lower bone mass than the female WT mice 9,24 .…”

“…It is reported that reactive oxygen species (ROS) acts as intracellular signaling molecules to regulate osteoclast differentiation, and the Keap1/Nrf2 axis plays a role in osteoclast differentiation by regulating intracellular ROS signaling 8 . More studies revealed that deletion of Nrf2 reduces skeletal mechanical properties 1,9 , decreases load-driven bone formation 1 , impairs fracture healing in mice 10 , induces oxidative stress and promotes RANKL-induced osteoclast differentiation 11 . So Nrf2 is considered as playing an important role in the regulation of bone homeostasis in bone cells 12 .…”

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…Black bear parathyroid hormone activates cAMP, mitigates apoptosis in osteoblast cultures and increases trabecular bone volume (247); hence, the anabolic effects of bear parathyroid hormone might also prevent disuse osteoporosis. In addition, NRF2 was reported to have a role in bone microarchitecture in a mouse model of osteoporosis (248) and inhibits receptor activator of NF-B ligand (RANKL)-mediated osteoclastogenesis in osteolysis-induced mice (249). Given the fact that increased NRF2 expression plays a major part in the antioxidant defences that are required for hibernation success in ground squirrels (250), the potential role of NRF2 in maintaining skeletal mass in hibernating bears warrants investigation.…”

Oxidative damage and the pathogenesis of menopause related disturbances and diseases

“…vasomotor complains, CVD, osteoporosis, cognitive impairment and urogenital dystrophy, etc.) [8,[10][11][12][13][14][15][16][17] grouped together in the "menopausal syndrome".…”