NRF2 function in osteocytes is required for bone homeostasis and drives osteocytic gene expression

Area of Science:

• Bone Biology and Metabolism
• Cellular and Molecular Medicine
• Mitochondrial Biology

Background:

• Osteocytes, the most abundant bone cells, originate from osteoblasts.
• Previous research linked nutrient restriction to enhanced osteocyte gene expression and mitochondrial biogenesis.
• Mitochondrial biogenesis is associated with increased reactive oxygen species (ROS) production.

Purpose of the Study:

• To investigate the role of reactive oxygen species (ROS) and NRF2 activity in osteocytogenesis.
• To determine the impact of NRF2 on osteocyte-specific gene expression and bone homeostasis.
• To evaluate the therapeutic potential of NRF2 activation in preventing bone loss.

Main Methods:

• Assessed ROS levels and NRF2 activity during osteocytogenesis.
• Utilized cell cultures (IDG-SW3, primary osteocytes, osteoblasts) and murine models with osteocyte/osteoblast-specific Nfe2l2 deficiency.
• Administered dimethyl fumarate treatment in an ovariectomy mouse model.

Main Results:

• Increased mitochondrial biogenesis elevated ROS levels, subsequently enhancing NRF2 activity during osteocytogenesis.
• NRF2 activation promoted osteocyte-specific expression of key genes (Dmp1, Mepe, Sost).
• Osteocyte/osteoblast Nfe2l2 ablation led to osteopenia and increased osteoclast numbers, with significant sexual dimorphism.
• Dimethyl fumarate treatment mitigated ovariectomy-induced bone loss and restored osteocytic gene expression.

Conclusions:

• NRF2 activity is essential for regulating osteocyte gene expression and maintaining bone homeostasis.
• Targeting NRF2 pathways offers a potential therapeutic strategy for bone diseases, including postmenopausal osteoporosis.