Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation

Area of Science:

• Bone Biology
• Skeletal Physiology
• Transcription Factor Regulation

Background:

• Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms.
• Nrf2 plays a role in various cell types, including bone cells like osteoblasts, osteocytes, and osteoclasts.
• Nrf2 deficiency is linked to pathologies in multiple organs.

Purpose of the Study:

• To investigate the function of Nrf2 in load-induced bone metabolism.
• To determine the impact of Nrf2 knockout on bone properties and response to mechanical loading.

Main Methods:

• Utilized Nrf2 knockout (KO) mice and age-matched wild-type controls.
• Assessed femoral bone mineral density, bone formation rate, and ultimate force.
• Performed ulna loading experiments to evaluate bone response to mechanical stress.
• Analyzed gene expression of antioxidant enzymes and Wnt5a in primary osteoblasts.

Main Results:

• Nrf2 KO mice exhibited significantly reduced femoral bone mineral density, bone formation rate, and ultimate force compared to controls.
• Mechanical loading of the ulna revealed diminished responsiveness in Nrf2 KO mice, with significant reductions in relative mineralizing surface and relative bone formation rate.
• Deletion of Nrf2 suppressed the load-induced expression of antioxidant enzymes and Wnt5a in osteoblasts.

Conclusions:

• Loss of Nrf2 function in bone impairs overall bone metabolism.
• Nrf2 is essential for the bone's response to mechanical loading and load-driven bone formation.