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

Area of Science:

• Bone biology and skeletal health
• Cellular signaling pathways
• Molecular mechanisms of bone remodeling

Background:

• Keap1 (Kelch-like ECH-associated protein 1) normally inhibits the transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2).
• The Keap1/Nrf2 pathway regulates cytoprotective genes and is present in osteoblasts and osteoclasts.
• Previous studies indicate Nrf2 deletion impairs bone formation, while hyperactivation causes osteopenia.

Purpose of the Study:

• To investigate the impact of moderate Nrf2 activation, achieved by disrupting Keap1, on bone metabolism.
• To determine if partial Keap1 deficiency influences bone phenotype and remodeling processes.

Main Methods:

• Examined the bone phenotype of Keap1 heterozygotic (Ht) mice compared to Keap1 wild-type (WT) littermates.
• Assessed gene expression of Nrf2, ALP, and wnt5a in cultured primary osteoblasts.
• Quantified bone formation rate, ultimate force, osteoclast numbers and surface, and serum bone resorption markers in male mice.

Main Results:

• Keap1 deletion/knockdown in osteoblasts increased Nrf2, ALP, and wnt5a gene expression.
• Keap1 Ht male mice exhibited a significant increase in bone formation rate (+30.7%) compared to WT controls.
• Osteoclast cell numbers (-32.45%) and surface (-32.58%) were significantly reduced in Keap1 Ht male mice, along with decreased serum bone resorption markers.

Conclusions:

• Moderate Nrf2 activation through Keap1 disruption enhances bone mass in male mice.
• This improvement in bone mass is attributed to regulated bone remodeling, with reduced osteoclast activity.
• The findings suggest a therapeutic potential for modulating the Keap1/Nrf2 pathway in bone metabolic disorders.