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Published on: February 7, 2025
Nrf2 is required for normal postnatal bone acquisition in mice
Jung-Hyun Kim1, Vandana Singhal2, Shyam Biswal1
1Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.
Abstract:
A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body's front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 (Nrf2(-/-)) exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2(-/-) mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells (BMSCs) from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine (NAC), suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2(-/-) animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.
Insights
The transcription factor Nrf2 is crucial for bone development. Mice lacking Nrf2 show significantly reduced bone growth due to impaired osteoblast formation, suggesting Nrf2 as a therapeutic target for osteoporosis.
Area of Science:
- Skeletal Biology
- Cellular Metabolism
- Oxidative Stress
Background:
- Reactive species contribute to cellular dysfunction and impact bone metabolism.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant and cellular defense pathways.
- The specific role of Nrf2 in skeletal biology remains underexplored.
Purpose of the Study:
- To investigate the role of Nrf2 in postnatal bone metabolism in mice.
- To determine the impact of Nrf2 deficiency on bone acquisition and osteoblastogenesis.
Main Methods:
- Utilized Nrf2-deficient (Nrf2(-/-)) mice and control littermates.
- Assessed bone acquisition and osteoblast numbers at different ages.
- Evaluated the function of primary osteoblasts and bone marrow stromal cells (BMSCs) in vitro.
- Investigated the effect of N-acetyl cysteine (NAC) on BMSC colony-forming capacity.
Main Results:
- Nrf2(-/-) mice displayed a significant deficit in postnatal bone acquisition, most pronounced at 3 weeks.
- Osteoblast numbers were markedly reduced (12-fold) in Nrf2(-/-) mice compared to controls.
- While primary osteoblasts functioned normally in vitro, BMSCs from Nrf2(-/-) mice showed reduced colony-forming capacity.
- Treatment with NAC rescued the BMSC defect, indicating reactive species stress impairs osteoblastogenesis.
Conclusions:
- Nrf2 plays a critical role in regulating postnatal bone metabolism and osteoblastogenesis.
- Impaired Nrf2 function leads to reduced bone acquisition, potentially due to increased oxidative stress in BMSCs.
- Nrf2 represents a promising therapeutic target for conditions like osteoporosis.
