Nrf2 is required for normal postnatal bone acquisition in mice

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.

Bone development: Regulating reactive oxygen species

A protein that regulates reactive oxygen species (ROS) levels, Nrf2, is critical for healthy bone growth. ROS are natural byproducts of cell metabolism and their levels are tightly controlled by regulators such as Nrf2. Elevated levels damage cells and are known to impair bone growth. However, whether Nrf2 plays a protective role in bone metabolism remained unknown. Douglas DiGirolamo and Rajesh Thimmulappa and coworkers at Johns Hopkins University, USA, examined bone tissue in mice lacking Nrf2. The mice showed up to 45% reduced bone mass and a 12-fold decrease in the number of bone-building cells known as osteoblasts. The osteoblasts were normal but their progenitors, bone marrow stromal cells (BMSCs), were impaired, indicating that elevated ROS levels prevented BMSCs from forming enough osteoblasts to build healthy bone. This research may help to develop therapies for osteoporosis.

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