Nrf2 is required for normal postnatal bone acquisition in mice.
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.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.
Jung-Hyun
JH
Kim
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA.
Vandana
V
Singhal
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.
Shyam
S
Biswal
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.
Rajesh K
RK
Thimmulappa
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore, MD, USA.
Douglas J
DJ
DiGirolamo