NRF2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age

Gretel Gisela Pellegrini, Meloney Cregor, Kevin Mcandrews, Cynthya Carolina Morales, Linda Doyle Mccabe, George P. Mccabe, Munro Peacock, David Burr, Connie Weaver, Teresita Bellido

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Accumulation of reactive oxygen species (ROS) is an important pathogenic mechanism underling the loss of bone mass and strength with aging and other conditions leading to osteoporosis. The transcription factor erythroid 2-related factor2 (Nrf2) plays a central role in activating the cellular response to ROS. Here, we examined the endogenous response of bone regulated by Nrf2, and its relationship with bone mass and architecture in the male and female murine skeleton. Young (3 month-old) and old (15 month-old) Nrf2 knockout (KO) mice of either sex exhibited the expected reduction in Nrf2 mRNA expression compared to wild type (WT) littermates. Nrf2 deletion did not lead to compensatory increase in Nrf1 or Nrf3, other members of this transcription factor family; and instead, Nrf1 expression was lower in KO mice. Compared to the respective WT littermate controls, female KO mice, young and old, exhibited lower expression of both detoxifying and antioxidant enzymes; young male KO mice, displayed lower expression of detoxifying enzymes but not antioxidant enzymes; and old male KO mice showed no differences in either detoxifying or antioxidant enzymes. Moreover, old male WT mice exhibited lower Nrf2 levels, and consequently lower expression of both detoxifying and antioxidant enzymes, compared to old female WT mice. These endogenous antioxidant responses lead to delayed rate of bone acquisition in female KO mice and higher bone acquisition in male KO mice as quantified by DXA and μCT, demonstrating that Nrf2 is required for full bone accrual in the female skeleton but unnecessary and even detrimental in the male skeleton. Therefore, Nrf2 regulates the antioxidant endogenous response and bone accrual differently depending on sex and age. These findings suggest that therapeutic interventions that target Nrf2 could be developed to enhance the endogenous antioxidant response in a sex-And age-selective manner.

Original languageEnglish (US)
Article numbere0171161
JournalPLoS One
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Knockout Mice
Bone
Antioxidants
bones
antioxidants
Bone and Bones
gender
mice
Skeleton
Enzymes
skeleton
enzymes
Reactive Oxygen Species
Transcription Factors
reactive oxygen species
transcription factors
Osteoporosis
osteoporosis
Aging of materials
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

NRF2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age. / Pellegrini, Gretel Gisela; Cregor, Meloney; Mcandrews, Kevin; Morales, Cynthya Carolina; Mccabe, Linda Doyle; Mccabe, George P.; Peacock, Munro; Burr, David; Weaver, Connie; Bellido, Teresita.

In: PLoS One, Vol. 12, No. 2, e0171161, 01.02.2017.

Research output: Contribution to journalArticle

Pellegrini, GG, Cregor, M, Mcandrews, K, Morales, CC, Mccabe, LD, Mccabe, GP, Peacock, M, Burr, D, Weaver, C & Bellido, T 2017, 'NRF2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age', PLoS One, vol. 12, no. 2, e0171161. https://doi.org/10.1371/journal.pone.0171161
Pellegrini, Gretel Gisela ; Cregor, Meloney ; Mcandrews, Kevin ; Morales, Cynthya Carolina ; Mccabe, Linda Doyle ; Mccabe, George P. ; Peacock, Munro ; Burr, David ; Weaver, Connie ; Bellido, Teresita. / NRF2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age. In: PLoS One. 2017 ; Vol. 12, No. 2.
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