Nrf2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age.
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.
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Gretel Gisela
GG
Pellegrini
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Meloney
M
Cregor
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Kevin
K
McAndrews
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Cynthya Carolina
CC
Morales
Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
Linda Doyle
LD
McCabe
Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
George P
GP
McCabe
Department of Medicine, Division of Endocrinology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Munro
M
Peacock
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
David
D
Burr
Department of Nutrition Science, Purdue University, West Lafayette, Indiana, United States of America.
Connie
C
Weaver
Department of Anatomy and Cell Biology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.|Department of Medicine, Division of Endocrinology, School of Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.|Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, United States of America.
Teresita
T
Bellido
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015519:Bone Density / Q000235:genetics / Q000502:physiology; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D055114:X-Ray Microtomography
D000975:Antioxidants; D050976:Basic-Leucine Zipper Transcription Factors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495634:Nrf1 protein, mouse; C485120:Nrf3 protein, mouse; D051266:Nuclear Respiratory Factor 1; D012333:RNA, Messenger