p47phox-Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging.
Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Progressive accumulation of reactive oxygen species (ROS) has been suspected to be the leading cause of many inflammatory and degenerative diseases, as well as an important factor underlying many effects of aging. In contrast, how reduced ROS signaling regulates inflammation and remodeling in bone remains unknown. Here, we utilized a p47(phox) knock-out mouse model, in which an essential cytosolic co-activator of Nox2 is lost, to characterize bone metabolism at 6 weeks and 2 years of age. Compared with their age-matched wild type controls, loss of Nox2 function in p47(phox-/-) mice resulted in age-related switch of bone mass and strength. Differences in bone mass were associated with increased bone formation in 6-week-old p47(phox-/-) mice but decreased in 2-year-old p47(phox-/-) mice. Despite decreases in ROS generation in bone marrow cells and p47(phox)-Nox2 signaling in osteoblastic cells, 2-year-old p47(phox-/-) mice showed increased senescence-associated secretory phenotype in bone compared with their wild type controls. These in vivo findings were mechanistically recapitulated in ex vivo cell culture of primary fetal calvarial cells from p47(phox-/-) mice. These cells showed accelerated cell senescence pathway accompanied by increased inflammation. These data indicate that the observed age-related switch of bone mass in p47(phox)-deficient mice occurs through an increased inflammatory milieu in bone and that p47(phox)-Nox2-dependent physiological ROS signaling suppresses inflammation in aging.
From the Arkansas Children's Nutrition Center and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202 chenjinran@uams.edu.
Jin-Ran
JR
Chen
From the Arkansas Children's Nutrition Center and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202.
Oxana P
OP
Lazarenko
From the Arkansas Children's Nutrition Center and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202.
Michael L
ML
Blackburn
From the Arkansas Children's Nutrition Center and.
Kelly E
KE
Mercer
From the Arkansas Children's Nutrition Center and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202.
Thomas M
TM
Badger
From the Arkansas Children's Nutrition Center and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202.
Martin J J
MJ
Ronis
D000375:Aging; D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000166:cytology / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017353:Gene Deletion; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D010006:Osteoblasts / Q000166:cytology / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D012886:Skull / Q000166:cytology
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
TNFα; aging; osteoblast; reactive oxygen species