p47 -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. Background: How reduced ROS signaling regulates inflammation and remodeling in bone remains unknown. Results: Age-related switch of bone mass in p47 phox -deficient mice occurs through an increased inflammatory milieu in bone. Conclusion: p47 phox -Nox2-dependent physiological ROS signaling suppresses inflammation in aging. Significance: p47 phox -Nox2 and Nox4 may play different roles during early development and skeletal involution because they serve unique functions on osteoblast differentiation and proliferation.