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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #308502
Title: Nox2-dependent ROS signaling protects against skeletal ageing

Author
item CHEN, JINRAN - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Society for Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: 5/8/2014
Publication Date: 2/1/2015
Citation: Chen, J., Lazarenko, O.P., Mercer, K., Blackburn, M.L., Badger, T.M., Ronis, M.J. 2015. Nox2-dependent ROS signaling protects against skeletal ageing. Journal of Bone and Mineral Research. 29(S1):Presentation Number: SA0463. Available at http://www.asbmr.org/education/2014-abstracts.

Interpretive Summary:

Technical Abstract: Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Progressive accumulation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, has been suspected to be the leading cause of many inflammatory and degenerative diseases and underlie the effects of ageing. In contrast, how reduced ROS signaling regulates inflammation and remodeling in bone remains unknown. Here, we utilized a p47phox knockout mouse model, in which an essential cytosolic co-activator of Nox2 is lost, in order to characterize bone metabolism at 6 weeks and 24 months of age. Using peripheral quantitative CT (pQCT), microCT and femur three point bending, and histomorphometric analyses, we show that bone mass and strength were all significantly higher in 6-week-old p47phox -/- mice, but these were reversed in 24-month-old p47phox -/- mice compared to their age-matched wild type controls. Increased bone formation with decreased bone resorption in 6-week-old p47phox -/- mice, and decreased bone formation in 24-months-old p47phox -/- mice reflected bone mass at these ages. Flow cytometric and Amplex Red hydrogen peroxide/peroxidase assays showed decreases in ROS generation in bone marrow cells and Nox2 signaling in osteoblastic cells from p47phox -/- mice compared to those from control wild type mice. Knocking down the Nox4 gene in neonatal osteoblastic cells from p47phox -/- mice in ex vivo blunted increased osteoblast differentiation. Expression of proinflammatory cytokines such as TNFa, IL6, RANKL and MMP9 in bone were all significantly increased in 24-month-old p47phox -/- mice compared to their wild type controls, while we did not observe any differences in proinflammatory cytokine expression in 6-week-old p47phox -/- mice compared to wild type mice. These in vivo findings were mechanistically recapitulated in ex vivo cell culture of primary fetal calvarial cells, showed accelerated premature cell senescence accompanied by increased inflammation in cells from p47phox -/- mice. These data indicate that the observed age-related switch of bone mass in p47phox deficient mice occurs through an increased inflammatory milieu in bone and that Nox2-dependent physiological ROS signaling is redundant for osteoblast differentiation in early development, but it is required for suppression of inflammation in ageing bone.