Location: Arkansas Children's Nutrition CenterTitle: Age-related switch of bone mass in p47phox deficient mice through increased inflammatory milieu in bone Author
Submitted to: Journal of Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: 7/15/2013
Publication Date: 11/15/2013
Citation: Chen, J., Lazarendo, O.P., Zhang, J., Mercer, K., Blackburn, M.L., Badger, T.M., Ronis, M.J. 2013. Age-related switch of bone mass in p47phox deficient mice through increased inflammatory milieu in bone [abstract]. Journal of Bone and Mineral Research. 28(Suppl 1). SU0002. Available at http://www.asbmr.org/education/AbstractDetail?aid=cc76e234-103b-4e92-a7b0-2b2cabcfa700. Interpretive Summary:
Technical Abstract: Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Excessive accumulation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, has been suggested to be the leading cause of many inflammatory and degenerative diseases and underlies the effects of aging. In contrast, how physiological levels of ROS regulate bone remodeling at each life stage remains unknown. In addition to the mitochondrial electron transport chain, the NADPH oxidase (NOX) complex produces a large amount of ROS in the plasma membrane and cytosol. Here, we utilized a p47phox knockout mouse model in which NOX2 activity is lost as the result of loss of an essential cytosolic co-activator to characterize the bone phenotype at both 6 weeks and 24 months of age in male mice. Using peripheral quantitative CT (pQCT), uCT and femur three point bending analyses, in p47phox -/- mice at 6 weeks of age, we found that bone mass (including both trabecular and cortical bone mineral density and bone mineral content), bone volume, trabecular number, and bone strength were all significantly higher compared to wild type mice (p< 0.05). On the other hand, in p47phox -/- mice at 24 months of age, bone mass, bone volume, and trabecular number were all significantly lower (p<0.05), while bone trabecular separation was higher compared to their age-matched wild type controls. Flow cytometric assay showed decreased ROS generation in bone marrow cells from both young and aged p47phox -/- mice compared with their respective controls. Serum bone formation marker alkaline phosphatase was higher in 6-week-old p47phox -/- mice compared to their wild type controls. Serum bone resorption marker TRAP 5b is higher in 24-month-old p47phox -/- mice compared to their wild type controls. While we did not observe any differences in proinflammatory cytokines such as IL6, TNFalpha, RANKL, and MMP9 expression in 6-week-old p47phox -/- mice compared to wild type mice, these cytokines were all significantly higher in 24-month-old p47phox -/- mice compared to their wild type controls. 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 suppresses inflammation in aging.