TY - JOUR T1 - NOX4 deletion in male mice exacerbates the effect of ethanol on trabecular bone and osteoblastogenesis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.247262 SP - jpet.117.247262 AU - James Watt AU - Alexander W. Alund AU - Casey F. Pulliam AU - Kelly E. Mercer AU - Larry J. Suva AU - Jin-Ran Chen AU - Martin J.J. Ronis Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/04/13/jpet.117.247262.abstract N2 - Chronic alcohol consumption increases bone resorption and decreases bone formation. A major component of ethanol (EtOH) pathology in bone is the generation of excess reactive oxygen species (ROS). The ROS-generating NADPH oxidase 4 (NOX4) is proposed to drive much of the EtOH-induced suppression of bone formation. Here, 13-week old male WT and NOX4 -/- mice were pair-fed (PF) a high fat (35%) Lieber-DeCarli liquid diet with or without EtOH at 30% of their total calories for 12 weeks. Micro-CT analysis of trabecular and cortical bone demonstrated significant decreases in bone volume/total volume (BV/TV%) and cortical thickness in WT, EtOH-fed mice compared to pair-fed (PF) controls. EtOH-fed NOX4 -/- mice also displayed decreased trabecular bone volume/total volume and trabecular number compared to PF (p<0.05). However, NOX4 -/- mice were protected against EtOH-induced decreases in cortical thickness (p<0.05) and decreases in collagen1 and osteocalcin mRNA expression in cortical bone (p<0.05). In WT and NOX4 -/- trabecular bone, ethanol suppressed expression of Wnt signaling components that promote osteoblast maturation. A role for NOX4 in EtOH inhibition of osteoblast differentiation was further demonstrated by protection against EtOH inhibition of osteoblastogenesis in ex-vivo bone marrow cultures from NOX4 -/-, but not NOX2 -/- mice. However, bone marrow cultures from NOX4 -/-mice formed fewer osteoblastic colonies compared to WT cultures (p<0.05), suggesting a role for NOX4 in the maintenance of mesenchymal progenitor cell populations. These data suggest that NOX4 deletion is partially protective against EtOH effects on osteoblast differentiation, but may predispose bone to osteogenic impairments. ER -