Role of NOX4 Expression in Osteoblast-Precursors in the Development of Alcohol- Induced Osteopenia

Location

Medical Education Building, LSUHSC-NO

Presentation Date

10-10-2019 10:00 AM

End Date

10-10-2019 12:00 PM

Description

Alcohol abuse is a well-known risk factor for skeletal toxicity and the development of osteoporosis. Ethanol (EtOH) has been demonstrated to inhibit bone formation and stimulate bone resorption. However, the molecular mechanisms underlying alcohol-induced osteopenia remain the subject of active investigation. Dr. Ronis’ research with whole-body knockout of NOX4 in mice has demonstrated that reactive oxygen species (ROS) signaling via the NADPH oxidase enzyme NOX4 plays a role in regulation of endogenous bone turnover and EtOH actions. To establish whether NOX4 expressed locally in osteoblast precursors mediate these effects, we have generated pre-osteoblast-specific Prx-Cre-Lox NOX4 conditional knockout mice where the enzyme is oblated specifically in osteoblast precursor cells in long bones and exposed both models to a high fat Leiber-DiCarli liquid with or without replacement of up to 28% of food calories with EtOH for 90 days. The hypothesis is that ROS produced in these cells by NOX4 play a significant role in the development of alcohol-induced osteopenia. To test this, the effects of EtOH were determined on bone microstructure of tibias and by femur shaft mRNA expression. In the cortical region of the tibia, the Prx-NOX4 Cre-Lox mice had overall decreased bone area (p = 0.038). In mice with the EtOH diet, there was a decrease in bone area and cortical thickness (p < 0.001 & p=0.001, respectively) independent of genotype. Results from femur shaft mRNA confirms that mRNA NOX4 expression is decreased by more than 95% in Prx-NOX4 Cre-Lox mice (p < 0.001) while RANKL, which controls bone reabsorption, is not affected by EtOH or NOX4 in this model. The data demonstrates that while the bone microstructure differs between males and females, EtOH and NOX4 independently affect the cortical bone region. Supported in part by NIH NIAAA R37 018282 (M.R.)

Comments

Mentor: Martin J Ronis, PhD (Department of Pharmacology and Experimental Therapeutics)

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Oct 10th, 10:00 AM Oct 10th, 12:00 PM

Role of NOX4 Expression in Osteoblast-Precursors in the Development of Alcohol- Induced Osteopenia

Medical Education Building, LSUHSC-NO

Alcohol abuse is a well-known risk factor for skeletal toxicity and the development of osteoporosis. Ethanol (EtOH) has been demonstrated to inhibit bone formation and stimulate bone resorption. However, the molecular mechanisms underlying alcohol-induced osteopenia remain the subject of active investigation. Dr. Ronis’ research with whole-body knockout of NOX4 in mice has demonstrated that reactive oxygen species (ROS) signaling via the NADPH oxidase enzyme NOX4 plays a role in regulation of endogenous bone turnover and EtOH actions. To establish whether NOX4 expressed locally in osteoblast precursors mediate these effects, we have generated pre-osteoblast-specific Prx-Cre-Lox NOX4 conditional knockout mice where the enzyme is oblated specifically in osteoblast precursor cells in long bones and exposed both models to a high fat Leiber-DiCarli liquid with or without replacement of up to 28% of food calories with EtOH for 90 days. The hypothesis is that ROS produced in these cells by NOX4 play a significant role in the development of alcohol-induced osteopenia. To test this, the effects of EtOH were determined on bone microstructure of tibias and by femur shaft mRNA expression. In the cortical region of the tibia, the Prx-NOX4 Cre-Lox mice had overall decreased bone area (p = 0.038). In mice with the EtOH diet, there was a decrease in bone area and cortical thickness (p < 0.001 & p=0.001, respectively) independent of genotype. Results from femur shaft mRNA confirms that mRNA NOX4 expression is decreased by more than 95% in Prx-NOX4 Cre-Lox mice (p < 0.001) while RANKL, which controls bone reabsorption, is not affected by EtOH or NOX4 in this model. The data demonstrates that while the bone microstructure differs between males and females, EtOH and NOX4 independently affect the cortical bone region. Supported in part by NIH NIAAA R37 018282 (M.R.)