Epidemiological data suggest that excessive alcohol consumption may cost the US economy $2 billion annually in skeletal pathology. Patients with alcoholic bone disease display marked impairment in bone formation. Alcohol may alter bone metabolism indirectly by elevating the secretion of cytokines shown to be critical factors in postmenopausal osteoporosis. It has been demonstrated that cytokines mediate bone loss due to estrogen deficiency by increasing bone resorption and decreasing bone formation. Furthermore, clinical studies show that cytokines are over-produced in alcohol-induced liver disease. Distraction osteogenesis (DO) is a clinical and experimental procedure for lengthening bones that has been used to isolate and study the effects of chronic ethanol exposure on intramembranous (direct osteoblastogenesis) bone formation, which is well organized and spatially distinct from resorptive processes. Previous work demonstrates that chronic ethanol exposure in the rat (enteral nutrition model) decreases tibial bending strength, inhibits bone formation during DO, and increases the expression of Tumor Necrosis Factor alpha (TNF) in the liver and DO gap. Further, treatment with TNF antagonists during DO prevents osteoinhibiton by ethanol, while treatment of control rats with TNF during DO inhibits bone formation. Preliminary results, combining a novel murine DO model with liquid ethanol delivery, demonstrate that chronic ethanol exposure decreases tibial strength and inhibits bone formation during DO. In this murine model, analogous to the rat, TNF antagonist treatment during DO protects bone formation and exogenous TNF inhibits bone formation.
The Specific Aims of this project are to determine 1) the downstream mediators of TNF actions, 2) the roles of cytochrome p450 2E1 (CYP2E1) and 3) the role of reactive oxygen species (ROS) in ethanol's induction of TNF. The working hypotheses are that ethanol induction of CYP2E1 increases ROS, inducing TNF, which binds to a specific receptor and triggers signal transduction pathways that inhibit bone formation. The long term goals of this research are to support future pharmacological and/or nutritional interventions in orthopaedic procedures in patients with ethanol or cytokine excess as risk factors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012223-06
Application #
7098786
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Velazquez, Jose M
Project Start
1999-05-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$269,514
Indirect Cost
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Fowlkes, John L; Nyman, Jeffry S; Bunn, R Clay et al. (2013) Osteo-promoting effects of insulin-like growth factor I (IGF-I) in a mouse model of type 1 diabetes. Bone 57:36-40
Wahl, Elizabeth C; Aronson, James; Liu, Lichu et al. (2012) Distraction osteogenesis in TNF receptor 1 deficient mice is protected from chronic ethanol exposure. Alcohol 46:133-8
Nyman, Jeffry S; Even, Jesse L; Jo, Chan-Hee et al. (2011) Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 48:733-40
Wahl, Elizabeth C; Aronson, James; Liu, Lichu et al. (2010) Restoration of regenerative osteoblastogenesis in aged mice: modulation of TNF. J Bone Miner Res 25:114-23
Wahl, Elizabeth C; Aronson, James; Liu, Lichu et al. (2010) Direct bone formation during distraction osteogenesis does not require TNFalpha receptors and elevated serum TNFalpha fails to inhibit bone formation in TNFR1 deficient mice. Bone 46:410-7
Fowlkes, John L; Bunn, R Clay; Liu, Lichu et al. (2008) Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology 149:1697-704
Liu, Zhendong; Aronson, James; Wahl, Elizabeth C et al. (2007) A novel rat model for the study of deficits in bone formation in type-2 diabetes. Acta Orthop 78:46-55
Wahl, Elizabeth C; Aronson, James; Liu, Lichu et al. (2007) Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: role of the TNF signaling axis. Toxicol Appl Pharmacol 220:302-10
Wahl, Elizabeth C; Liu, Lichu; Perrien, Daniel S et al. (2006) A novel mouse model for the study of the inhibitory effects of chronic ethanol exposure on direct bone formation. Alcohol 39:159-67
Wahl, Elizabeth C; Perrien, Daniel S; Aronson, James et al. (2005) Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: a role for the tumor necrosis factor signaling axis. Alcohol Clin Exp Res 29:1466-72

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