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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #214329
Title: Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: role of the TNF signaling axis

Author
item WAHL, ELIZABETH - ACH
item ARONSON, J - ACH/UAMS
item LIU, LICHU - ACH/UAMS
item LIU, Z - ACH/UAMS
item PERRIEN, DANIAL - ACH/UAMS
item SKINNER, R - ACH/UAMS
item BADGER, THOMAS - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS
item LUMPKIN, CHARLES - ACH/UAMS

Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2007
Publication Date: 2/5/2007
Citation: Wahl, E.C., Aronson, J., Liu, L., Liu, Z., Perrien, D.S., Skinner, R.A., Badger, T.M., Ronis, M.J., Lumpkin, C.K. 2007. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis. Journal of Toxicology and Applied Pharmacology. 220(3):302-310.

Interpretive Summary: We are interested in bone development and bone health in children. Distraction osteogenesis is a procedure used to lengthen and straighten bones. It essentially causes the bone to go through a process very similar to that occurring during normal bone development in children. Thus, this is an excellent model to study the mechanisms by which normal bone develops and factors that alter the process. We found that alcohol inhibits this bone development process by inhibiting the actions of a specific protein, TNF. This may be important for future studies of dietary factors and nutrients.

Technical Abstract: Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-alpha signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-alpha (rmTNF-alpha) to ethanol naïve mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-alpha (10 microg/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model.