Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: role of the TNF signaling axis.

Wahl EC, Aronson J, Liu L, Liu Z, Perrien DS, Skinner RA, Badger TM, Ronis MJ, Lumpkin CK
Toxicol Appl Pharmacol. 2007 220 (3): 302-10

PMID: 17391719 · PMCID: PMC1892174 · DOI:10.1016/j.taap.2007.02.011

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.

MeSH Terms (20)

Animals Bone Marrow Central Nervous System Depressants Cytochrome P-450 CYP2E1 Ethanol Interleukin-6 Mice Mice, Inbred C57BL Models, Animal Osteogenesis Osteogenesis, Distraction Osteotomy Receptors, Tumor Necrosis Factor Recombinant Proteins Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Tibia TNF Receptor-Associated Factor 1 Tumor Necrosis Factor-alpha

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