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

Tumor necrosis factor-alpha (TNF-α) 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-α 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-α (rmTNF-α) 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-α (10 μg/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.