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Chronic alcohol consumption is a risk factor for osteoporosis and inhibits osseous repair and regeneration. We investigated the hypothesis that chronic ethanol exposure induces the expression of TNF-α and/or IL-1β and inhibits proliferation during distraction osteogenesis (DO). Following six weeks of liquid diet infusion (±ethanol) and 14 days of DO, the expression of TNF-α and IL-1β in the distraction gap and contralateral femoral marrow of adult male rats was examined by immunohistochemistry and RT-PCR, respectively. In the bone marrow, the expression of both TNF-α and IL-1β mRNA was significantly increased by ethanol (p<0.04 for both). In the DO gap, ethanol exposure increased the expression of TNF-α in both the fibrous interzone and primary matrix front (PMF), while IL-1β expression was not significantly affected in either region. A negative correlation was found between the percentage of PCNA+ and TNF+ cells in the PMF (p<0.015, R2=0.655). Incubation of MC3T3-E1 cells with ethanol for 24 or 48 h produced a time and dose dependent two- to fourfold increase in TNF-α transcripts as measured by RT-PCR, demonstrating that ethanol can directly induce TNF-α expression in osteoblast-like cells. These results support the hypothesis that attenuation of bone formation by ethanol may be mediated, in part, by local increases in TNF-α during osteogenesis.