Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: a role for the tumor necrosis factor signaling axis.

BACKGROUND: Chronic ethanol exposure inhibits the rapid bone formation demonstrated during limb lengthening by distraction osteogenesis (DO). This inhibition is attenuated by simultaneous administration of antagonists to the cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. The individual effects on inhibition of osteogenesis by these cytokines were tested. We hypothesized that administration of individual antagonists to these cytokines [IL-1 receptor antagonist (IL-1ra) or polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1)] would enhance DO and that the individual administration of each cytokine [recombinant rat (rr) IL-1 or recombinant rat (rr) TNF] would inhibit DO.
METHODS: Rats were either infused with a liquid diet with or without ethanol (antagonist studies) or given rat chow (recombinant studies) and underwent tibial fractures stabilized with external fixators for DO. The bioactive substances were administered by systemic (antagonist studies) or local (recombinant) diffusion.
RESULTS: A comparison of histologic sections from these distracted tibias demonstrated a protective effect on bone formation by sTNFR1 (p<0.05), unexpectedly, an IL-1ra-related decrease in bone formation (p<0.02), significant decreases in bone formation with rrTNF compared with the vehicle controls (p<0.02), and no significant changes in bone formation with rrIL-1. The cellular responses (fibroblastic and inflammatory cells) were unique for each recombinant cytokine administered.
CONCLUSIONS: These results suggest that the osteoinhibitory effects of chronic ethanol exposure are mediated in part by the TNF signaling axis.