Distraction osteogenesis in TNF receptor 1 deficient mice is protected from chronic ethanol exposure

Distraction osteogenesis (DO) is an orthopedic protocol, which induces direct new bone formation as a result of the stimulating effects of mechanical distraction. Chronic ethanol exposure has been demonstrated to inhibit bone formation in rodent models of DO. Further, it has been demonstrated that (1) tumor necrosis factor-α (TNF) blockers are protective against ethanol exposure and (2) recombinant mouse TNF (rmTNF) inhibits direct bone formation in ethanol naïve mice through TNF receptor 1 (TNFR1). These results suggest that the inhibitory effects are significantly mediated by TNF signaling. Therefore, we hypothesized that direct new bone formation in TNFR1 knockout (KO) mice would be protected from ethanol exposure. We used a unique model of mouse DO combined with liquid/chow diets to compare the effects of ethanol on both a strain of TNFR1 knockout (TNFR1 KO) mice and on mice of their C57BL/6 (B6) control strain. In the B6 study, and in concordance with previous work, both radiological and histological analyses of direct bone formation in the distraction gaps demonstrated significant osteoinhibition due to ethanol compared with chow- or pair-fed mice. In the TNFR1 KO study and in support of the hypothesis, both radiological and histological analyses of distraction gap bone formation demonstrated no significant differences between the ethanol, chow fed, or pair fed. We conclude that exogenous rmTNF and ethanol-induced endogenous TNF act to inhibit new bone formation during DO by signaling primarily through TNFR1.