Vol. 303, Issue 3, 904-908, December 2002

Interleukin-1 and Tumor Necrosis Factor Antagonists Attenuate Ethanol-Induced Inhibition of Bone Formation in a Rat Model of Distraction Osteogenesis

Daniel S. Perrien¹ , Elizabeth C. Brown¹ , Terry W. Fletcher, David J. Irby, James Aronson , Guan G. Gao, Robert A. Skinner, William R. Hogue, Ulrich Feige, Larry J. Suva, Martin J. J. Ronis, Thomas M. Badger and Charles K. Lumpkin, Jr.

Departments of Pediatrics (T.W.F., D.J.I., J.A., M.J.J.R., T.M.B., C.K.L.) and Orthopaedics (J.A., R.A.S., W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Laboratory for Limb Regeneration Research (D.S.P., E.C.B., J.A., G.G.G., C.K.L.), Arkansas Children's Hospital Research Institute, Little Rock, Arkansas; and Department of Inflammation Research (U.F.), Amgen, Inc., Thousand Oaks, California

Chronic ethanol exposure inhibits rapid bone formation during distraction osteogenesis (DO; fracture and limb lengthening) and decreases volumetric bone mineral density (BMD) in a model of intragastric dietary infusion [total enteral nutrition (TEN)] in the rat. The hypothesis tested herein was that overexpression of interleukin (IL)-1 and tumor necrosis factor (TNF)- mediates these deleterious effects of ethanol on the rat skeleton. Two studies (study 1, female rats; study 2, male rats) were performed to test the potential protective effects of the IL-1 and TNF antagonists: IL-1 receptor antagonist (IL-1ra) and 30-kDa polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1). All rats were infused with a liquid diet ± ethanol (EtOH) and underwent tibial fractures and DO. During distraction, the animals received a combination of IL-1ra (1.8-2.0 mg/kg/day) and sTNFR1 (2.0 mg/kg/2 days) or vehicle. A comparison of distracted tibial histological sections demonstrated 1) significant antagonist-related increases in bone column formation over the EtOH controls (studies 1 and 2), and 2) restoration of new bone equivalent to that of the TEN controls (study 2). In contrast, examination of intact proximal tibial metaphyses by peripheral quantitative computerized tomography revealed decreases in volumetric BMD of both EtOH control and EtOH antagonist groups (study 2). These results demonstrate that short-term systemic administration of IL-1 and TNF antagonists together protect rapid bone formation during DO from the deleterious effects of chronic ethanol but are ineffective in regard to intact bone homeostasis.