Interleukin-1 and tumor necrosis factor antagonists attenuate ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis.

Perrien DS, Brown EC, Fletcher TW, Irby DJ, Aronson J, Gao GG, Skinner RA, Hogue WR, Feige U, Suva LJ, Ronis MJ, Badger TM, Lumpkin CK
J Pharmacol Exp Ther. 2002 303 (3): 904-8

PMID: 12438508 · DOI:10.1124/jpet.102.039636

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)-1beta and tumor necrosis factor (TNF)-alpha 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.

MeSH Terms (17)

Animals Antigens, CD Bone Density Ethanol Female Interleukin-1 Interleukin 1 Receptor Antagonist Protein Male Models, Animal Osteogenesis Osteogenesis, Distraction Rats Rats, Sprague-Dawley Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Sialoglycoproteins Tumor Necrosis Factor-alpha

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